Proteopedia - User contributions [en]

Sandbox Reserved 1565

2019-12-09T06:47:49Z

Alyssa Ragner:

{{Sandbox_Reserved_BHall_Chem351_F19}}
=='''Inosine-5'-monophosphate dehydrogenase'''==
<StructureSection load='6rpu' size='340' side='right' caption='Structure of the ternary complex of the IMPDH enzyme from Ashbya gossypii bound to the dinucleoside polyphosphate Ap5G and GDP' scene=''>

== Function(s) and Biological Relevance ==

<scene name='82/823089/Cartoon_view/1'>Inosine-5'-monophosphate dehydrogenase</scene> (IMPDH) is the enzyme that catalyzes the rate-limiting step in the ''de novo'' guanine nucleotide biosynthetic pathway, converting inosine monophosphate (IMP) to xanthosine monophosphate (XMP) with the reduction of nicotinamide adenine dinucleotide (NAD). Organisms that undergo the purine nucleotide biosynthetic pathway have IMPDH, including humans. This particular form of IMPDH described and highlighted comes from the recently studied fungus ''Ashbya gossypii'' <ref>PMID: 31416831</ref>. Additional ligands of IMPDH include nicotinamide adenine dinucleotide (NAD), acetate (ACT), and guanosine-5’ monophosphate (5GP), and guanosine-5'-diphosphate (GDP). IMPDH is a regulator of the intracellular guanine nucleotide pool amount and helps control control cell division and proliferation, and therefore related to malignant transformation, tumor cell proliferation, and intracellular and extracellular pathogenic infections. Purine dinucleoside polyphosphates are found to bind to the Bateman domain of ''Ashbya gossypii'' IMPDH to allosterically regulate the catalytic activity by competing against purine mononucleotides<ref>PMID: 31416831</ref>.

== Broader Implications ==

The disease pathophysiology is extensive as the improper IMPDH regulation may lead to uncontrolled cell division and proliferation, affecting the immune system's ability to fight off pathogens and signal tumor cells to apoptose. Therapeutic studies using dinucleoside polyphosphates may allosterically regulate the inhibition of IMPDH activity. Dinucleoside polyphosphates have physiological functions including cell division, neurotransmission, apoptosis, vasoconstriction, platelet aggregation, and cellular process variety enhancement from DNA replication to repair<ref>PMID: 31416831</ref>. Selected IMPDH inhibitors composed of dinucleoside polyphosphates may be used to make IMPDHs targets for immunosuppressive, antiviral, and anticancer drugs<ref>PMID: 21517780</ref>, with antibacterial and chemotherapeutic strategies feasibile<ref>PMID: 22928911</ref>.

== Structural Highlights and Structure-Function Relationships ==

The <scene name='82/823089/Secondary_structure/1'>secondary structure</scene> shows alpha helices and beta sheets. The ''Ashbya gossypii'' IMPDH is 31% helical and 15% beta sheet, with the other percentages including random coils and residue structures. The active site is located towards the C-terminus within the TIM barrel, containing 8 alpha-helices and 8 beta sheets. The CBS region is recognized in the secondary structure through its beta-alpha-beta-beta-alpha pattern -- IMPDH contains a CBS-pair (Bateman domain) that arranges two of these patterns together.

IMPDH quaternary structures include multiunit complexes, such as <scene name='82/823089/Quaternary_view/1'>tetramers</scene>, extended octamers, and compacted octamers. These quaternary structures are created through the binding of multiple subunits of <scene name='82/823089/Tertiary_structure/1'>tertiary</scene> structures (monomers), that are strengthened and structurally formed through hydrogen-bonding, cysteine-cysteine disulfide bonds, and hydrophobic interactions. Different quaternary forms of IMPDH relate to the kinetic favorability of the IMPDH mechanism as Bateman domain allosteric binding sites and competitive nature changes with unit composition. The secondary structure of IMPDH's Bateman domain is folded, so its antiparallel beta-sheets are surrounded by the alpha helices (one on each side) to form a globular tertiary structure. The [6] beta-sheets of the <scene name='82/823089/Batemancbs/2'>Bateman domain</scene> swirl to form an opening, known as the TIM barrel (zoomed in, in image) with the [4] alpha helices surrounding the beta-sheet-forming tunnel. This CBS-pair (cystathionine beta synthase motif) allows for monocovalent cations to move through and activate IMPDH as amino acid residues in the active site interact with ligands.

This <scene name='82/823089/Space-filled/2'>space-filled view</scene> helps show the Van der Waals interactions and areas for movement within the structure. The ability for monovalent cations to move within the charged tunnel with the phosphate chain (TIM barrel) directly relates to activation levels. The phosphate chain relates to the ligands that further interact with the binding site to form the covalent intermediate, E-XMP*.

The <scene name='82/823089/Hydrophobicity_view/1'>hydrophobicity</scene> is within the interior of the molecule as the hydrophilic residues are able to interact in a physiological environment. The hydrophobic region of Gly361 and Gly383 interact with the main chain phosphate (TIM), further allowing monovalent cation movement. Hydrophilic regions contain amino acid residues that hydrogen-bond, some conserving tertiary structure and others relating to necessary interactions in the active site (see below).

Acetate ions, G5P, and GDP molecules are <scene name='82/823089/Ligands/1'>ligands</scene> of IMPDH. NAD serves a function as a ligand as is necessary in the hydrolysis of IMP. The phosphates of the G5P, GDP, and NAD (not pictured) ligands interact through hydrogen bonds and hydrophobic interactions (depending on the amino acid residue; see active binding site below). The monocovalent cations that pass through interact with the phosphates as they activate IMPDH.

The IMPDH <scene name='82/823089/Catalytic_triad/1'>catalytic triad</scene> includes Arg (325), Asn (306), and Asp (272). This is represented by the solid purple structures in the image. This triad is important as it makes cysteine more reactive as a nucleophilic component. This conserved cysteine, Cys334, (Cys331 in human type II IMPDH) induces binding after becoming more reactive (Cysteine shown in image with "active binding site" link).

The <scene name='82/823089/Active_site/1'>active binding site</scene> includes the Bateman domains, which are components within the TIM barrel. Binding occurs after the catalytic triad makes cysteine more reactive. The cysteines that become more reactive are shown in green in the image, and are closely related to the active binding site. Asp259 (blue) hydrogen bonds with the ribose hydroxyls of NAD (nicotinamide region), and Ser315 (blue) hydrogen bonds to the ribose phosphate through hydroxyl groups. Gly361 and Gly383 (orange) have hydrophobic interactions with the phosphate of the ligand NAD. Other important interactions include Tyr403 hydrogen bonding to ribose phosphate (NAD), and Glu402 and Glu440 hydrogen bonding with the IMP purine ring.

IMPDH <scene name='82/823089/Charge_view/2'>charge</scene> is not positively or negatively strong as an entire protein, as shown by this view. There are positive and negative components within the structure, but a relatively neutral substance is better received in this mechanism due to a physiological environment. Negatively-charged glutamic acid and positively-charged histidine within this enzyme play a role within the covalent bindings in the mechanism. Covalent binding is necessary to form the covalent intermediate after NAD is reduced (after interacting with the active site residues).

This enzyme's <scene name='82/823089/Composition_view/1'>composition</scene> contains mostly protein (brown) with no solvent. The dark pink RNA regions coincide with G5P and GDP ligands as they contain ribose groups. NAD, containing two ribose groups, (not pictured) is another ligand that is necessary in the hydrolysis of IMP in the mechanism. The green acetate ions are anions that function as ligands as as intermediate-step metabolites in the mechanism. Monocovalent cations travel through and activate IMPDH as anionic acetate ions buffer the system.

== Energy Transformation ==

IMPDH is activated by monovalent cations, such as K+ and Na+, within the triose-phosphate isomerase (TIM) barrel. The Arg325-Asn306-Asp272 catalytic triad (Arg322-Asn303-Asp274 in human type II IMPDH) works inter-dependently and synergistically in the TIM barrel active site to make the nucleophilic component, cysteine, highly reactive to form a temporary covalent bond with the substrate<ref>PMID: 8555204</ref>. Substrates bind randomly to IMPDH as the hydride transfer is quick and NAD is reduced to hydrolyze the covalent intermediate within the enzyme-substrate complex. A covalent intermediate, E-XMP*, is formed, which decreases the energy needed in later nucleophilic and covalent catalysis steps<ref>PMID: 10390600</ref>. Based on normal physiological conditions, the IMPDH mechanism is often not kinetically favorable. The Bateman domains within the TIM barrel are composed of cystathionine beta-synthase motifs that perceive metal ion concentration, cellular energy status, and ionic strength; and will allosterically regulate IMPDH activity<ref>PMID: 31416831</ref>. Eukaryotic IMPDHs have three nucleotide-binding sites in the Bateman domain that allosterically modulate catalytic activity. These three nucleotide-binding sites bind adenine/guanine dinucleoside polyphosphates, and the affinity for these sites increases for these dinucleoside polyphosphates as the activity of IMPDH increases. Purine dinucleoside polyphosphates compete with purine mononucleotides within these sites, so the Bateman domain sites make IMPDH more sensitive to inhibition<ref>PMID: 31416831</ref>. Enzyme catalysis is able to finish with the energy need reduced as the covalent bond is broken later in the reaction to regenerate the enzyme.

</StructureSection>
== References ==

<references />

Sandbox Reserved 1565

2019-12-09T06:46:19Z

Alyssa Ragner:

{{Sandbox_Reserved_BHall_Chem351_F19}}
=='''Inosine-5'-monophosphate dehydrogenase'''==
<StructureSection load='6rpu' size='340' side='right' caption='Structure of the ternary complex of the IMPDH enzyme from Ashbya gossypii bound to the dinucleoside polyphosphate Ap5G and GDP' scene=''>

== Function(s) and Biological Relevance ==

<scene name='82/823089/Cartoon_view/1'>Inosine-5'-monophosphate dehydrogenase</scene> (IMPDH) is the enzyme that catalyzes the rate-limiting step in the ''de novo'' guanine nucleotide biosynthetic pathway, converting inosine monophosphate (IMP) to xanthosine monophosphate (XMP) with the reduction of nicotinamide adenine dinucleotide (NAD). Organisms that undergo the purine nucleotide biosynthetic pathway have IMPDH, including humans. This particular form of IMPDH described and highlighted comes from the recently studied fungus ''Ashbya gossypii'' <ref>PMID: 31416831</ref>. Additional ligands of IMPDH include nicotinamide adenine dinucleotide (NAD), acetate (ACT), and guanosine-5’ monophosphate (5GP), and guanosine-5'-diphosphate (GDP). IMPDH is a regulator of the intracellular guanine nucleotide pool amount and helps control control cell division and proliferation, and therefore related to malignant transformation, tumor cell proliferation, and intracellular and extracellular pathogenic infections. Purine dinucleoside polyphosphates are found to bind to the Bateman domain of ''Ashbya gossypii'' IMPDH to allosterically regulate the catalytic activity by competing against purine mononucleotides<ref>PMID: 31416831</ref>.

== Broader Implications ==

The disease pathophysiology is extensive as the improper IMPDH regulation may lead to uncontrolled cell division and proliferation, affecting the immune system's ability to fight off pathogens and signal tumor cells to apoptose. Therapeutic studies using dinucleoside polyphosphates may allosterically regulate the inhibition of IMPDH activity. Dinucleoside polyphosphates have physiological functions including cell division, neurotransmission, apoptosis, vasoconstriction, platelet aggregation, and cellular process variety enhancement from DNA replication to repair<ref>PMID: 31416831</ref>. Selected IMPDH inhibitors composed of dinucleoside polyphosphates may be used to make IMPDHs targets for immunosuppressive, antiviral, and anticancer drugs<ref>PMID: 21517780</ref>, with antibacterial and chemotherapeutic strategies feasibile<ref>PMID: 22928911</ref>.

== Structural Highlights and Structure-Function Relationships ==

The <scene name='82/823089/Secondary_structure/1'>secondary structure</scene> shows alpha helices and beta sheets. The ''Ashbya gossypii'' IMPDH is 31% helical and 15% beta sheet, with the other percentages including random coils and residue structures. The active site is located towards the C-terminus within the TIM barrel, containing 8 alpha-helices and 8 beta sheets. The CBS region is recognized in the secondary structure through its beta-alpha-beta-beta-alpha pattern -- IMPDH contains a CBS-pair (Bateman domain) that arranges two of these patterns together.

IMPDH quaternary structures include multiunit complexes, such as <scene name='82/823089/Quaternary_view/1'>tetramers</scene>, extended octamers, and compacted octamers. These quaternary structures are created through the binding of multiple subunits of <scene name='82/823089/Tertiary_structure/1'>tertiary</scene> structures (monomers), that are strengthened and structurally formed through hydrogen-bonding, cysteine-cysteine disulfide bonds, and hydrophobic interactions. Different quaternary forms of IMPDH relate to the kinetic favorability of the IMPDH mechanism as Bateman domain allosteric binding sites and competitive nature changes with unit composition. The secondary structure of IMPDH's Bateman domain is folded, so its antiparallel beta-sheets are surrounded by the alpha helices (one on each side) to form a globular tertiary structure. The [6] beta-sheets of the <scene name='82/823089/Batemancbs/1'>Bateman domain</scene> swirl to form an opening, known as the TIM barrel (zoomed in, in image) with the [4] alpha helices surrounding the beta-sheet-forming tunnel. This CBS-pair (cystathionine beta synthase motif) allows for monocovalent cations to move through and activate IMPDH as amino acid residues in the active site interact with ligands.

This <scene name='82/823089/Space-filled/2'>space-filled view</scene> helps show the Van der Waals interactions and areas for movement within the structure. The ability for monovalent cations to move within the charged tunnel with the phosphate chain (TIM barrel) directly relates to activation levels. The phosphate chain relates to the ligands that further interact with the binding site to form the covalent intermediate, E-XMP*.

The <scene name='82/823089/Hydrophobicity_view/1'>hydrophobicity</scene> is within the interior of the molecule as the hydrophilic residues are able to interact in a physiological environment. The hydrophobic region of Gly361 and Gly383 interact with the main chain phosphate (TIM), further allowing monovalent cation movement. Hydrophilic regions contain amino acid residues that hydrogen-bond, some conserving tertiary structure and others relating to necessary interactions in the active site (see below).

Acetate ions, G5P, and GDP molecules are <scene name='82/823089/Ligands/1'>ligands</scene> of IMPDH. NAD serves a function as a ligand as is necessary in the hydrolysis of IMP. The phosphates of the G5P, GDP, and NAD (not pictured) ligands interact through hydrogen bonds and hydrophobic interactions (depending on the amino acid residue; see active binding site below). The monocovalent cations that pass through interact with the phosphates as they activate IMPDH.

The IMPDH <scene name='82/823089/Catalytic_triad/1'>catalytic triad</scene> includes Arg (325), Asn (306), and Asp (272). This is represented by the solid purple structures in the image. This triad is important as it makes cysteine more reactive as a nucleophilic component. This conserved cysteine, Cys334, (Cys331 in human type II IMPDH) induces binding after becoming more reactive (Cysteine shown in image with "active binding site" link).

The <scene name='82/823089/Active_site/1'>active binding site</scene> includes the Bateman domains, which are components within the TIM barrel. Binding occurs after the catalytic triad makes cysteine more reactive. The cysteines that become more reactive are shown in green in the image, and are closely related to the active binding site. Asp259 (blue) hydrogen bonds with the ribose hydroxyls of NAD (nicotinamide region), and Ser315 (blue) hydrogen bonds to the ribose phosphate through hydroxyl groups. Gly361 and Gly383 (orange) have hydrophobic interactions with the phosphate of the ligand NAD. Other important interactions include Tyr403 hydrogen bonding to ribose phosphate (NAD), and Glu402 and Glu440 hydrogen bonding with the IMP purine ring.

IMPDH <scene name='82/823089/Charge_view/2'>charge</scene> is not positively or negatively strong as an entire protein, as shown by this view. There are positive and negative components within the structure, but a relatively neutral substance is better received in this mechanism due to a physiological environment. Negatively-charged glutamic acid and positively-charged histidine within this enzyme play a role within the covalent bindings in the mechanism. Covalent binding is necessary to form the covalent intermediate after NAD is reduced (after interacting with the active site residues).

This enzyme's <scene name='82/823089/Composition_view/1'>composition</scene> contains mostly protein (brown) with no solvent. The dark pink RNA regions coincide with G5P and GDP ligands as they contain ribose groups. NAD, containing two ribose groups, (not pictured) is another ligand that is necessary in the hydrolysis of IMP in the mechanism. The green acetate ions are anions that function as ligands as as intermediate-step metabolites in the mechanism. Monocovalent cations travel through and activate IMPDH as anionic acetate ions buffer the system.

== Energy Transformation ==

IMPDH is activated by monovalent cations, such as K+ and Na+, within the triose-phosphate isomerase (TIM) barrel. The Arg325-Asn306-Asp272 catalytic triad (Arg322-Asn303-Asp274 in human type II IMPDH) works inter-dependently and synergistically in the TIM barrel active site to make the nucleophilic component, cysteine, highly reactive to form a temporary covalent bond with the substrate<ref>PMID: 8555204</ref>. Substrates bind randomly to IMPDH as the hydride transfer is quick and NAD is reduced to hydrolyze the covalent intermediate within the enzyme-substrate complex. A covalent intermediate, E-XMP*, is formed, which decreases the energy needed in later nucleophilic and covalent catalysis steps<ref>PMID: 10390600</ref>. Based on normal physiological conditions, the IMPDH mechanism is often not kinetically favorable. The Bateman domains within the TIM barrel are composed of cystathionine beta-synthase motifs that perceive metal ion concentration, cellular energy status, and ionic strength; and will allosterically regulate IMPDH activity<ref>PMID: 31416831</ref>. Eukaryotic IMPDHs have three nucleotide-binding sites in the Bateman domain that allosterically modulate catalytic activity. These three nucleotide-binding sites bind adenine/guanine dinucleoside polyphosphates, and the affinity for these sites increases for these dinucleoside polyphosphates as the activity of IMPDH increases. Purine dinucleoside polyphosphates compete with purine mononucleotides within these sites, so the Bateman domain sites make IMPDH more sensitive to inhibition<ref>PMID: 31416831</ref>. Enzyme catalysis is able to finish with the energy need reduced as the covalent bond is broken later in the reaction to regenerate the enzyme.

</StructureSection>
== References ==

<references />

Sandbox Reserved 1565

2019-12-09T06:37:56Z

Alyssa Ragner:

{{Sandbox_Reserved_BHall_Chem351_F19}}
=='''Inosine-5'-monophosphate dehydrogenase'''==
<StructureSection load='6rpu' size='340' side='right' caption='Structure of the ternary complex of the IMPDH enzyme from Ashbya gossypii bound to the dinucleoside polyphosphate Ap5G and GDP' scene=''>

== Function(s) and Biological Relevance ==

<scene name='82/823089/Cartoon_view/1'>Inosine-5'-monophosphate dehydrogenase</scene> (IMPDH) is the enzyme that catalyzes the rate-limiting step in the ''de novo'' guanine nucleotide biosynthetic pathway, converting inosine monophosphate (IMP) to xanthosine monophosphate (XMP) with the reduction of nicotinamide adenine dinucleotide (NAD). Organisms that undergo the purine nucleotide biosynthetic pathway have IMPDH, including humans. This particular form of IMPDH described and highlighted comes from the recently studied fungus ''Ashbya gossypii'' <ref>PMID: 31416831</ref>. Additional ligands of IMPDH include nicotinamide adenine dinucleotide (NAD), acetate (ACT), and guanosine-5’ monophosphate (5GP), and guanosine-5'-diphosphate (GDP). IMPDH is a regulator of the intracellular guanine nucleotide pool amount and helps control control cell division and proliferation, and therefore related to malignant transformation, tumor cell proliferation, and intracellular and extracellular pathogenic infections. Purine dinucleoside polyphosphates are found to bind to the Bateman domain of ''Ashbya gossypii'' IMPDH to allosterically regulate the catalytic activity by competing against purine mononucleotides<ref>PMID: 31416831</ref>.

== Broader Implications ==

The disease pathophysiology is extensive as the improper IMPDH regulation may lead to uncontrolled cell division and proliferation, affecting the immune system's ability to fight off pathogens and signal tumor cells to apoptose. Therapeutic studies using dinucleoside polyphosphates may allosterically regulate the inhibition of IMPDH activity. Dinucleoside polyphosphates have physiological functions including cell division, neurotransmission, apoptosis, vasoconstriction, platelet aggregation, and cellular process variety enhancement from DNA replication to repair<ref>PMID: 31416831</ref>. Selected IMPDH inhibitors composed of dinucleoside polyphosphates may be used to make IMPDHs targets for immunosuppressive, antiviral, and anticancer drugs<ref>PMID: 21517780</ref>, with antibacterial and chemotherapeutic strategies feasibile<ref>PMID: 22928911</ref>.

== Structural Highlights and Structure-Function Relationships ==

The <scene name='82/823089/Secondary_structure/1'>secondary structure</scene> shows alpha helices and beta sheets. The ''Ashbya gossypii'' IMPDH is 31% helical and 15% beta sheet, with the other percentages including random coils and residue structures. The active site is located towards the C-terminus within the TIM barrel, containing 8 alpha-helices and 8 beta sheets. The CBS region is recognized in the secondary structure through its beta-alpha-beta-beta-alpha pattern -- IMPDH contains a CBS-pair (Bateman domain) that arranges two of these patterns together.

IMPDH quaternary structures include multiunit complexes, such as <scene name='82/823089/Quaternary_view/1'>tetramers</scene>, extended octamers, and compacted octamers. These quaternary structures are created through the binding of multiple subunits of <scene name='82/823089/Tertiary_structure/1'>tertiary</scene> structures (monomers), that are strengthened and structurally formed through hydrogen-bonding, cysteine-cysteine disulfide bonds, and hydrophobic interactions. Different quaternary forms of IMPDH relate to the kinetic favorability of the IMPDH mechanism as Bateman domain allosteric binding sites and competitive nature changes with unit composition. The secondary structure of IMPDH's Bateman domain is folded, so its antiparallel beta-sheets are surrounded by the alpha helices (one on each side) to form a globular tertiary structure.

This <scene name='82/823089/Space-filled/2'>space-filled view</scene> helps show the Van der Waals interactions and areas for movement within the structure. The ability for monovalent cations to move within the charged tunnel with the phosphate chain (TIM barrel) directly relates to activation levels. The phosphate chain relates to the ligands that further interact with the binding site to form the covalent intermediate, E-XMP*.

The <scene name='82/823089/Hydrophobicity_view/1'>hydrophobicity</scene> is within the interior of the molecule as the hydrophilic residues are able to interact in a physiological environment. The hydrophobic region of Gly361 and Gly383 interact with the main chain phosphate (TIM), further allowing monovalent cation movement. Hydrophilic regions contain amino acid residues that hydrogen-bond, some conserving tertiary structure and others relating to necessary interactions in the active site (see below).

Acetate ions, G5P, and GDP molecules are <scene name='82/823089/Ligands/1'>ligands</scene> of IMPDH. NAD serves a function as a ligand as is necessary in the hydrolysis of IMP. The phosphates of the G5P, GDP, and NAD (not pictured) ligands interact through hydrogen bonds and hydrophobic interactions (depending on the amino acid residue; see active binding site below). The monocovalent cations that pass through interact with the phosphates as they activate IMPDH.

The IMPDH <scene name='82/823089/Catalytic_triad/1'>catalytic triad</scene> includes Arg (325), Asn (306), and Asp (272). This is represented by the solid purple structures in the image. This triad is important as it makes cysteine more reactive as a nucleophilic component. This conserved cysteine, Cys334, (Cys331 in human type II IMPDH) induces binding after becoming more reactive (Cysteine shown in image with "active binding site" link).

The <scene name='82/823089/Active_site/1'>active binding site</scene> includes the Bateman domains, which are components within the TIM barrel. Binding occurs after the catalytic triad makes cysteine more reactive. The cysteines that become more reactive are shown in green in the image, and are closely related to the active binding site. Asp259 (blue) hydrogen bonds with the ribose hydroxyls of NAD (nicotinamide region), and Ser315 (blue) hydrogen bonds to the ribose phosphate through hydroxyl groups. Gly361 and Gly383 (orange) have hydrophobic interactions with the phosphate of the ligand NAD. Other important interactions include Tyr403 hydrogen bonding to ribose phosphate (NAD), and Glu402 and Glu440 hydrogen bonding with the IMP purine ring.

IMPDH <scene name='82/823089/Charge_view/2'>charge</scene> is not positively or negatively strong as an entire protein, as shown by this view. There are positive and negative components within the structure, but a relatively neutral substance is better received in this mechanism due to a physiological environment. Negatively-charged glutamic acid and positively-charged histidine within this enzyme play a role within the covalent bindings in the mechanism. Covalent binding is necessary to form the covalent intermediate after NAD is reduced (after interacting with the active site residues).

This enzyme's <scene name='82/823089/Composition_view/1'>composition</scene> contains mostly protein (brown) with no solvent. The dark pink RNA regions coincide with G5P and GDP ligands as they contain ribose groups. NAD, containing two ribose groups, (not pictured) is another ligand that is necessary in the hydrolysis of IMP in the mechanism. The green acetate ions are anions that function as ligands as as intermediate-step metabolites in the mechanism. Monocovalent cations travel through and activate IMPDH as anionic acetate ions buffer the system.

== Energy Transformation ==

IMPDH is activated by monovalent cations, such as K+ and Na+, within the triose-phosphate isomerase (TIM) barrel. The Arg325-Asn306-Asp272 catalytic triad (Arg322-Asn303-Asp274 in human type II IMPDH) works inter-dependently and synergistically in the TIM barrel active site to make the nucleophilic component, cysteine, highly reactive to form a temporary covalent bond with the substrate<ref>PMID: 8555204</ref>. Substrates bind randomly to IMPDH as the hydride transfer is quick and NAD is reduced to hydrolyze the covalent intermediate within the enzyme-substrate complex. A covalent intermediate, E-XMP*, is formed, which decreases the energy needed in later nucleophilic and covalent catalysis steps<ref>PMID: 10390600</ref>. Based on normal physiological conditions, the IMPDH mechanism is often not kinetically favorable. The Bateman domains within the TIM barrel are composed of cystathionine beta-synthase motifs that perceive metal ion concentration, cellular energy status, and ionic strength; and will allosterically regulate IMPDH activity<ref>PMID: 31416831</ref>. Eukaryotic IMPDHs have three nucleotide-binding sites in the Bateman domain that allosterically modulate catalytic activity. These three nucleotide-binding sites bind adenine/guanine dinucleoside polyphosphates, and the affinity for these sites increases for these dinucleoside polyphosphates as the activity of IMPDH increases. Purine dinucleoside polyphosphates compete with purine mononucleotides within these sites, so the Bateman domain sites make IMPDH more sensitive to inhibition<ref>PMID: 31416831</ref>. Enzyme catalysis is able to finish with the energy need reduced as the covalent bond is broken later in the reaction to regenerate the enzyme.

</StructureSection>
== References ==

<references />

Sandbox Reserved 1565

2019-12-09T06:35:45Z

Alyssa Ragner:

{{Sandbox_Reserved_BHall_Chem351_F19}}
=='''Inosine-5'-monophosphate dehydrogenase'''==
<StructureSection load='6rpu' size='340' side='right' caption='Structure of the ternary complex of the IMPDH enzyme from Ashbya gossypii bound to the dinucleoside polyphosphate Ap5G and GDP' scene=''>

== Function(s) and Biological Relevance ==

<scene name='82/823089/Cartoon_view/1'>Inosine-5'-monophosphate dehydrogenase</scene> (IMPDH) is the enzyme that catalyzes the rate-limiting step in the ''de novo'' guanine nucleotide biosynthetic pathway, converting inosine monophosphate (IMP) to xanthosine monophosphate (XMP) with the reduction of nicotinamide adenine dinucleotide (NAD). Organisms that undergo the purine nucleotide biosynthetic pathway have IMPDH, including humans. This particular form of IMPDH described and highlighted comes from the recently studied fungus ''Ashbya gossypii'' <ref>PMID: 31416831</ref>. Additional ligands of IMPDH include nicotinamide adenine dinucleotide (NAD), acetate (ACT), and guanosine-5’ monophosphate (5GP), and guanosine-5'-diphosphate (GDP). IMPDH is a regulator of the intracellular guanine nucleotide pool amount and helps control control cell division and proliferation, and therefore related to malignant transformation, tumor cell proliferation, and intracellular and extracellular pathogenic infections. Purine dinucleoside polyphosphates are found to bind to the Bateman domain of ''Ashbya gossypii'' IMPDH to allosterically regulate the catalytic activity by competing against purine mononucleotides<ref>PMID: 31416831</ref>.

== Broader Implications ==

The disease pathophysiology is extensive as the improper IMPDH regulation may lead to uncontrolled cell division and proliferation, affecting the immune system's ability to fight off pathogens and signal tumor cells to apoptose. Therapeutic studies using dinucleoside polyphosphates may allosterically regulate the inhibition of IMPDH activity. Dinucleoside polyphosphates have physiological functions including cell division, neurotransmission, apoptosis, vasoconstriction, platelet aggregation, and cellular process variety enhancement from DNA replication to repair<ref>PMID: 31416831</ref>. Selected IMPDH inhibitors composed of dinucleoside polyphosphates may be used to make IMPDHs targets for immunosuppressive, antiviral, and anticancer drugs<ref>PMID: 21517780</ref>, with antibacterial and chemotherapeutic strategies feasibile<ref>PMID: 22928911</ref>.

== Structural Highlights and Structure-Function Relationships ==

The <scene name='82/823089/Secondary_structure/1'>secondary structure</scene> shows alpha helices and beta sheets. The ''Ashbya gossypii'' IMPDH is 31% helical and 15% beta sheet, with the other percentages including random coils and residue structures. The active site is located towards the C-terminus within the TIM barrel, containing 8 alpha-helices and 8 beta sheets. The CBS (Bateman) domain is recognized in the secondary structure through its beta-alpha-beta-beta-alpha pattern.

IMPDH quaternary structures include multiunit complexes, such as <scene name='82/823089/Quaternary_view/1'>tetramers</scene>, extended octamers, and compacted octamers. These quaternary structures are created through the binding of multiple subunits of <scene name='82/823089/Tertiary_structure/1'>tertiary</scene> structures (monomers), that are strengthened and structurally formed through hydrogen-bonding, cysteine-cysteine disulfide bonds, and hydrophobic interactions. Different quaternary forms of IMPDH relate to the kinetic favorability of the IMPDH mechanism as Bateman domain allosteric binding sites and competitive nature changes with unit composition. The secondary structure of IMPDH's Bateman domain is folded, so its antiparallel beta-sheets are surrounded by the alpha helices (one on each side) to form a globular tertiary structure.

This <scene name='82/823089/Space-filled/2'>space-filled view</scene> helps show the Van der Waals interactions and areas for movement within the structure. The ability for monovalent cations to move within the charged tunnel with the phosphate chain (TIM barrel) directly relates to activation levels. The phosphate chain relates to the ligands that further interact with the binding site to form the covalent intermediate, E-XMP*.

The <scene name='82/823089/Hydrophobicity_view/1'>hydrophobicity</scene> is within the interior of the molecule as the hydrophilic residues are able to interact in a physiological environment. The hydrophobic region of Gly361 and Gly383 interact with the main chain phosphate (TIM), further allowing monovalent cation movement. Hydrophilic regions contain amino acid residues that hydrogen-bond, some conserving tertiary structure and others relating to necessary interactions in the active site (see below).

Acetate ions, G5P, and GDP molecules are <scene name='82/823089/Ligands/1'>ligands</scene> of IMPDH. NAD serves a function as a ligand as is necessary in the hydrolysis of IMP. The phosphates of the G5P, GDP, and NAD (not pictured) ligands interact through hydrogen bonds and hydrophobic interactions (depending on the amino acid residue; see active binding site below). The monocovalent cations that pass through interact with the phosphates as they activate IMPDH.

The IMPDH <scene name='82/823089/Catalytic_triad/1'>catalytic triad</scene> includes Arg (325), Asn (306), and Asp (272). This is represented by the solid purple structures in the image. This triad is important as it makes cysteine more reactive as a nucleophilic component. This conserved cysteine, Cys334, (Cys331 in human type II IMPDH) induces binding after becoming more reactive (Cysteine shown in image with "active binding site" link).

The <scene name='82/823089/Active_site/1'>active binding site</scene> includes the Bateman domains, which are components within the TIM barrel. Binding occurs after the catalytic triad makes cysteine more reactive. The cysteines that become more reactive are shown in green in the image, and are closely related to the active binding site. Asp259 (blue) hydrogen bonds with the ribose hydroxyls of NAD (nicotinamide region), and Ser315 (blue) hydrogen bonds to the ribose phosphate through hydroxyl groups. Gly361 and Gly383 (orange) have hydrophobic interactions with the phosphate of the ligand NAD. Other important interactions include Tyr403 hydrogen bonding to ribose phosphate (NAD), and Glu402 and Glu440 hydrogen bonding with the IMP purine ring.

IMPDH <scene name='82/823089/Charge_view/2'>charge</scene> is not positively or negatively strong as an entire protein, as shown by this view. There are positive and negative components within the structure, but a relatively neutral substance is better received in this mechanism due to a physiological environment. Negatively-charged glutamic acid and positively-charged histidine within this enzyme play a role within the covalent bindings in the mechanism. Covalent binding is necessary to form the covalent intermediate after NAD is reduced (after interacting with the active site residues).

This enzyme's <scene name='82/823089/Composition_view/1'>composition</scene> contains mostly protein (brown) with no solvent. The dark pink RNA regions coincide with G5P and GDP ligands as they contain ribose groups. NAD, containing two ribose groups, (not pictured) is another ligand that is necessary in the hydrolysis of IMP in the mechanism. The green acetate ions are anions that function as ligands as as intermediate-step metabolites in the mechanism. Monocovalent cations travel through and activate IMPDH as anionic acetate ions buffer the system.

== Energy Transformation ==

IMPDH is activated by monovalent cations, such as K+ and Na+, within the triose-phosphate isomerase (TIM) barrel. The Arg325-Asn306-Asp272 catalytic triad (Arg322-Asn303-Asp274 in human type II IMPDH) works inter-dependently and synergistically in the TIM barrel active site to make the nucleophilic component, cysteine, highly reactive to form a temporary covalent bond with the substrate<ref>PMID: 8555204</ref>. Substrates bind randomly to IMPDH as the hydride transfer is quick and NAD is reduced to hydrolyze the covalent intermediate within the enzyme-substrate complex. A covalent intermediate, E-XMP*, is formed, which decreases the energy needed in later nucleophilic and covalent catalysis steps<ref>PMID: 10390600</ref>. Based on normal physiological conditions, the IMPDH mechanism is often not kinetically favorable. The Bateman domains within the TIM barrel are composed of cystathionine beta-synthase motifs that perceive metal ion concentration, cellular energy status, and ionic strength; and will allosterically regulate IMPDH activity<ref>PMID: 31416831</ref>. Eukaryotic IMPDHs have three nucleotide-binding sites in the Bateman domain that allosterically modulate catalytic activity. These three nucleotide-binding sites bind adenine/guanine dinucleoside polyphosphates, and the affinity for these sites increases for these dinucleoside polyphosphates as the activity of IMPDH increases. Purine dinucleoside polyphosphates compete with purine mononucleotides within these sites, so the Bateman domain sites make IMPDH more sensitive to inhibition<ref>PMID: 31416831</ref>. Enzyme catalysis is able to finish with the energy need reduced as the covalent bond is broken later in the reaction to regenerate the enzyme.

</StructureSection>
== References ==

<references />

Sandbox Reserved 1565

2019-12-09T05:56:07Z

Alyssa Ragner:

{{Sandbox_Reserved_BHall_Chem351_F19}}
=='''Inosine-5'-monophosphate dehydrogenase'''==
<StructureSection load='6rpu' size='340' side='right' caption='Structure of the ternary complex of the IMPDH enzyme from Ashbya gossypii bound to the dinucleoside polyphosphate Ap5G and GDP' scene=''>

== Function(s) and Biological Relevance ==

<scene name='82/823089/Cartoon_view/1'>Inosine-5'-monophosphate dehydrogenase</scene> (IMPDH) is the enzyme that catalyzes the rate-limiting step in the ''de novo'' guanine nucleotide biosynthetic pathway, converting inosine monophosphate (IMP) to xanthosine monophosphate (XMP) with the reduction of nicotinamide adenine dinucleotide (NAD). Organisms that undergo the purine nucleotide biosynthetic pathway have IMPDH, including humans. This particular form of IMPDH described and highlighted comes from the recently studied fungus ''Ashbya gossypii'' <ref>PMID: 31416831</ref>. Additional ligands of IMPDH include nicotinamide adenine dinucleotide (NAD), acetate (ACT), and guanosine-5’ monophosphate (5GP), and guanosine-5'-diphosphate (GDP). IMPDH is a regulator of the intracellular guanine nucleotide pool amount and helps control control cell division and proliferation, and therefore related to malignant transformation, tumor cell proliferation, and intracellular and extracellular pathogenic infections. Purine dinucleoside polyphosphates are found to bind to the Bateman domain of ''Ashbya gossypii'' IMPDH to allosterically regulate the catalytic activity by competing against purine mononucleotides<ref>PMID: 31416831</ref>.

== Broader Implications ==

The disease pathophysiology is extensive as the improper IMPDH regulation may lead to uncontrolled cell division and proliferation, affecting the immune system's ability to fight off pathogens and signal tumor cells to apoptose. Therapeutic studies using dinucleoside polyphosphates may allosterically regulate the inhibition of IMPDH activity. Dinucleoside polyphosphates have physiological functions including cell division, neurotransmission, apoptosis, vasoconstriction, platelet aggregation, and cellular process variety enhancement from DNA replication to repair<ref>PMID: 31416831</ref>. Selected IMPDH inhibitors composed of dinucleoside polyphosphates may be used to make IMPDHs targets for immunosuppressive, antiviral, and anticancer drugs<ref>PMID: 21517780</ref>, with antibacterial and chemotherapeutic strategies feasibile<ref>PMID: 22928911</ref>.

== Structural Highlights and Structure-Function Relationships ==

The <scene name='82/823089/Secondary_structure/1'>secondary structure</scene> shows alpha helices and beta sheets. The ''Ashbya gossypii'' IMPDH is 31% helical and 15% beta sheet, with the other percentages including random coils and residue structures. The active site is located towards the C-terminus within the TIM barrel, containing 8 alpha-helices and 8 beta sheets.

IMPDH quaternary structures include multiunit complexes, such as <scene name='82/823089/Quaternary_view/1'>tetramers</scene>, extended octamers, and compacted octamers. These quaternary structures are created through the binding of multiple subunits of <scene name='82/823089/Tertiary_structure/1'>tertiary</scene> structures (monomers), that are strengthened and structurally formed through hydrogen-bonding, cysteine-cysteine disulfide bonds, and hydrophobic interactions. Different quaternary forms of IMPDH relate to the kinetic favorability of the IMPDH mechanism as Bateman domain allosteric binding sites and competitive nature changes with unit composition.

This <scene name='82/823089/Space-filled/2'>space-filled view</scene> helps show the Van der Waals interactions and areas for movement within the structure. The ability for monovalent cations to move within the charged tunnel with the phosphate chain (TIM barrel) directly relates to activation levels. The phosphate chain relates to the ligands that further interact with the binding site to form the covalent intermediate, E-XMP*.

The <scene name='82/823089/Hydrophobicity_view/1'>hydrophobicity</scene> is within the interior of the molecule as the hydrophilic residues are able to interact in a physiological environment. The hydrophobic region of Gly361 and Gly383 interact with the main chain phosphate (TIM), further allowing monovalent cation movement. Hydrophilic regions contain amino acid residues that hydrogen-bond, some conserving tertiary structure and others relating to necessary interactions in the active site (see below).

Acetate ions, G5P, and GDP molecules are <scene name='82/823089/Ligands/1'>ligands</scene> of IMPDH. NAD serves a function as a ligand as is necessary in the hydrolysis of IMP. The phosphates of the G5P, GDP, and NAD (not pictured) ligands interact through hydrogen bonds and hydrophobic interactions (depending on the amino acid residue; see active binding site below). The monocovalent cations that pass through interact with the phosphates as they activate IMPDH.

The IMPDH <scene name='82/823089/Catalytic_triad/1'>catalytic triad</scene> includes Arg (325), Asn (306), and Asp (272). This is represented by the solid purple structures in the image. This triad is important as it makes cysteine more reactive as a nucleophilic component. This conserved cysteine, Cys334, (Cys331 in human type II IMPDH) induces binding after becoming more reactive (Cysteine shown in image with "active binding site" link).

The <scene name='82/823089/Active_site/1'>active binding site</scene> includes the Bateman domains, which are components within the TIM barrel. Binding occurs after the catalytic triad makes cysteine more reactive. The cysteines that become more reactive are shown in green in the image, and are closely related to the active binding site. Asp259 (blue) hydrogen bonds with the ribose hydroxyls of NAD (nicotinamide region), and Ser315 (blue) hydrogen bonds to the ribose phosphate through hydroxyl groups. Gly361 and Gly383 (orange) have hydrophobic interactions with the phosphate of the ligand NAD. Other important interactions include Tyr403 hydrogen bonding to ribose phosphate (NAD), and Glu402 and Glu440 hydrogen bonding with the IMP purine ring.

IMPDH <scene name='82/823089/Charge_view/2'>charge</scene> is not positively or negatively strong as an entire protein, as shown by this view. There are positive and negative components within the structure, but a relatively neutral substance is better received in this mechanism due to a physiological environment. Negatively-charged glutamic acid and positively-charged histidine within this enzyme play a role within the covalent bindings in the mechanism. Covalent binding is necessary to form the covalent intermediate after NAD is reduced (after interacting with the active site residues).

This enzyme's <scene name='82/823089/Composition_view/1'>composition</scene> contains mostly protein (brown) with no solvent. The dark pink RNA regions coincide with G5P and GDP ligands as they contain ribose groups. NAD, containing two ribose groups, (not pictured) is another ligand that is necessary in the hydrolysis of IMP in the mechanism. The green acetate ions are anions that function as ligands as as intermediate-step metabolites in the mechanism. Monocovalent cations travel through and activate IMPDH as anionic acetate ions buffer the system.

== Energy Transformation ==

IMPDH is activated by monovalent cations, such as K+ and Na+, within the triose-phosphate isomerase (TIM) barrel. The Arg325-Asn306-Asp272 catalytic triad (Arg322-Asn303-Asp274 in human type II IMPDH) works inter-dependently and synergistically in the TIM barrel active site to make the nucleophilic component, cysteine, highly reactive to form a temporary covalent bond with the substrate<ref>PMID: 8555204</ref>. Substrates bind randomly to IMPDH as the hydride transfer is quick and NAD is reduced to hydrolyze the covalent intermediate within the enzyme-substrate complex. A covalent intermediate, E-XMP*, is formed, which decreases the energy needed in later nucleophilic and covalent catalysis steps<ref>PMID: 10390600</ref>. Based on normal physiological conditions, the IMPDH mechanism is often not kinetically favorable. The Bateman domains within the TIM barrel are composed of cystathionine beta-synthase motifs that perceive metal ion concentration, cellular energy status, and ionic strength; and will allosterically regulate IMPDH activity<ref>PMID: 31416831</ref>. Eukaryotic IMPDHs have three nucleotide-binding sites in the Bateman domain that allosterically modulate catalytic activity. These three nucleotide-binding sites bind adenine/guanine dinucleoside polyphosphates, and the affinity for these sites increases for these dinucleoside polyphosphates as the activity of IMPDH increases. Purine dinucleoside polyphosphates compete with purine mononucleotides within these sites, so the Bateman domain sites make IMPDH more sensitive to inhibition<ref>PMID: 31416831</ref>. Enzyme catalysis is able to finish with the energy need reduced as the covalent bond is broken later in the reaction to regenerate the enzyme.

</StructureSection>
== References ==

<references />

Sandbox Reserved 1565

2019-12-09T05:53:51Z

Alyssa Ragner:

{{Sandbox_Reserved_BHall_Chem351_F19}}
=='''Inosine-5'-monophosphate dehydrogenase'''==
<StructureSection load='6rpu' size='340' side='right' caption='Structure of the ternary complex of the IMPDH enzyme from Ashbya gossypii bound to the dinucleoside polyphosphate Ap5G and GDP' scene=''>

== Function(s) and Biological Relevance ==

<scene name='82/823089/Cartoon_view/1'>Inosine-5'-monophosphate dehydrogenase</scene> (IMPDH) is the enzyme that catalyzes the rate-limiting step in the ''de novo'' guanine nucleotide biosynthetic pathway, converting inosine monophosphate (IMP) to xanthosine monophosphate (XMP) with the reduction of nicotinamide adenine dinucleotide (NAD). Organisms that undergo the purine nucleotide biosynthetic pathway have IMPDH, including humans. This particular form of IMPDH described and highlighted comes from the recently studied fungus ''Ashbya gossypii'' <ref>PMID: 31416831</ref>. Additional ligands of IMPDH include nicotinamide adenine dinucleotide (NAD), acetate (ACT), and guanosine-5’ monophosphate (5GP), and guanosine-5'-diphosphate (GDP). IMPDH is a regulator of the intracellular guanine nucleotide pool amount and helps control control cell division and proliferation, and therefore related to malignant transformation, tumor cell proliferation, and intracellular and extracellular pathogenic infections. Purine dinucleoside polyphosphates are found to bind to the Bateman domain of ''Ashbya gossypii'' IMPDH to allosterically regulate the catalytic activity by competing against purine mononucleotides<ref>PMID: 31416831</ref>.

== Broader Implications ==

The disease pathophysiology is extensive as the improper IMPDH regulation may lead to uncontrolled cell division and proliferation, affecting the immune system's ability to fight off pathogens and signal tumor cells to apoptose. Therapeutic studies using dinucleoside polyphosphates may allosterically regulate the inhibition of IMPDH activity. Dinucleoside polyphosphates have physiological functions including cell division, neurotransmission, apoptosis, vasoconstriction, platelet aggregation, and cellular process variety enhancement from DNA replication to repair<ref>PMID: 31416831</ref>. Selected IMPDH inhibitors composed of dinucleoside polyphosphates may be used to make IMPDHs targets for immunosuppressive, antiviral, and anticancer drugs<ref>PMID: 21517780</ref>, with antibacterial and chemotherapeutic strategies feasibile<ref>PMID: 22928911</ref>.

== Structural Highlights and Structure-Function Relationships ==

The <scene name='82/823089/Secondary_structure/1'>secondary structure</scene> shows alpha helices and beta sheets. The ''Ashbya gossypii'' IMPDH is 31% helical and 15% beta sheet, with the other percentages including random coils and residue structures. The active site is located towards the C-terminus within the TIM barrel, containing 8 alpha-helices and 8 beta sheets.

IMPDH quaternary structures include multiunit complexes, such as <scene name='82/823089/Quaternary_view/1'>tetramers</scene>, extended octamers, and compacted octamers. These quaternary structures are created through the binding of multiple subunits of <scene name='82/823089/Tertiary_structure/1'>tertiary</scene> structures (monomers), that are strengthened and structurally formed through hydrogen-bonding, cysteine-cysteine disulfide bonds, and hydrophobic interactions. Different quaternary forms of IMPDH relate to the kinetic favorability of the IMPDH mechanism as Bateman domain allosteric binding sites and competitive nature changes with unit composition.

This <scene name='82/823089/Space-filled/2'>space-filled view</scene> helps show the Van der Waals interactions and areas for movement within the structure. The ability for monovalent cations to move within the charged tunnel with the phosphate chain directly relates to activation levels. The phosphate chain relates to the ligands that further interact with the binding site to form the covalent intermediate, E-XMP*.

The <scene name='82/823089/Hydrophobicity_view/1'>hydrophobicity</scene> is within the interior of the molecule as the hydrophilic residues are able to interact in a physiological environment. The hydrophobic region of Gly361 and Gly383 interact with the main chain phosphate, further allowing monovalent cation movement. Hydrophilic regions contain amino acid residues that hydrogen-bond, some conserving tertiary structure and others relating to necessary interactions in the active site (see below).

Acetate ions, G5P, and GDP molecules are <scene name='82/823089/Ligands/1'>ligands</scene> of IMPDH. NAD serves a function as a ligand as is necessary in the hydrolysis of IMP. The phosphates of the G5P, GDP, and NAD (not pictured) ligands interact through hydrogen bonds and hydrophobic interactions (depending on the amino acid residue; see active binding site below). The monocovalent cations that pass through interact with the phosphates as they activate IMPDH.

The IMPDH <scene name='82/823089/Catalytic_triad/1'>catalytic triad</scene> includes Arg (325), Asn (306), and Asp (272). This is represented by the solid purple structures in the image. This triad is important as it makes cysteine more reactive as a nucleophilic component. This conserved cysteine, Cys334, (Cys331 in human type II IMPDH) induces binding after becoming more reactive (Cysteine shown in image with "active binding site" link).

The <scene name='82/823089/Active_site/1'>active binding site</scene> includes the Bateman domains, which are components within the TIM barrel. Binding occurs after the catalytic triad makes cysteine more reactive. The cysteines that become more reactive are shown in green in the image, and are closely related to the active binding site. Asp259 (blue) hydrogen bonds with the ribose hydroxyls of NAD (nicotinamide region), and Ser315 (blue) hydrogen bonds to the ribose phosphate through hydroxyl groups. Gly361 and Gly383 (orange) have hydrophobic interactions with the phosphate of the ligand NAD. Other important interactions include Tyr403 hydrogen bonding to ribose phosphate (NAD), and Glu402 and Glu440 hydrogen bonding with the IMP purine ring.

IMPDH <scene name='82/823089/Charge_view/2'>charge</scene> is not positively or negatively strong as an entire protein, as shown by this view. There are positive and negative components within the structure, but a relatively neutral substance is better received in this mechanism due to a physiological environment. Negatively-charged glutamic acid and positively-charged histidine within this enzyme play a role within the covalent bindings in the mechanism. Covalent binding is necessary to form the covalent intermediate after NAD is reduced (after interacting with the active site residues).

This enzyme's <scene name='82/823089/Composition_view/1'>composition</scene> contains mostly protein (brown) with no solvent. The dark pink RNA regions coincide with G5P and GDP ligands as they contain ribose groups. NAD, containing two ribose groups, (not pictured) is another ligand that is necessary in the hydrolysis of IMP in the mechanism. The green acetate ions are anions that function as ligands as as intermediate-step metabolites in the mechanism. Monocovalent cations travel through and activate IMPDH as anionic acetate ions buffer the system.

== Energy Transformation ==

IMPDH is activated by monovalent cations, such as K+ and Na+, within the triose-phosphate isomerase (TIM) barrel. The Arg325-Asn306-Asp272 catalytic triad (Arg322-Asn303-Asp274 in human type II IMPDH) works inter-dependently and synergistically in the TIM barrel active site to make the nucleophilic component, cysteine, highly reactive to form a temporary covalent bond with the substrate<ref>PMID: 8555204</ref>. Substrates bind randomly to IMPDH as the hydride transfer is quick and NAD is reduced to hydrolyze the covalent intermediate within the enzyme-substrate complex. A covalent intermediate, E-XMP*, is formed, which decreases the energy needed in later nucleophilic and covalent catalysis steps<ref>PMID: 10390600</ref>. Based on normal physiological conditions, the IMPDH mechanism is often not kinetically favorable. The Bateman domains within the TIM barrel are composed of cystathionine beta-synthase motifs that perceive metal ion concentration, cellular energy status, and ionic strength; and will allosterically regulate IMPDH activity<ref>PMID: 31416831</ref>. Eukaryotic IMPDHs have three nucleotide-binding sites in the Bateman domain that allosterically modulate catalytic activity. These three nucleotide-binding sites bind adenine/guanine dinucleoside polyphosphates, and the affinity for these sites increases for these dinucleoside polyphosphates as the activity of IMPDH increases. Purine dinucleoside polyphosphates compete with purine mononucleotides within these sites, so the Bateman domain sites make IMPDH more sensitive to inhibition<ref>PMID: 31416831</ref>. Enzyme catalysis is able to finish with the energy need reduced as the covalent bond is broken later in the reaction to regenerate the enzyme.

</StructureSection>
== References ==

<references />

Sandbox Reserved 1565

2019-12-09T05:51:08Z

Alyssa Ragner:

{{Sandbox_Reserved_BHall_Chem351_F19}}
=='''Inosine-5'-monophosphate dehydrogenase'''==
<StructureSection load='6rpu' size='340' side='right' caption='Structure of the ternary complex of the IMPDH enzyme from Ashbya gossypii bound to the dinucleoside polyphosphate Ap5G and GDP' scene=''>

== Function(s) and Biological Relevance ==

<scene name='82/823089/Cartoon_view/1'>Inosine-5'-monophosphate dehydrogenase</scene> (IMPDH) is the enzyme that catalyzes the rate-limiting step in the ''de novo'' guanine nucleotide biosynthetic pathway, converting inosine monophosphate (IMP) to xanthosine monophosphate (XMP) with the reduction of nicotinamide adenine dinucleotide (NAD). Organisms that undergo the purine nucleotide biosynthetic pathway have IMPDH, including humans. This particular form of IMPDH described and highlighted comes from the recently studied fungus ''Ashbya gossypii'' <ref>PMID: 31416831</ref>. Additional ligands of IMPDH include nicotinamide adenine dinucleotide (NAD), acetate (ACT), and guanosine-5’ monophosphate (5GP), and guanosine-5'-diphosphate (GDP). IMPDH is a regulator of the intracellular guanine nucleotide pool amount and helps control control cell division and proliferation, and therefore related to malignant transformation, tumor cell proliferation, and intracellular and extracellular pathogenic infections. Purine dinucleoside polyphosphates are found to bind to the Bateman domain of ''Ashbya gossypii'' IMPDH to allosterically regulate the catalytic activity by competing against purine mononucleotides<ref>PMID: 31416831</ref>.

== Broader Implications ==

The disease pathophysiology is extensive as the improper IMPDH regulation may lead to uncontrolled cell division and proliferation, affecting the immune system's ability to fight off pathogens and signal tumor cells to apoptose. Therapeutic studies using dinucleoside polyphosphates may allosterically regulate the inhibition of IMPDH activity. Dinucleoside polyphosphates have physiological functions including cell division, neurotransmission, apoptosis, vasoconstriction, platelet aggregation, and cellular process variety enhancement from DNA replication to repair<ref>PMID: 31416831</ref>. Selected IMPDH inhibitors composed of dinucleoside polyphosphates may be used to make IMPDHs targets for immunosuppressive, antiviral, and anticancer drugs<ref>PMID: 21517780</ref>, with antibacterial and chemotherapeutic strategies feasibile<ref>PMID: 22928911</ref>.

== Structural Highlights and Structure-Function Relationships ==

The <scene name='82/823089/Secondary_structure/1'>secondary structure</scene> shows alpha helices and beta sheets. The ''Ashbya gossypii'' IMPDH is 31% helical and 15% beta sheet, with the other percentages including random coils and residue structures. The active site is located towards the C-terminus within the TIM barrel, containing 8 alpha-helices and 8 beta sheets.

IMPDH quaternary structures include multiunit complexes, such as <scene name='82/823089/Quaternary_view/1'>tetramers</scene>, extended octamers, and compacted octamers. These quaternary structures are created through the binding of multiple subunits of <scene name='82/823089/Tertiary_structure/1'>tertiary</scene> structures (monomers), that are strengthened and structurally formed through hydrogen-bonding, cysteine-cysteine disulfide bonds, and hydrophobic interactions. Different quaternary forms of IMPDH relate to the kinetic favorability of the IMPDH mechanism as Bateman domain allosteric binding sites and competitive nature changes with unit composition.

This <scene name='82/823089/Space-filled/2'>space-filled view</scene> helps show the Van der Waals interactions and areas for movement within the structure. The ability for monovalent cations to move within the charged tunnel with the phosphate chain directly relates to activation levels. The phosphate chain relates to the ligands that further interact with the binding site to form the covalent intermediate, E-XMP*.

The <scene name='82/823089/Hydrophobicity_view/1'>hydrophobicity</scene> is within the interior of the molecule as the hydrophilic residues are able to interact in a physiological environment. The hydrophobic region of Gly361 and Gly383 interact with the main chain phosphate, further allowing monovalent cation movement. Hydrophilic regions contain amino acid residues that hydrogen-bond, some conserving tertiary structure and others relating to necessary interactions in the active site (see below).

Acetate ions, G5P, and GDP ions are <scene name='82/823089/Ligands/1'>ligands</scene> of IMPDH. NAD serves a function as a ligand as is necessary in the hydrolysis of IMP. The phosphates of the G5P, GDP, and NAD (not pictured) ligands interact through hydrogen bonds and hydrophobic interactions (depending on the amino acid residue; see active binding site below). The monocovalent cations that pass through interact with the phosphates as they activate IMPDH.

The IMPDH <scene name='82/823089/Catalytic_triad/1'>catalytic triad</scene> includes Arg (325), Asn (306), and Asp (272). This is represented by the solid purple structures in the image. This triad is important as it makes cysteine more reactive as a nucleophilic component. This conserved cysteine, Cys334, (Cys331 in human type II IMPDH) induces binding after becoming more reactive (Cysteine shown in image with "active binding site" link).

The <scene name='82/823089/Active_site/1'>active binding site</scene> includes the Bateman domains, which are components within the TIM barrel. Binding occurs after the catalytic triad makes cysteine more reactive. The cysteines that become more reactive are shown in green in the image, and are closely related to the active binding site. Asp259 (blue) hydrogen bonds with the ribose hydroxyls of NAD (nicotinamide region), and Ser315 (blue) hydrogen bonds to the ribose phosphate through hydroxyl groups. Gly361 and Gly383 (orange) have hydrophobic interactions with the phosphate of the ligand NAD. Other important interactions include Tyr403 hydrogen bonding to ribose phosphate (NAD), and Glu402 and Glu440 hydrogen bonding with the IMP purine ring.

IMPDH <scene name='82/823089/Charge_view/2'>charge</scene> is not positively or negatively strong as an entire protein, as shown by this view. There are positive and negative components within the structure, but a relatively neutral substance is better received in this mechanism due to a physiological environment. Negatively-charged glutamic acid and positively-charged histidine within this enzyme play a role within the covalent bindings in the mechanism. Covalent binding is necessary to form the covalent intermediate after NAD is reduced (after interacting with the active site residues).

This enzyme's <scene name='82/823089/Composition_view/1'>composition</scene> contains mostly protein (brown) with no solvent. The dark pink RNA regions coincide with G5P and GDP ligands as they contain ribose groups. NAD, containing two ribose groups, (not pictured) is another ligand that is necessary in the hydrolysis of IMP in the mechanism. The green acetate ions are anions that function as ligands as as intermediate-step metabolites in the mechanism. Monocovalent cations travel through and activate IMPDH as anionic acetate ions buffer the system.

== Energy Transformation ==

IMPDH is activated by monovalent cations, such as K+ and Na+, within the triose-phosphate isomerase (TIM) barrel. The Arg325-Asn306-Asp272 catalytic triad (Arg322-Asn303-Asp274 in human type II IMPDH) works inter-dependently and synergistically in the TIM barrel active site to make the nucleophilic component, cysteine, highly reactive to form a temporary covalent bond with the substrate<ref>PMID: 8555204</ref>. Substrates bind randomly to IMPDH as the hydride transfer is quick and NAD is reduced to hydrolyze the covalent intermediate within the enzyme-substrate complex. A covalent intermediate, E-XMP*, is formed, which decreases the energy needed in later nucleophilic and covalent catalysis steps<ref>PMID: 10390600</ref>. Based on normal physiological conditions, the IMPDH mechanism is often not kinetically favorable. The Bateman domains within the TIM barrel are composed of cystathionine beta-synthase motifs that perceive metal ion concentration, cellular energy status, and ionic strength; and will allosterically regulate IMPDH activity<ref>PMID: 31416831</ref>. Eukaryotic IMPDHs have three nucleotide-binding sites in the Bateman domain that allosterically modulate catalytic activity. These three nucleotide-binding sites bind adenine/guanine dinucleoside polyphosphates, and the affinity for these sites increases for these dinucleoside polyphosphates as the activity of IMPDH increases. Purine dinucleoside polyphosphates compete with purine mononucleotides within these sites, so the Bateman domain sites make IMPDH more sensitive to inhibition<ref>PMID: 31416831</ref>. Enzyme catalysis is able to finish with the energy need reduced as the covalent bond is broken later in the reaction to regenerate the enzyme.

</StructureSection>
== References ==

<references />

Sandbox Reserved 1565

2019-12-09T05:46:56Z

Alyssa Ragner:

{{Sandbox_Reserved_BHall_Chem351_F19}}
=='''Inosine-5'-monophosphate dehydrogenase'''==
<StructureSection load='6rpu' size='340' side='right' caption='Structure of the ternary complex of the IMPDH enzyme from Ashbya gossypii bound to the dinucleoside polyphosphate Ap5G and GDP' scene=''>

== Function(s) and Biological Relevance ==

<scene name='82/823089/Cartoon_view/1'>Inosine-5'-monophosphate dehydrogenase</scene> (IMPDH) is the enzyme that catalyzes the rate-limiting step in the ''de novo'' guanine nucleotide biosynthetic pathway, converting inosine monophosphate (IMP) to xanthosine monophosphate (XMP) with the reduction of nicotinamide adenine dinucleotide (NAD). Organisms that undergo the purine nucleotide biosynthetic pathway have IMPDH, including humans. This particular form of IMPDH described and highlighted comes from the recently studied fungus ''Ashbya gossypii'' <ref>PMID: 31416831</ref>. Additional ligands of IMPDH include nicotinamide adenine dinucleotide (NAD), acetate (ACT), and guanosine-5’ monophosphate (5GP), and guanosine-5'-diphosphate (GDP). IMPDH is a regulator of the intracellular guanine nucleotide pool amount and helps control control cell division and proliferation, and therefore related to malignant transformation, tumor cell proliferation, and intracellular and extracellular pathogenic infections. Purine dinucleoside polyphosphates are found to bind to the Bateman domain of ''Ashbya gossypii'' IMPDH to allosterically regulate the catalytic activity by competing against purine mononucleotides<ref>PMID: 31416831</ref>.

== Broader Implications ==

The disease pathophysiology is extensive as the improper IMPDH regulation may lead to uncontrolled cell division and proliferation, affecting the immune system's ability to fight off pathogens and signal tumor cells to apoptose. Therapeutic studies using dinucleoside polyphosphates may allosterically regulate the inhibition of IMPDH activity. Dinucleoside polyphosphates have physiological functions including cell division, neurotransmission, apoptosis, vasoconstriction, platelet aggregation, and cellular process variety enhancement from DNA replication to repair<ref>PMID: 31416831</ref>. Selected IMPDH inhibitors composed of dinucleoside polyphosphates may be used to make IMPDHs targets for immunosuppressive, antiviral, and anticancer drugs<ref>PMID: 21517780</ref>, with antibacterial and chemotherapeutic strategies feasibile<ref>PMID: 22928911</ref>.

== Structural Highlights and Structure-Function Relationships ==

The <scene name='82/823089/Secondary_structure/1'>secondary structure</scene> shows alpha helices and beta sheets. The ''Ashbya gossypii'' IMPDH is 31% helical and 15% beta sheet, with the other percentages including random coils and residue structures. The active site is located towards the C-terminus within the TIM barrel, containing 8 alpha-helices and 8 beta sheets.

IMPDH quaternary structures include multiunit complexes, such as <scene name='82/823089/Quaternary_view/1'>tetramers</scene>, extended octamers, and compacted octamers. These quaternary structures are created through the binding of multiple subunits of <scene name='82/823089/Tertiary_structure/1'>tertiary</scene> structures (monomers), that are strengthened and structurally formed through hydrogen-bonding, cysteine-cysteine disulfide bonds, and hydrophobic interactions. Different quaternary forms of IMPDH relate to the kinetic favorability of the IMPDH mechanism as Bateman domain allosteric binding sites and competitive nature changes with unit composition.

This <scene name='82/823089/Space-filled/2'>space-filled view</scene> helps show the Van der Waals interactions and areas for movement within the structure. The ability for monovalent cations to move within the charged tunnel with the phosphate chain directly relates to activation levels. The phosphate chain relates to the ligands that further interact with the binding site to form the covalent intermediate, E-XMP*.

The <scene name='82/823089/Hydrophobicity_view/1'>hydrophobicity</scene> is within the interior of the molecule as the hydrophilic residues are able to interact in a physiological environment. The hydrophobic region of Gly361 and Gly383 interact with the main chain phosphate, further allowing monovalent cation movement. Hydrophilic regions contain amino acid residues that hydrogen-bond, some conserving tertiary structure and others relating to necessary interactions in the active site (see below).

Acetate ions, G5P, and GDP ions are <scene name='82/823089/Ligands/1'>ligands</scene> of IMPDH. NAD serves a function as a ligand as is necessary in the hydrolysis of IMP. The phosphates of the G5P, GDP, and NAD (not pictured) ligands interact through hydrogen bonds and hydrophobic interactions (depending on the amino acid residue; see active binding site below). The monocovalent cations that pass through interact with the phosphates as they activate IMPDH.

The IMPDH <scene name='82/823089/Catalytic_triad/1'>catalytic triad</scene> includes Arg (325), Asn (306), and Asp (272). This is represented by the solid purple structures in the image. This triad is important as it makes cysteine more reactive as a nucleophilic component. This conserved cysteine, Cys334, (Cys331 in human type II IMPDH) induces binding after becoming more reactive.

The <scene name='82/823089/Active_site/1'>active binding site</scene> includes the Bateman domains, which are components within the TIM barrel. Binding occurs after the catalytic triad makes cysteine more reactive. The cysteines that become more reactive are shown in green in the image, and are closely related to the active binding site. Asp259 (blue) hydrogen bonds with the ribose hydroxyls of NAD (nicotinamide region), and Ser315 (blue) hydrogen bonds to the ribose phosphate through hydroxyl groups. Gly361 and Gly383 (orange) have hydrophobic interactions with the phosphate of the ligand NAD. Other important interactions include Tyr403 hydrogen bonding to ribose phosphate (NAD), and Glu402 and Glu440 hydrogen bonding with the IMP purine ring.

IMPDH <scene name='82/823089/Charge_view/2'>charge</scene> is not positively or negatively strong as an entire protein, as shown by this view. There are positive and negative components within the structure, but a relatively neutral substance is better received in this mechanism due to a physiological environment. Negatively-charged glutamic acid and positively-charged histidine within this enzyme play a role within the covalent bindings in the mechanism. Covalent binding is necessary to form the covalent intermediate after NAD is reduced (after interacting with the active site residues).

This enzyme's <scene name='82/823089/Composition_view/1'>composition</scene> contains mostly protein (brown) with no solvent. The dark pink RNA regions coincide with G5P and GDP ligands as they contain ribose groups. NAD, containing two ribose groups, (not pictured) is another ligand that is necessary in the hydrolysis of IMP in the mechanism. The green acetate ions are anions that function as ligands as as intermediate-step metabolites in the mechanism. Monocovalent cations travel through and activate IMPDH as anionic acetate ions buffer the system.

== Energy Transformation ==

IMPDH is activated by monovalent cations, such as K+ and Na+, within the triose-phosphate isomerase (TIM) barrel. The Arg325-Asn306-Asp272 catalytic triad (Arg322-Asn303-Asp274 in human type II IMPDH) works inter-dependently and synergistically in the TIM barrel active site to make the nucleophilic component, cysteine, highly reactive to form a temporary covalent bond with the substrate<ref>PMID: 8555204</ref>. Substrates bind randomly to IMPDH as the hydride transfer is quick and NAD is reduced to hydrolyze the covalent intermediate within the enzyme-substrate complex. A covalent intermediate, E-XMP*, is formed, which decreases the energy needed in later nucleophilic and covalent catalysis steps<ref>PMID: 10390600</ref>. Based on normal physiological conditions, the IMPDH mechanism is often not kinetically favorable. The Bateman domains within the TIM barrel are composed of cystathionine beta-synthase motifs that perceive metal ion concentration, cellular energy status, and ionic strength; and will allosterically regulate IMPDH activity<ref>PMID: 31416831</ref>. Eukaryotic IMPDHs have three nucleotide-binding sites in the Bateman domain that allosterically modulate catalytic activity. These three nucleotide-binding sites bind adenine/guanine dinucleoside polyphosphates, and the affinity for these sites increases for these dinucleoside polyphosphates as the activity of IMPDH increases. Purine dinucleoside polyphosphates compete with purine mononucleotides within these sites, so the Bateman domain sites make IMPDH more sensitive to inhibition<ref>PMID: 31416831</ref>. Enzyme catalysis is able to finish with the energy need reduced as the covalent bond is broken later in the reaction to regenerate the enzyme.

</StructureSection>
== References ==

<references />

Sandbox Reserved 1565

2019-12-09T05:44:34Z

Alyssa Ragner:

{{Sandbox_Reserved_BHall_Chem351_F19}}
=='''Inosine-5'-monophosphate dehydrogenase'''==
<StructureSection load='6rpu' size='340' side='right' caption='Structure of the ternary complex of the IMPDH enzyme from Ashbya gossypii bound to the dinucleoside polyphosphate Ap5G and GDP' scene=''>

== Function(s) and Biological Relevance ==

<scene name='82/823089/Cartoon_view/1'>Inosine-5'-monophosphate dehydrogenase</scene> (IMPDH) is the enzyme that catalyzes the rate-limiting step in the ''de novo'' guanine nucleotide biosynthetic pathway, converting inosine monophosphate (IMP) to xanthosine monophosphate (XMP) with the reduction of nicotinamide adenine dinucleotide (NAD). Organisms that undergo the purine nucleotide biosynthetic pathway have IMPDH, including humans. This particular form of IMPDH described and highlighted comes from the recently studied fungus ''Ashbya gossypii'' <ref>PMID: 31416831</ref>. Additional ligands of IMPDH include nicotinamide adenine dinucleotide (NAD), acetate (ACT), and guanosine-5’ monophosphate (5GP), and guanosine-5'-diphosphate (GDP). IMPDH is a regulator of the intracellular guanine nucleotide pool amount and helps control control cell division and proliferation, and therefore related to malignant transformation, tumor cell proliferation, and intracellular and extracellular pathogenic infections. Purine dinucleoside polyphosphates are found to bind to the Bateman domain of ''Ashbya gossypii'' IMPDH to allosterically regulate the catalytic activity by competing against purine mononucleotides<ref>PMID: 31416831</ref>.

== Broader Implications ==

The disease pathophysiology is extensive as the improper IMPDH regulation may lead to uncontrolled cell division and proliferation, affecting the immune system's ability to fight off pathogens and signal tumor cells to apoptose. Therapeutic studies using dinucleoside polyphosphates may allosterically regulate the inhibition of IMPDH activity. Dinucleoside polyphosphates have physiological functions including cell division, neurotransmission, apoptosis, vasoconstriction, platelet aggregation, and cellular process variety enhancement from DNA replication to repair<ref>PMID: 31416831</ref>. Selected IMPDH inhibitors composed of dinucleoside polyphosphates may be used to make IMPDHs targets for immunosuppressive, antiviral, and anticancer drugs<ref>PMID: 21517780</ref>, with antibacterial and chemotherapeutic strategies feasibile<ref>PMID: 22928911</ref>.

== Structural Highlights and Structure-Function Relationships ==

The <scene name='82/823089/Secondary_structure/1'>secondary structure</scene> shows alpha helices and beta sheets. The ''Ashbya gossypii'' IMPDH is 31% helical and 15% beta sheet, with the other percentages including random coils and residue structures. The active site is located towards the C-terminus within the TIM barrel, containing 8 alpha-helices and 8 beta sheets.

IMPDH quaternary structures include multiunit complexes, such as <scene name='82/823089/Quaternary_view/1'>tetramers</scene>, extended octamers, and compacted octamers. These quaternary structures are created through the binding of multiple subunits of <scene name='82/823089/Tertiary_structure/1'>tertiary</scene> structures (monomers), that are strengthened and structurally formed through hydrogen-bonding, cysteine-cysteine disulfide bonds, and hydrophobic interactions. Different quaternary forms of IMPDH relate to the kinetic favorability of the IMPDH mechanism as Bateman domain allosteric binding sites and competitive nature changes with unit composition.

This <scene name='82/823089/Space-filled/2'>space-filled view</scene> helps show the Van der Waals interactions and areas for movement within the structure. The ability for monovalent cations to move within the charged tunnel with the phosphate chain directly relates to activation levels. The phosphate chain relates to the ligands that further interact with the binding site to form the covalent intermediate, E-XMP*.

The <scene name='82/823089/Hydrophobicity_view/1'>hydrophobicity</scene> is within the interior of the molecule as the hydrophilic residues are able to interact in a physiological environment. The hydrophobic region of Gly361 and Gly383 interact with the main chain phosphate, further allowing monovalent cation movement. Hydrophilic regions contain amino acid residues that hydrogen-bond, some conserving tertiary structure and others relating to necessary interactions in the active site (see below).

Acetate ions, G5P, and GDP ions are <scene name='82/823089/Ligands/1'>ligands</scene> of IMPDH. NAD serves a function as a ligand as is necessary in the hydrolysis of IMP. The phosphates of the G5P, GDP, and NAD (not pictured) ligands interact through hydrogen bonds and hydrophobic interactions (depending on the amino acid residue; see active binding site below). The monocovalent cations that pass through interact with the phosphates as they activate IMPDH.

The IMPDH <scene name='82/823089/Catalytic_triad/1'>catalytic triad</scene> includes Arg (325), Asn (306), and Asp (272). This is represented by the solid purple structures in the image. This triad is important as it makes cysteine more reactive as a nucleophilic component. This conserved cysteine, Cys334, (Cys331 in human type II IMPDH) induces binding after becoming more reactive.

<scene name='82/823089/Active_site/1'>Active Binding Site</scene> The active binding site includes the Bateman domains, which are components within the TIM barrel. Binding occurs after the catalytic triad makes cysteine more reactive. The cysteines that become more reactive are shown in green in the image, and are closely related to the active binding site. Asp259 (blue) hydrogen bonds with the ribose hydroxyls of NAD (nicotinamide region), and Ser315 (blue) hydrogen bonds to the ribose phosphate through hydroxyl groups. Gly361 and Gly383 (orange) have hydrophobic interactions with the phosphate of the ligand NAD. Other important interactions include Tyr403 hydrogen bonding to ribose phosphate (NAD), and Glu402 and Glu440 hydrogen bonding with the IMP purine ring.

<scene name='82/823089/Charge_view/2'>IMPDH charge</scene> is not strong, as shown by this view. There are positive and negative components within the structure, but a relatively neutral substance is better received in this mechanism due to a physiological environment. Negatively-charged glutamic acid and positively-charged histidine within this enzyme play a role within the covalent bindings in the mechanism. Covalent binding is necessary to form the covalent intermediate after NAD is reduced (after interacting with the active site residues).

<scene name='82/823089/Composition_view/1'>IMPDH composition</scene> The dark pink RNA regions coincide with G5P and GDP ligands as they contain ribose groups. NAD, containing two ribose groups, (not pictured) is another ligand that is necessary in the hydrolysis of IMP in the mechanism. The green acetate ions are anions that function as ligands as as intermediate-step metabolites in the mechanism. Monocovalent cations travel through and activate IMPDH as anionic acetate ions buffer the system.

== Energy Transformation ==

IMPDH is activated by monovalent cations, such as K+ and Na+, within the triose-phosphate isomerase (TIM) barrel. The Arg325-Asn306-Asp272 catalytic triad (Arg322-Asn303-Asp274 in human type II IMPDH) works inter-dependently and synergistically in the TIM barrel active site to make the nucleophilic component, cysteine, highly reactive to form a temporary covalent bond with the substrate<ref>PMID: 8555204</ref>. Substrates bind randomly to IMPDH as the hydride transfer is quick and NAD is reduced to hydrolyze the covalent intermediate within the enzyme-substrate complex. A covalent intermediate, E-XMP*, is formed, which decreases the energy needed in later nucleophilic and covalent catalysis steps<ref>PMID: 10390600</ref>. Based on normal physiological conditions, the IMPDH mechanism is often not kinetically favorable. The Bateman domains within the TIM barrel are composed of cystathionine beta-synthase motifs that perceive metal ion concentration, cellular energy status, and ionic strength; and will allosterically regulate IMPDH activity<ref>PMID: 31416831</ref>. Eukaryotic IMPDHs have three nucleotide-binding sites in the Bateman domain that allosterically modulate catalytic activity. These three nucleotide-binding sites bind adenine/guanine dinucleoside polyphosphates, and the affinity for these sites increases for these dinucleoside polyphosphates as the activity of IMPDH increases. Purine dinucleoside polyphosphates compete with purine mononucleotides within these sites, so the Bateman domain sites make IMPDH more sensitive to inhibition<ref>PMID: 31416831</ref>. Enzyme catalysis is able to finish with the energy need reduced as the covalent bond is broken later in the reaction to regenerate the enzyme.

</StructureSection>
== References ==

<references />

Sandbox Reserved 1565

2019-12-09T05:43:39Z

Alyssa Ragner:

{{Sandbox_Reserved_BHall_Chem351_F19}}
=='''Inosine-5'-monophosphate dehydrogenase'''==
<StructureSection load='6rpu' size='340' side='right' caption='Structure of the ternary complex of the IMPDH enzyme from Ashbya gossypii bound to the dinucleoside polyphosphate Ap5G and GDP' scene=''>

== Function(s) and Biological Relevance ==

<scene name='82/823089/Cartoon_view/1'>Inosine-5'-monophosphate dehydrogenase</scene> (IMPDH) is the enzyme that catalyzes the rate-limiting step in the ''de novo'' guanine nucleotide biosynthetic pathway, converting inosine monophosphate (IMP) to xanthosine monophosphate (XMP) with the reduction of nicotinamide adenine dinucleotide (NAD). Organisms that undergo the purine nucleotide biosynthetic pathway have IMPDH, including humans. This particular form of IMPDH described and highlighted comes from the recently studied fungus ''Ashbya gossypii'' <ref>PMID: 31416831</ref>. Additional ligands of IMPDH include nicotinamide adenine dinucleotide (NAD), acetate (ACT), and guanosine-5’ monophosphate (5GP), and guanosine-5'-diphosphate (GDP). IMPDH is a regulator of the intracellular guanine nucleotide pool amount and helps control control cell division and proliferation, and therefore related to malignant transformation, tumor cell proliferation, and intracellular and extracellular pathogenic infections. Purine dinucleoside polyphosphates are found to bind to the Bateman domain of ''Ashbya gossypii'' IMPDH to allosterically regulate the catalytic activity by competing against purine mononucleotides<ref>PMID: 31416831</ref>.

== Broader Implications ==

The disease pathophysiology is extensive as the improper IMPDH regulation may lead to uncontrolled cell division and proliferation, affecting the immune system's ability to fight off pathogens and signal tumor cells to apoptose. Therapeutic studies using dinucleoside polyphosphates may allosterically regulate the inhibition of IMPDH activity. Dinucleoside polyphosphates have physiological functions including cell division, neurotransmission, apoptosis, vasoconstriction, platelet aggregation, and cellular process variety enhancement from DNA replication to repair<ref>PMID: 31416831</ref>. Selected IMPDH inhibitors composed of dinucleoside polyphosphates may be used to make IMPDHs targets for immunosuppressive, antiviral, and anticancer drugs<ref>PMID: 21517780</ref>, with antibacterial and chemotherapeutic strategies feasibile<ref>PMID: 22928911</ref>.

== Structural Highlights and Structure-Function Relationships ==

The <scene name='82/823089/Secondary_structure/1'>secondary structure</scene> shows alpha helices and beta sheets. The ''Ashbya gossypii'' IMPDH is 31% helical and 15% beta sheet, with the other percentages including random coils and residue structures. The active site is located towards the C-terminus within the TIM barrel, containing 8 alpha-helices and 8 beta sheets.

IMPDH quaternary structures include multiunit complexes, such as <scene name='82/823089/Quaternary_view/1'>tetramers</scene>, extended octamers, and compacted octamers. These quaternary structures are created through the binding of multiple subunits of <scene name='82/823089/Tertiary_structure/1'>tertiary</scene> structures (monomers), that are strengthened and structurally formed through hydrogen-bonding, cysteine-cysteine disulfide bonds, and hydrophobic interactions. Different quaternary forms of IMPDH relate to the kinetic favorability of the IMPDH mechanism as Bateman domain allosteric binding sites and competitive nature changes with unit composition.

This <scene name='82/823089/Space-filled/2'>space-filled view</scene> helps show the Van der Waals interactions and areas for movement within the structure. The ability for monovalent cations to move within the charged tunnel with the phosphate chain directly relates to activation levels. The phosphate chain relates to the ligands that further interact with the binding site to form the covalent intermediate, E-XMP*.

The <scene name='82/823089/Hydrophobicity_view/1'>hydrophobicity</scene> is within the interior of the molecule as the hydrophilic residues are able to interact in a physiological environment. The hydrophobic region of Gly361 and Gly383 interact with the main chain phosphate, further allowing monovalent cation movement. Hydrophilic regions contain amino acid residues that hydrogen-bond, some conserving tertiary structure and others relating to necessary interactions in the active site (see below).

Acetate ions, G5P, and GDP ions are <scene name='82/823089/Ligands/1'>ligands</scene> of IMPDH. NAD serves a function as a ligand as is necessary in the hydrolysis of IMP. The phosphates of the G5P, GDP, and NAD (not pictured) ligands interact through hydrogen bonds and hydrophobic interactions (depending on the amino acid residue; see active binding site below). The monocovalent cations that pass through interact with the phosphates as they activate IMPDH.

<scene name='82/823089/Catalytic_triad/1'>Catalytic Triad</scene> The IMPDH triad includes Arg (325), Asn (306), and Asp (272). This is represented by the solid purple structures in the image. This triad is important as it makes cysteine more reactive as a nucleophilic component. This conserved cysteine, Cys334, (Cys331 in human type II IMPDH) induces binding after becoming more reactive.

<scene name='82/823089/Active_site/1'>Active Binding Site</scene> The active binding site includes the Bateman domains, which are components within the TIM barrel. Binding occurs after the catalytic triad makes cysteine more reactive. The cysteines that become more reactive are shown in green in the image, and are closely related to the active binding site. Asp259 (blue) hydrogen bonds with the ribose hydroxyls of NAD (nicotinamide region), and Ser315 (blue) hydrogen bonds to the ribose phosphate through hydroxyl groups. Gly361 and Gly383 (orange) have hydrophobic interactions with the phosphate of the ligand NAD. Other important interactions include Tyr403 hydrogen bonding to ribose phosphate (NAD), and Glu402 and Glu440 hydrogen bonding with the IMP purine ring.

<scene name='82/823089/Charge_view/2'>IMPDH charge</scene> is not strong, as shown by this view. There are positive and negative components within the structure, but a relatively neutral substance is better received in this mechanism due to a physiological environment. Negatively-charged glutamic acid and positively-charged histidine within this enzyme play a role within the covalent bindings in the mechanism. Covalent binding is necessary to form the covalent intermediate after NAD is reduced (after interacting with the active site residues).

<scene name='82/823089/Composition_view/1'>IMPDH composition</scene> The dark pink RNA regions coincide with G5P and GDP ligands as they contain ribose groups. NAD, containing two ribose groups, (not pictured) is another ligand that is necessary in the hydrolysis of IMP in the mechanism. The green acetate ions are anions that function as ligands as as intermediate-step metabolites in the mechanism. Monocovalent cations travel through and activate IMPDH as anionic acetate ions buffer the system.

== Energy Transformation ==

IMPDH is activated by monovalent cations, such as K+ and Na+, within the triose-phosphate isomerase (TIM) barrel. The Arg325-Asn306-Asp272 catalytic triad (Arg322-Asn303-Asp274 in human type II IMPDH) works inter-dependently and synergistically in the TIM barrel active site to make the nucleophilic component, cysteine, highly reactive to form a temporary covalent bond with the substrate<ref>PMID: 8555204</ref>. Substrates bind randomly to IMPDH as the hydride transfer is quick and NAD is reduced to hydrolyze the covalent intermediate within the enzyme-substrate complex. A covalent intermediate, E-XMP*, is formed, which decreases the energy needed in later nucleophilic and covalent catalysis steps<ref>PMID: 10390600</ref>. Based on normal physiological conditions, the IMPDH mechanism is often not kinetically favorable. The Bateman domains within the TIM barrel are composed of cystathionine beta-synthase motifs that perceive metal ion concentration, cellular energy status, and ionic strength; and will allosterically regulate IMPDH activity<ref>PMID: 31416831</ref>. Eukaryotic IMPDHs have three nucleotide-binding sites in the Bateman domain that allosterically modulate catalytic activity. These three nucleotide-binding sites bind adenine/guanine dinucleoside polyphosphates, and the affinity for these sites increases for these dinucleoside polyphosphates as the activity of IMPDH increases. Purine dinucleoside polyphosphates compete with purine mononucleotides within these sites, so the Bateman domain sites make IMPDH more sensitive to inhibition<ref>PMID: 31416831</ref>. Enzyme catalysis is able to finish with the energy need reduced as the covalent bond is broken later in the reaction to regenerate the enzyme.

</StructureSection>
== References ==

<references />

Sandbox Reserved 1565

2019-12-09T05:40:51Z

Alyssa Ragner:

{{Sandbox_Reserved_BHall_Chem351_F19}}
=='''Inosine-5'-monophosphate dehydrogenase'''==
<StructureSection load='6rpu' size='340' side='right' caption='Structure of the ternary complex of the IMPDH enzyme from Ashbya gossypii bound to the dinucleoside polyphosphate Ap5G and GDP' scene=''>

== Function(s) and Biological Relevance ==

<scene name='82/823089/Cartoon_view/1'>Inosine-5'-monophosphate dehydrogenase</scene> (IMPDH) is the enzyme that catalyzes the rate-limiting step in the ''de novo'' guanine nucleotide biosynthetic pathway, converting inosine monophosphate (IMP) to xanthosine monophosphate (XMP) with the reduction of nicotinamide adenine dinucleotide (NAD). Organisms that undergo the purine nucleotide biosynthetic pathway have IMPDH, including humans. This particular form of IMPDH described and highlighted comes from the recently studied fungus ''Ashbya gossypii'' <ref>PMID: 31416831</ref>. Additional ligands of IMPDH include nicotinamide adenine dinucleotide (NAD), acetate (ACT), and guanosine-5’ monophosphate (5GP), and guanosine-5'-diphosphate (GDP). IMPDH is a regulator of the intracellular guanine nucleotide pool amount and helps control control cell division and proliferation, and therefore related to malignant transformation, tumor cell proliferation, and intracellular and extracellular pathogenic infections. Purine dinucleoside polyphosphates are found to bind to the Bateman domain of ''Ashbya gossypii'' IMPDH to allosterically regulate the catalytic activity by competing against purine mononucleotides<ref>PMID: 31416831</ref>.

== Broader Implications ==

The disease pathophysiology is extensive as the improper IMPDH regulation may lead to uncontrolled cell division and proliferation, affecting the immune system's ability to fight off pathogens and signal tumor cells to apoptose. Therapeutic studies using dinucleoside polyphosphates may allosterically regulate the inhibition of IMPDH activity. Dinucleoside polyphosphates have physiological functions including cell division, neurotransmission, apoptosis, vasoconstriction, platelet aggregation, and cellular process variety enhancement from DNA replication to repair<ref>PMID: 31416831</ref>. Selected IMPDH inhibitors composed of dinucleoside polyphosphates may be used to make IMPDHs targets for immunosuppressive, antiviral, and anticancer drugs<ref>PMID: 21517780</ref>, with antibacterial and chemotherapeutic strategies feasibile<ref>PMID: 22928911</ref>.

== Structural Highlights and Structure-Function Relationships ==

The <scene name='82/823089/Secondary_structure/1'>secondary structure</scene> shows alpha helices and beta sheets. The ''Ashbya gossypii'' IMPDH is 31% helical and 15% beta sheet, with the other percentages including random coils and residue structures. The active site is located towards the C-terminus within the TIM barrel, containing 8 alpha-helices and 8 beta sheets.

IMPDH quaternary structures include multiunit complexes, such as <scene name='82/823089/Quaternary_view/1'>tetramers</scene>, extended octamers, and compacted octamers. These quaternary structures are created through the binding of multiple subunits of <scene name='82/823089/Tertiary_structure/1'>tertiary</scene> structures (monomers), that are strengthened and structurally formed through hydrogen-bonding, cysteine-cysteine disulfide bonds, and hydrophobic interactions. Different quaternary forms of IMPDH relate to the kinetic favorability of the IMPDH mechanism as Bateman domain allosteric binding sites and competitive nature changes with unit composition.

This <scene name='82/823089/Space-filled/2'>space-filled view</scene> helps show the Van der Waals interactions and areas for movement within the structure. The ability for monovalent cations to move within the charged tunnel with the phosphate chain directly relates to activation levels. The phosphate chain relates to the ligands that further interact with the binding site to form the covalent intermediate, E-XMP*.

The <scene name='82/823089/Hydrophobicity_view/1'>hydrophobicity</scene> is within the interior of the molecule as the hydrophilic residues are able to interact in a physiological environment. The hydrophobic region of Gly361 and Gly383 interact with the main chain phosphate, further allowing monovalent cation movement. Hydrophilic regions contain amino acid residues that hydrogen-bond, some conserving tertiary structure and others relating to necessary interactions in the active site (see below).

Acetate ions, G5P, and GDP ions are <scene name='82/823089/Ligands/1'>ligands</scene> of IMPDH. NAD serves a function as a ligand as is necessary in the hydrolysis of IMP.

<scene name='82/823089/Catalytic_triad/1'>Catalytic Triad</scene> The IMPDH triad includes Arg (325), Asn (306), and Asp (272). This is represented by the solid purple structures in the image. This triad is important as it makes cysteine more reactive as a nucleophilic component. This conserved cysteine, Cys334, (Cys331 in human type II IMPDH) induces binding after becoming more reactive.

<scene name='82/823089/Active_site/1'>Active Binding Site</scene> The active binding site includes the Bateman domains, which are components within the TIM barrel. Binding occurs after the catalytic triad makes cysteine more reactive. The cysteines that become more reactive are shown in green in the image, and are closely related to the active binding site. Asp259 (blue) hydrogen bonds with the ribose hydroxyls of NAD (nicotinamide region), and Ser315 (blue) hydrogen bonds to the ribose phosphate through hydroxyl groups. Gly361 and Gly383 (orange) have hydrophobic interactions with the phosphate of the ligand NAD. Other important interactions include Tyr403 hydrogen bonding to ribose phosphate (NAD), and Glu402 and Glu440 hydrogen bonding with the IMP purine ring.

<scene name='82/823089/Charge_view/2'>IMPDH charge</scene> is not strong, as shown by this view. There are positive and negative components within the structure, but a relatively neutral substance is better received in this mechanism due to a physiological environment. Negatively-charged glutamic acid and positively-charged histidine within this enzyme play a role within the covalent bindings in the mechanism. Covalent binding is necessary to form the covalent intermediate after NAD is reduced (after interacting with the active site residues).

<scene name='82/823089/Composition_view/1'>IMPDH composition</scene> The dark pink RNA regions coincide with G5P and GDP ligands as they contain ribose groups. NAD, containing two ribose groups, (not pictured) is another ligand that is necessary in the hydrolysis of IMP in the mechanism. The green acetate ions are anions that function as ligands as as intermediate-step metabolites in the mechanism. Monocovalent cations travel through and activate IMPDH as anionic acetate ions buffer the system.

== Energy Transformation ==

IMPDH is activated by monovalent cations, such as K+ and Na+, within the triose-phosphate isomerase (TIM) barrel. The Arg325-Asn306-Asp272 catalytic triad (Arg322-Asn303-Asp274 in human type II IMPDH) works inter-dependently and synergistically in the TIM barrel active site to make the nucleophilic component, cysteine, highly reactive to form a temporary covalent bond with the substrate<ref>PMID: 8555204</ref>. Substrates bind randomly to IMPDH as the hydride transfer is quick and NAD is reduced to hydrolyze the covalent intermediate within the enzyme-substrate complex. A covalent intermediate, E-XMP*, is formed, which decreases the energy needed in later nucleophilic and covalent catalysis steps<ref>PMID: 10390600</ref>. Based on normal physiological conditions, the IMPDH mechanism is often not kinetically favorable. The Bateman domains within the TIM barrel are composed of cystathionine beta-synthase motifs that perceive metal ion concentration, cellular energy status, and ionic strength; and will allosterically regulate IMPDH activity<ref>PMID: 31416831</ref>. Eukaryotic IMPDHs have three nucleotide-binding sites in the Bateman domain that allosterically modulate catalytic activity. These three nucleotide-binding sites bind adenine/guanine dinucleoside polyphosphates, and the affinity for these sites increases for these dinucleoside polyphosphates as the activity of IMPDH increases. Purine dinucleoside polyphosphates compete with purine mononucleotides within these sites, so the Bateman domain sites make IMPDH more sensitive to inhibition<ref>PMID: 31416831</ref>. Enzyme catalysis is able to finish with the energy need reduced as the covalent bond is broken later in the reaction to regenerate the enzyme.

</StructureSection>
== References ==

<references />

Sandbox Reserved 1565

2019-12-09T05:39:05Z

Alyssa Ragner:

{{Sandbox_Reserved_BHall_Chem351_F19}}
=='''Inosine-5'-monophosphate dehydrogenase'''==
<StructureSection load='6rpu' size='340' side='right' caption='Structure of the ternary complex of the IMPDH enzyme from Ashbya gossypii bound to the dinucleoside polyphosphate Ap5G and GDP' scene=''>

== Function(s) and Biological Relevance ==

<scene name='82/823089/Cartoon_view/1'>Inosine-5'-monophosphate dehydrogenase</scene> (IMPDH) is the enzyme that catalyzes the rate-limiting step in the ''de novo'' guanine nucleotide biosynthetic pathway, converting inosine monophosphate (IMP) to xanthosine monophosphate (XMP) with the reduction of nicotinamide adenine dinucleotide (NAD). Organisms that undergo the purine nucleotide biosynthetic pathway have IMPDH, including humans. This particular form of IMPDH described and highlighted comes from the recently studied fungus ''Ashbya gossypii'' <ref>PMID: 31416831</ref>. Additional ligands of IMPDH include nicotinamide adenine dinucleotide (NAD), acetate (ACT), and guanosine-5’ monophosphate (5GP), and guanosine-5'-diphosphate (GDP). IMPDH is a regulator of the intracellular guanine nucleotide pool amount and helps control control cell division and proliferation, and therefore related to malignant transformation, tumor cell proliferation, and intracellular and extracellular pathogenic infections. Purine dinucleoside polyphosphates are found to bind to the Bateman domain of ''Ashbya gossypii'' IMPDH to allosterically regulate the catalytic activity by competing against purine mononucleotides<ref>PMID: 31416831</ref>.

== Broader Implications ==

The disease pathophysiology is extensive as the improper IMPDH regulation may lead to uncontrolled cell division and proliferation, affecting the immune system's ability to fight off pathogens and signal tumor cells to apoptose. Therapeutic studies using dinucleoside polyphosphates may allosterically regulate the inhibition of IMPDH activity. Dinucleoside polyphosphates have physiological functions including cell division, neurotransmission, apoptosis, vasoconstriction, platelet aggregation, and cellular process variety enhancement from DNA replication to repair<ref>PMID: 31416831</ref>. Selected IMPDH inhibitors composed of dinucleoside polyphosphates may be used to make IMPDHs targets for immunosuppressive, antiviral, and anticancer drugs<ref>PMID: 21517780</ref>, with antibacterial and chemotherapeutic strategies feasibile<ref>PMID: 22928911</ref>.

== Structural Highlights and Structure-Function Relationships ==

The <scene name='82/823089/Secondary_structure/1'>secondary structure</scene> shows alpha helices and beta sheets. The ''Ashbya gossypii'' IMPDH is 31% helical and 15% beta sheet, with the other percentages including random coils and residue structures. The active site is located towards the C-terminus within the TIM barrel, containing 8 alpha-helices and 8 beta sheets.

IMPDH quaternary structures include multiunit complexes, such as <scene name='82/823089/Quaternary_view/1'>tetramers</scene>, extended octamers, and compacted octamers. These quaternary structures are created through the binding of multiple subunits of <scene name='82/823089/Tertiary_structure/1'>tertiary</scene> structures (monomers), that are strengthened and structurally formed through hydrogen-bonding, cysteine-cysteine disulfide bonds, and hydrophobic interactions. Different quaternary forms of IMPDH relate to the kinetic favorability of the IMPDH mechanism as Bateman domain allosteric binding sites and competitive nature changes with unit composition.

This <scene name='82/823089/Space-filled/2'>space-filled view</scene> helps show the Van der Waals interactions and areas for movement within the structure. The ability for monovalent cations to move within the charged tunnel with the phosphate chain directly relates to activation levels. The phosphate chain relates to the ligands that further interact with the binding site to form the covalent intermediate, E-XMP*.

The <scene name='82/823089/Hydrophobicity_view/1'>hydrophobicity</scene> is within the interior of the molecule as the hydrophilic residues are able to interact in a physiological environment. The hydrophobic region of Gly361 and Gly383 interact with the main chain phosphate, further allowing monovalent cation movement. Hydrophilic regions contain amino acid residues that hydrogen-bond, some conserving tertiary structure and others relating to necessary interactions in the active site (see below).

<scene name='82/823089/Ligands/1'>Ligand View</scene> In this view the black structures are the ACT molecules. These are the ligands of the IMPDH protein. Other ligands include G5P and GDP.

<scene name='82/823089/Catalytic_triad/1'>Catalytic Triad</scene> The IMPDH triad includes Arg (325), Asn (306), and Asp (272). This is represented by the solid purple structures in the image. This triad is important as it makes cysteine more reactive as a nucleophilic component. This conserved cysteine, Cys334, (Cys331 in human type II IMPDH) induces binding after becoming more reactive.

<scene name='82/823089/Active_site/1'>Active Binding Site</scene> The active binding site includes the Bateman domains, which are components within the TIM barrel. Binding occurs after the catalytic triad makes cysteine more reactive. The cysteines that become more reactive are shown in green in the image, and are closely related to the active binding site. Asp259 (blue) hydrogen bonds with the ribose hydroxyls of NAD (nicotinamide region), and Ser315 (blue) hydrogen bonds to the ribose phosphate through hydroxyl groups. Gly361 and Gly383 (orange) have hydrophobic interactions with the phosphate of the ligand NAD. Other important interactions include Tyr403 hydrogen bonding to ribose phosphate (NAD), and Glu402 and Glu440 hydrogen bonding with the IMP purine ring.

<scene name='82/823089/Charge_view/2'>IMPDH charge</scene> is not strong, as shown by this view. There are positive and negative components within the structure, but a relatively neutral substance is better received in this mechanism due to a physiological environment. Negatively-charged glutamic acid and positively-charged histidine within this enzyme play a role within the covalent bindings in the mechanism. Covalent binding is necessary to form the covalent intermediate after NAD is reduced (after interacting with the active site residues).

<scene name='82/823089/Composition_view/1'>IMPDH composition</scene> The dark pink RNA regions coincide with G5P and GDP ligands as they contain ribose groups. NAD, containing two ribose groups, (not pictured) is another ligand that is necessary in the hydrolysis of IMP in the mechanism. The green acetate ions are anions that function as ligands as as intermediate-step metabolites in the mechanism. Monocovalent cations travel through and activate IMPDH as anionic acetate ions buffer the system.

== Energy Transformation ==

IMPDH is activated by monovalent cations, such as K+ and Na+, within the triose-phosphate isomerase (TIM) barrel. The Arg325-Asn306-Asp272 catalytic triad (Arg322-Asn303-Asp274 in human type II IMPDH) works inter-dependently and synergistically in the TIM barrel active site to make the nucleophilic component, cysteine, highly reactive to form a temporary covalent bond with the substrate<ref>PMID: 8555204</ref>. Substrates bind randomly to IMPDH as the hydride transfer is quick and NAD is reduced to hydrolyze the covalent intermediate within the enzyme-substrate complex. A covalent intermediate, E-XMP*, is formed, which decreases the energy needed in later nucleophilic and covalent catalysis steps<ref>PMID: 10390600</ref>. Based on normal physiological conditions, the IMPDH mechanism is often not kinetically favorable. The Bateman domains within the TIM barrel are composed of cystathionine beta-synthase motifs that perceive metal ion concentration, cellular energy status, and ionic strength; and will allosterically regulate IMPDH activity<ref>PMID: 31416831</ref>. Eukaryotic IMPDHs have three nucleotide-binding sites in the Bateman domain that allosterically modulate catalytic activity. These three nucleotide-binding sites bind adenine/guanine dinucleoside polyphosphates, and the affinity for these sites increases for these dinucleoside polyphosphates as the activity of IMPDH increases. Purine dinucleoside polyphosphates compete with purine mononucleotides within these sites, so the Bateman domain sites make IMPDH more sensitive to inhibition<ref>PMID: 31416831</ref>. Enzyme catalysis is able to finish with the energy need reduced as the covalent bond is broken later in the reaction to regenerate the enzyme.

</StructureSection>
== References ==

<references />

Sandbox Reserved 1565

2019-12-09T05:37:28Z

Alyssa Ragner:

{{Sandbox_Reserved_BHall_Chem351_F19}}
=='''Inosine-5'-monophosphate dehydrogenase'''==
<StructureSection load='6rpu' size='340' side='right' caption='Structure of the ternary complex of the IMPDH enzyme from Ashbya gossypii bound to the dinucleoside polyphosphate Ap5G and GDP' scene=''>

== Function(s) and Biological Relevance ==

<scene name='82/823089/Cartoon_view/1'>Inosine-5'-monophosphate dehydrogenase</scene> (IMPDH) is the enzyme that catalyzes the rate-limiting step in the ''de novo'' guanine nucleotide biosynthetic pathway, converting inosine monophosphate (IMP) to xanthosine monophosphate (XMP) with the reduction of nicotinamide adenine dinucleotide (NAD). Organisms that undergo the purine nucleotide biosynthetic pathway have IMPDH, including humans. This particular form of IMPDH described and highlighted comes from the recently studied fungus ''Ashbya gossypii'' <ref>PMID: 31416831</ref>. Additional ligands of IMPDH include nicotinamide adenine dinucleotide (NAD), acetate (ACT), and guanosine-5’ monophosphate (5GP), and guanosine-5'-diphosphate (GDP). IMPDH is a regulator of the intracellular guanine nucleotide pool amount and helps control control cell division and proliferation, and therefore related to malignant transformation, tumor cell proliferation, and intracellular and extracellular pathogenic infections. Purine dinucleoside polyphosphates are found to bind to the Bateman domain of ''Ashbya gossypii'' IMPDH to allosterically regulate the catalytic activity by competing against purine mononucleotides<ref>PMID: 31416831</ref>.

== Broader Implications ==

The disease pathophysiology is extensive as the improper IMPDH regulation may lead to uncontrolled cell division and proliferation, affecting the immune system's ability to fight off pathogens and signal tumor cells to apoptose. Therapeutic studies using dinucleoside polyphosphates may allosterically regulate the inhibition of IMPDH activity. Dinucleoside polyphosphates have physiological functions including cell division, neurotransmission, apoptosis, vasoconstriction, platelet aggregation, and cellular process variety enhancement from DNA replication to repair<ref>PMID: 31416831</ref>. Selected IMPDH inhibitors composed of dinucleoside polyphosphates may be used to make IMPDHs targets for immunosuppressive, antiviral, and anticancer drugs<ref>PMID: 21517780</ref>, with antibacterial and chemotherapeutic strategies feasibile<ref>PMID: 22928911</ref>.

== Structural Highlights and Structure-Function Relationships ==

The <scene name='82/823089/Secondary_structure/1'>secondary structure</scene> shows alpha helices and beta sheets. The ''Ashbya gossypii'' IMPDH is 31% helical and 15% beta sheet, with the other percentages including random coils and residue structures. The active site is located towards the C-terminus within the TIM barrel, containing 8 alpha-helices and 8 beta sheets.

IMPDH quaternary structures include multiunit complexes, such as <scene name='82/823089/Quaternary_view/1'>tetramers</scene>, extended octamers, and compacted octamers. These quaternary structures are created through the binding of multiple subunits of <scene name='82/823089/Tertiary_structure/1'>tertiary</scene> structures, that are strengthened and structurally formed through hydrogen-bonding, Cysteine-Cysteine disulfide bonds, and hydrophobic interactions. Different quaternary forms of IMPDH relate to the kinetic favorability of the IMPDH mechanism as Bateman domain allosteric binding sites and competitive nature changes with unit composition.

This <scene name='82/823089/Space-filled/2'>space-filled view</scene> helps show the Van der Waals interactions and areas for movement within the structure. The ability for monovalent cations to move within the charged tunnel with the phosphate chain directly relates to activation levels. The phosphate chain relates to the ligands that further interact with the binding site to form the covalent intermediate, E-XMP*.

<scene name='82/823089/Hydrophobicity_view/1'>Hydrophobicity view</scene> Purple represents polar molecules and gray represents hydrophobic molecules. The hydrophobicity is within the interior of the molecule as the hydrophilic residues are able to interact in a physiological environment. The hydrophobic region of Gly361 and Gly383 interact with the main chain phosphate, further allowing monovalent cation movement. Hydrophilic regions contain amino acid residues that hydrogen-bond, some conserving tertiary structure and others relating to necessary interactions in the active site (see below).

<scene name='82/823089/Ligands/1'>Ligand View</scene> In this view the black structures are the ACT molecules. These are the ligands of the IMPDH protein. Other ligands include G5P and GDP.

<scene name='82/823089/Catalytic_triad/1'>Catalytic Triad</scene> The IMPDH triad includes Arg (325), Asn (306), and Asp (272). This is represented by the solid purple structures in the image. This triad is important as it makes cysteine more reactive as a nucleophilic component. This conserved cysteine, Cys334, (Cys331 in human type II IMPDH) induces binding after becoming more reactive.

<scene name='82/823089/Active_site/1'>Active Binding Site</scene> The active binding site includes the Bateman domains, which are components within the TIM barrel. Binding occurs after the catalytic triad makes cysteine more reactive. The cysteines that become more reactive are shown in green in the image, and are closely related to the active binding site. Asp259 (blue) hydrogen bonds with the ribose hydroxyls of NAD (nicotinamide region), and Ser315 (blue) hydrogen bonds to the ribose phosphate through hydroxyl groups. Gly361 and Gly383 (orange) have hydrophobic interactions with the phosphate of the ligand NAD. Other important interactions include Tyr403 hydrogen bonding to ribose phosphate (NAD), and Glu402 and Glu440 hydrogen bonding with the IMP purine ring.

<scene name='82/823089/Charge_view/2'>IMPDH charge</scene> is not strong, as shown by this view. There are positive and negative components within the structure, but a relatively neutral substance is better received in this mechanism due to a physiological environment. Negatively-charged glutamic acid and positively-charged histidine within this enzyme play a role within the covalent bindings in the mechanism. Covalent binding is necessary to form the covalent intermediate after NAD is reduced (after interacting with the active site residues).

<scene name='82/823089/Composition_view/1'>IMPDH composition</scene> The dark pink RNA regions coincide with G5P and GDP ligands as they contain ribose groups. NAD, containing two ribose groups, (not pictured) is another ligand that is necessary in the hydrolysis of IMP in the mechanism. The green acetate ions are anions that function as ligands as as intermediate-step metabolites in the mechanism. Monocovalent cations travel through and activate IMPDH as anionic acetate ions buffer the system.

== Energy Transformation ==

IMPDH is activated by monovalent cations, such as K+ and Na+, within the triose-phosphate isomerase (TIM) barrel. The Arg325-Asn306-Asp272 catalytic triad (Arg322-Asn303-Asp274 in human type II IMPDH) works inter-dependently and synergistically in the TIM barrel active site to make the nucleophilic component, cysteine, highly reactive to form a temporary covalent bond with the substrate<ref>PMID: 8555204</ref>. Substrates bind randomly to IMPDH as the hydride transfer is quick and NAD is reduced to hydrolyze the covalent intermediate within the enzyme-substrate complex. A covalent intermediate, E-XMP*, is formed, which decreases the energy needed in later nucleophilic and covalent catalysis steps<ref>PMID: 10390600</ref>. Based on normal physiological conditions, the IMPDH mechanism is often not kinetically favorable. The Bateman domains within the TIM barrel are composed of cystathionine beta-synthase motifs that perceive metal ion concentration, cellular energy status, and ionic strength; and will allosterically regulate IMPDH activity<ref>PMID: 31416831</ref>. Eukaryotic IMPDHs have three nucleotide-binding sites in the Bateman domain that allosterically modulate catalytic activity. These three nucleotide-binding sites bind adenine/guanine dinucleoside polyphosphates, and the affinity for these sites increases for these dinucleoside polyphosphates as the activity of IMPDH increases. Purine dinucleoside polyphosphates compete with purine mononucleotides within these sites, so the Bateman domain sites make IMPDH more sensitive to inhibition<ref>PMID: 31416831</ref>. Enzyme catalysis is able to finish with the energy need reduced as the covalent bond is broken later in the reaction to regenerate the enzyme.

</StructureSection>
== References ==

<references />

Sandbox Reserved 1565

2019-12-09T05:36:07Z

Alyssa Ragner:

{{Sandbox_Reserved_BHall_Chem351_F19}}
=='''Inosine-5'-monophosphate dehydrogenase'''==
<StructureSection load='6rpu' size='340' side='right' caption='Structure of the ternary complex of the IMPDH enzyme from Ashbya gossypii bound to the dinucleoside polyphosphate Ap5G and GDP' scene=''>

== Function(s) and Biological Relevance ==

<scene name='82/823089/Cartoon_view/1'>Inosine-5'-monophosphate dehydrogenase</scene> (IMPDH) is the enzyme that catalyzes the rate-limiting step in the ''de novo'' guanine nucleotide biosynthetic pathway, converting inosine monophosphate (IMP) to xanthosine monophosphate (XMP) with the reduction of nicotinamide adenine dinucleotide (NAD). Organisms that undergo the purine nucleotide biosynthetic pathway have IMPDH, including humans. This particular form of IMPDH described and highlighted comes from the recently studied fungus ''Ashbya gossypii'' <ref>PMID: 31416831</ref>. Additional ligands of IMPDH include nicotinamide adenine dinucleotide (NAD), acetate (ACT), and guanosine-5’ monophosphate (5GP), and guanosine-5'-diphosphate (GDP). IMPDH is a regulator of the intracellular guanine nucleotide pool amount and helps control control cell division and proliferation, and therefore related to malignant transformation, tumor cell proliferation, and intracellular and extracellular pathogenic infections. Purine dinucleoside polyphosphates are found to bind to the Bateman domain of ''Ashbya gossypii'' IMPDH to allosterically regulate the catalytic activity by competing against purine mononucleotides<ref>PMID: 31416831</ref>.

== Broader Implications ==

The disease pathophysiology is extensive as the improper IMPDH regulation may lead to uncontrolled cell division and proliferation, affecting the immune system's ability to fight off pathogens and signal tumor cells to apoptose. Therapeutic studies using dinucleoside polyphosphates may allosterically regulate the inhibition of IMPDH activity. Dinucleoside polyphosphates have physiological functions including cell division, neurotransmission, apoptosis, vasoconstriction, platelet aggregation, and cellular process variety enhancement from DNA replication to repair<ref>PMID: 31416831</ref>. Selected IMPDH inhibitors composed of dinucleoside polyphosphates may be used to make IMPDHs targets for immunosuppressive, antiviral, and anticancer drugs<ref>PMID: 21517780</ref>, with antibacterial and chemotherapeutic strategies feasibile<ref>PMID: 22928911</ref>.

== Structural Highlights and Structure-Function Relationships ==

The <scene name='82/823089/Secondary_structure/1'>secondary structure</scene> shows alpha helices and beta sheets. The ''Ashbya gossypii'' IMPDH is 31% helical and 15% beta sheet, with the other percentages including random coils and residue structures. The active site is located towards the C-terminus within the TIM barrel, containing 8 alpha-helices and 8 beta sheets.

IMPDH quaternary structures include multiunit complexes, such as <scene name='82/823089/Quaternary_view/1'>tetramers</scene>, extended octamers, and compacted octamers. These quaternary structures are created through the binding of multiple subunits of <scene name='82/823089/Tertiary_structure/1'>tertiary</scene> structures, that are strengthened and structurally formed through hydrogen-bonding, Cysteine-Cysteine disulfide bonds, and hydrophobic interactions. Different quaternary forms of IMPDH relate to the kinetic favorability of the IMPDH mechanism as Bateman domain allosteric binding sites and competitive nature changes with unit composition.

This <scene name='82/823089/Space-filled/2'>space-filled view</scene> helps show the Van der Waals interactions and areas for movement within the structure. The ability for monovalent cations to move within the charged tunnel with the phosphate chain directly relates to activation levels. The phosphate chain relates to the ligands that further interact with the binding site to form the covalent intermediate, E-XMP*.

<scene name='82/823089/Hydrophobicity_view/1'>Hydrophobicity view</scene> Purple represents polar molecules and gray represents hydrophobic molecules. The hydrophobicity is within the interior of the molecule as the hydrophilic residues are able to interact in a physiological environment. The hydrophobic region of Gly361 and Gly383 interact with the main chain phosphate, further allowing monovalent cation movement. Hydrophilic regions contain amino acid residues that hydrogen-bond, some conserving tertiary structure and others relating to necessary interactions in the active site (see below).

<scene name='82/823089/Ligands/1'>Ligand View</scene> In this view the black structures are the ACT molecules. These are the ligands of the IMPDH protein. Other ligands include G5P and GDP.

<scene name='82/823089/Catalytic_triad/1'>Catalytic Triad</scene> The IMPDH triad includes Arg (325), Asn (306), and Asp (272). This is represented by the solid purple structures in the image. This triad is important as it makes cysteine more reactive as a nucleophilic component. This conserved cysteine (Cys331 in human type II IMPDH) induces binding after becoming more reactive.

<scene name='82/823089/Active_site/1'>Active Binding Site</scene> The active binding site includes the Bateman domains, which are components within the TIM barrel. Binding occurs after the catalytic triad makes cysteine more reactive. The cysteines that become more reactive are shown in green in the image, and are closely related to the active binding site. Asp259 (blue) hydrogen bonds with the ribose hydroxyls of NAD (nicotinamide region), and Ser315 (blue) hydrogen bonds to the ribose phosphate through hydroxyl groups. Gly361 and Gly383 (orange) have hydrophobic interactions with the phosphate of the ligand NAD. Other important interactions include Tyr403 hydrogen bonding to ribose phosphate (NAD), and Glu402 and Glu440 hydrogen bonding with the IMP purine ring.

<scene name='82/823089/Charge_view/2'>IMPDH charge</scene> is not strong, as shown by this view. There are positive and negative components within the structure, but a relatively neutral substance is better received in this mechanism due to a physiological environment. Negatively-charged glutamic acid and positively-charged histidine within this enzyme play a role within the covalent bindings in the mechanism. Covalent binding is necessary to form the covalent intermediate after NAD is reduced (after interacting with the active site residues).

<scene name='82/823089/Composition_view/1'>IMPDH composition</scene> The dark pink RNA regions coincide with G5P and GDP ligands as they contain ribose groups. NAD, containing two ribose groups, (not pictured) is another ligand that is necessary in the hydrolysis of IMP in the mechanism. The green acetate ions are anions that function as ligands as as intermediate-step metabolites in the mechanism. Monocovalent cations travel through and activate IMPDH as anionic acetate ions buffer the system.

== Energy Transformation ==

IMPDH is activated by monovalent cations, such as K+ and Na+, within the triose-phosphate isomerase (TIM) barrel. The Arg325-Asn306-Asp272 catalytic triad (Arg322-Asn303-Asp274 in human type II IMPDH) works inter-dependently and synergistically in the TIM barrel active site to make the nucleophilic component, cysteine, highly reactive to form a temporary covalent bond with the substrate<ref>PMID: 8555204</ref>. Substrates bind randomly to IMPDH as the hydride transfer is quick and NAD is reduced to hydrolyze the covalent intermediate within the enzyme-substrate complex. A covalent intermediate, E-XMP*, is formed, which decreases the energy needed in later nucleophilic and covalent catalysis steps<ref>PMID: 10390600</ref>. Based on normal physiological conditions, the IMPDH mechanism is often not kinetically favorable. The Bateman domains within the TIM barrel are composed of cystathionine beta-synthase motifs that perceive metal ion concentration, cellular energy status, and ionic strength; and will allosterically regulate IMPDH activity<ref>PMID: 31416831</ref>. Eukaryotic IMPDHs have three nucleotide-binding sites in the Bateman domain that allosterically modulate catalytic activity. These three nucleotide-binding sites bind adenine/guanine dinucleoside polyphosphates, and the affinity for these sites increases for these dinucleoside polyphosphates as the activity of IMPDH increases. Purine dinucleoside polyphosphates compete with purine mononucleotides within these sites, so the Bateman domain sites make IMPDH more sensitive to inhibition<ref>PMID: 31416831</ref>. Enzyme catalysis is able to finish with the energy need reduced as the covalent bond is broken later in the reaction to regenerate the enzyme.

</StructureSection>
== References ==

<references />

Sandbox Reserved 1565

2019-12-09T05:34:14Z

Alyssa Ragner:

{{Sandbox_Reserved_BHall_Chem351_F19}}
=='''Inosine-5'-monophosphate dehydrogenase'''==
<StructureSection load='6rpu' size='340' side='right' caption='Structure of the ternary complex of the IMPDH enzyme from Ashbya gossypii bound to the dinucleoside polyphosphate Ap5G and GDP' scene=''>

== Function(s) and Biological Relevance ==

<scene name='82/823089/Cartoon_view/1'>Inosine-5'-monophosphate dehydrogenase</scene> (IMPDH) is the enzyme that catalyzes the rate-limiting step in the ''de novo'' guanine nucleotide biosynthetic pathway, converting inosine monophosphate (IMP) to xanthosine monophosphate (XMP) with the reduction of nicotinamide adenine dinucleotide (NAD). Organisms that undergo the purine nucleotide biosynthetic pathway have IMPDH, including humans. This particular form of IMPDH described and highlighted comes from the recently studied fungus ''Ashbya gossypii'' <ref>PMID: 31416831</ref>. Additional ligands of IMPDH include nicotinamide adenine dinucleotide (NAD), acetate (ACT), and guanosine-5’ monophosphate (5GP), and guanosine-5'-diphosphate (GDP). IMPDH is a regulator of the intracellular guanine nucleotide pool amount and helps control control cell division and proliferation, and therefore related to malignant transformation, tumor cell proliferation, and intracellular and extracellular pathogenic infections. Purine dinucleoside polyphosphates are found to bind to the Bateman domain of ''Ashbya gossypii'' IMPDH to allosterically regulate the catalytic activity by competing against purine mononucleotides<ref>PMID: 31416831</ref>.

== Broader Implications ==

The disease pathophysiology is extensive as the improper IMPDH regulation may lead to uncontrolled cell division and proliferation, affecting the immune system's ability to fight off pathogens and signal tumor cells to apoptose. Therapeutic studies using dinucleoside polyphosphates may allosterically regulate the inhibition of IMPDH activity. Dinucleoside polyphosphates have physiological functions including cell division, neurotransmission, apoptosis, vasoconstriction, platelet aggregation, and cellular process variety enhancement from DNA replication to repair<ref>PMID: 31416831</ref>. Selected IMPDH inhibitors composed of dinucleoside polyphosphates may be used to make IMPDHs targets for immunosuppressive, antiviral, and anticancer drugs<ref>PMID: 21517780</ref>, with antibacterial and chemotherapeutic strategies feasibile<ref>PMID: 22928911</ref>.

== Structural Highlights and Structure-Function Relationships ==

The <scene name='82/823089/Secondary_structure/1'>secondary structure</scene> shows alpha helices and beta sheets. The ''Ashbya gossypii'' IMPDH is 31% helical and 15% beta sheet, with the other percentages including random coils and residue structures. The active site is located towards the C-terminus within the TIM barrel, containing 8 alpha-helices and 8 beta sheets.

IMPDH quaternary structures include multiunit complexes, such as <scene name='82/823089/Quaternary_view/1'>tetramers</scene>, extended octamers, and compacted octamers. These quaternary structures are created through the binding of multiple subunits of <scene name='82/823089/Tertiary_structure/1'>tertiary</scene> structures, that are strengthened and structurally formed through hydrogen-bonding, Cysteine-Cysteine disulfide bonds, and hydrophobic interactions. Different quaternary forms of IMPDH relate to the kinetic favorability of the IMPDH mechanism as Bateman domain allosteric binding sites and competitive nature changes with unit composition.

This <scene name='82/823089/Space-filled/2'>space-filled view</scene> helps show the Van der Waals interactions and areas for movement within the structure. The ability for monovalent cations to move within the charged tunnel with the phosphate chain directly relates to activation levels. The phosphate chain relates to the ligands that further interact with the binding site to form the covalent intermediate, E-XMP*.

<scene name='82/823089/Hydrophobicity_view/1'>Hydrophobicity view</scene> Purple represents polar molecules and gray represents hydrophobic molecules. The hydrophobicity is within the interior of the molecule as the hydrophilic residues are able to interact in a physiological environment. The hydrophobic region of Gly361 and Gly383 interact with the main chain phosphate, further allowing monovalent cation movement. Hydrophilic regions contain amino acid residues that hydrogen-bond, some conserving tertiary structure and others relating to necessary interactions in the active site (see below).

<scene name='82/823089/Ligands/1'>Ligand View</scene> In this view the black structures are the ACT molecules. These are the ligands of the IMPDH protein. Other ligands include G5P and GDP.

<scene name='82/823089/Catalytic_triad/1'>Catalytic Triad</scene> The IMPDH triad includes Arg (325), Asn (306), and Asp (272). This is represented by the solid purple structures in the image. This triad is important as it makes cysteine more reactive as a nucleophilic component. This conserved cysteine (Cys331 in human type II IMPDH) induces binding after becoming more reactive.

<scene name='82/823089/Active_site/1'>Active Binding Site</scene> The active binding site includes the Bateman domains, which are components within the TIM barrel. Binding occurs after the catalytic triad makes cysteine more reactive. The cysteines that become more reactive are shown in green in the image, and are closely related to the active binding site. Asp259 (blue) hydrogen bonds with the ribose hydroxyls of NAD (nicotinamide region), and Ser315 (blue) hydrogen bonds to the ribose phosphate through hydroxyl groups. Gly361 and Gly383 (orange) have hydrophobic interactions with the phosphate of the ligand NAD. Other important interactions include Tyr403 hydrogen bonding to ribose phosphate (NAD), and Glu402 and Glu440 hydrogen bonding with the IMP purine ring.

<scene name='82/823089/Charge_view/2'>IMPDH charge</scene> is not strong, as shown by this view. There are positive and negative components within the structure, but a relatively neutral substance is better received in this mechanism due to a physiological environment. Negatively-charged glutamic acid and positively-charged histidine within this enzyme play a role within the covalent bindings in the mechanism. Covalent binding is necessary to form the covalent intermediate after NAD is reduced (after interacting with the active site residues).

<scene name='82/823089/Composition_view/1'>IMPDH composition</scene> The dark pink RNA regions coincide with G5P and GDP ligands as they contain ribose groups. NAD, containing two ribose groups, (not pictured) is another ligand that is necessary in the hydrolysis of IMP in the mechanism. The green acetate ions are anions that function as ligands as as intermediate-step metabolites in the mechanism.

== Energy Transformation ==

IMPDH is activated by monovalent cations, such as K+ and Na+, within the triose-phosphate isomerase (TIM) barrel. The Arg325-Asn306-Asp272 catalytic triad (Arg322-Asn303-Asp274 in human type II IMPDH) works inter-dependently and synergistically in the TIM barrel active site to make the nucleophilic component, cysteine, highly reactive to form a temporary covalent bond with the substrate<ref>PMID: 8555204</ref>. Substrates bind randomly to IMPDH as the hydride transfer is quick and NAD is reduced to hydrolyze the covalent intermediate within the enzyme-substrate complex. A covalent intermediate, E-XMP*, is formed, which decreases the energy needed in later nucleophilic and covalent catalysis steps<ref>PMID: 10390600</ref>. Based on normal physiological conditions, the IMPDH mechanism is often not kinetically favorable. The Bateman domains within the TIM barrel are composed of cystathionine beta-synthase motifs that perceive metal ion concentration, cellular energy status, and ionic strength; and will allosterically regulate IMPDH activity<ref>PMID: 31416831</ref>. Eukaryotic IMPDHs have three nucleotide-binding sites in the Bateman domain that allosterically modulate catalytic activity. These three nucleotide-binding sites bind adenine/guanine dinucleoside polyphosphates, and the affinity for these sites increases for these dinucleoside polyphosphates as the activity of IMPDH increases. Purine dinucleoside polyphosphates compete with purine mononucleotides within these sites, so the Bateman domain sites make IMPDH more sensitive to inhibition<ref>PMID: 31416831</ref>. Enzyme catalysis is able to finish with the energy need reduced as the covalent bond is broken later in the reaction to regenerate the enzyme.

</StructureSection>
== References ==

<references />

Sandbox Reserved 1565

2019-12-09T05:28:39Z

Alyssa Ragner:

{{Sandbox_Reserved_BHall_Chem351_F19}}
=='''Inosine-5'-monophosphate dehydrogenase'''==
<StructureSection load='6rpu' size='340' side='right' caption='Structure of the ternary complex of the IMPDH enzyme from Ashbya gossypii bound to the dinucleoside polyphosphate Ap5G and GDP' scene=''>

== Function(s) and Biological Relevance ==

<scene name='82/823089/Cartoon_view/1'>Inosine-5'-monophosphate dehydrogenase</scene> (IMPDH) is the enzyme that catalyzes the rate-limiting step in the ''de novo'' guanine nucleotide biosynthetic pathway, converting inosine monophosphate (IMP) to xanthosine monophosphate (XMP) with the reduction of nicotinamide adenine dinucleotide (NAD). Organisms that undergo the purine nucleotide biosynthetic pathway have IMPDH, including humans. This particular form of IMPDH described and highlighted comes from the recently studied fungus ''Ashbya gossypii'' <ref>PMID: 31416831</ref>. Additional ligands of IMPDH include nicotinamide adenine dinucleotide (NAD), acetate (ACT), and guanosine-5’ monophosphate (5GP), and guanosine-5'-diphosphate (GDP). IMPDH is a regulator of the intracellular guanine nucleotide pool amount and helps control control cell division and proliferation, and therefore related to malignant transformation, tumor cell proliferation, and intracellular and extracellular pathogenic infections. Purine dinucleoside polyphosphates are found to bind to the Bateman domain of ''Ashbya gossypii'' IMPDH to allosterically regulate the catalytic activity by competing against purine mononucleotides<ref>PMID: 31416831</ref>.

== Broader Implications ==

The disease pathophysiology is extensive as the improper IMPDH regulation may lead to uncontrolled cell division and proliferation, affecting the immune system's ability to fight off pathogens and signal tumor cells to apoptose. Therapeutic studies using dinucleoside polyphosphates may allosterically regulate the inhibition of IMPDH activity. Dinucleoside polyphosphates have physiological functions including cell division, neurotransmission, apoptosis, vasoconstriction, platelet aggregation, and cellular process variety enhancement from DNA replication to repair<ref>PMID: 31416831</ref>. Selected IMPDH inhibitors composed of dinucleoside polyphosphates may be used to make IMPDHs targets for immunosuppressive, antiviral, and anticancer drugs<ref>PMID: 21517780</ref>, with antibacterial and chemotherapeutic strategies feasibile<ref>PMID: 22928911</ref>.

== Structural Highlights and Structure-Function Relationships ==

The <scene name='82/823089/Secondary_structure/1'>secondary structure</scene> shows alpha helices and beta sheets. The ''Ashbya gossypii'' IMPDH is 31% helical and 15% beta sheet, with the other percentages including random coils and residue structures. The active site is located towards the C-terminus within the TIM barrel, containing 8 alpha-helices and 8 beta sheets.

IMPDH quaternary structures include multiunit complexes, such as <scene name='82/823089/Quaternary_view/1'>tetramers</scene>, extended octamers, and compacted octamers. These quaternary structures are created through the binding of multiple subunits of <scene name='82/823089/Tertiary_structure/1'>tertiary</scene> structures, that are strengthened and structurally formed through hydrogen-bonding, Cysteine-Cysteine disulfide bonds, and hydrophobic interactions. Different quaternary forms of IMPDH relate to the kinetic favorability of the IMPDH mechanism as Bateman domain allosteric binding sites and competitive nature changes with unit composition.

This <scene name='82/823089/Space-filled/2'>space-filled view</scene> helps show the Van der Waals interactions and areas for movement within the structure. The ability for monovalent cations to move within the charged tunnel with the phosphate chain directly relates to activation levels. The phosphate chain relates to the ligands that further interact with the binding site to form the covalent intermediate, E-XMP*.

<scene name='82/823089/Hydrophobicity_view/1'>Hydrophobicity view</scene> Purple represents polar molecules and gray represents hydrophobic molecules. The hydrophobicity is within the interior of the molecule as the hydrophilic residues are able to interact in a physiological environment. The hydrophobic region of Gly361 and Gly383 interact with the main chain phosphate, further allowing monovalent cation movement. Hydrophilic regions contain amino acid residues that hydrogen-bond, some conserving tertiary structure and others relating to necessary interactions in the active site (see below).

<scene name='82/823089/Ligands/1'>Ligand View</scene> In this view the black structures are the ACT molecules. These are the ligands of the IMPDH protein. Other ligands include G5P and GDP.

<scene name='82/823089/Catalytic_triad/1'>Catalytic Triad</scene> The IMPDH triad includes Arg (325), Asn (306), and Asp (272). This is represented by the solid purple structures in the image. This triad is important as it makes cysteine more reactive as a nucleophilic component. This conserved cysteine (Cys331 in human type II IMPDH) induces binding after becoming more reactive.

<scene name='82/823089/Active_site/1'>Active Binding Site</scene> The active binding site includes the Bateman domains, which are components within the TIM barrel. Binding occurs after the catalytic triad makes cysteine more reactive. The cysteines that become more reactive are shown in green in the image, and are closely related to the active binding site. Asp259 (blue) hydrogen bonds with the ribose hydroxyls of NAD (nicotinamide region), and Ser315 (blue) hydrogen bonds to the ribose phosphate through hydroxyl groups. Gly361 and Gly383 (orange) have hydrophobic interactions with the phosphate of the ligand NAD. Other important interactions include Tyr403 hydrogen bonding to ribose phosphate (NAD), and Glu402 and Glu440 hydrogen bonding with the IMP purine ring.

<scene name='82/823089/Charge_view/2'>IMPDH charge</scene> is not strong, as shown by this view. There are positive and negative components within the structure, but a relatively neutral substance is better received in this mechanism due to a physiological environment. Negatively-charged glutamate and positively-charged histidine within this enzyme play a role within the covalent bindings in the mechanism. Covalent binding is necessary to form the covalent intermediate after NAD is reduced (after interacting with the active site residues).

<scene name='82/823089/Composition_view/1'>IMPDH composition</scene> The brown represents a protein, red represents a RNA, and green represents ligands.

== Energy Transformation ==

IMPDH is activated by monovalent cations, such as K+ and Na+, within the triose-phosphate isomerase (TIM) barrel. The Arg325-Asn306-Asp272 catalytic triad (Arg322-Asn303-Asp274 in human type II IMPDH) works inter-dependently and synergistically in the TIM barrel active site to make the nucleophilic component, cysteine, highly reactive to form a temporary covalent bond with the substrate<ref>PMID: 8555204</ref>. Substrates bind randomly to IMPDH as the hydride transfer is quick and NAD is reduced to hydrolyze the covalent intermediate within the enzyme-substrate complex. A covalent intermediate, E-XMP*, is formed, which decreases the energy needed in later nucleophilic and covalent catalysis steps<ref>PMID: 10390600</ref>. Based on normal physiological conditions, the IMPDH mechanism is often not kinetically favorable. The Bateman domains within the TIM barrel are composed of cystathionine beta-synthase motifs that perceive metal ion concentration, cellular energy status, and ionic strength; and will allosterically regulate IMPDH activity<ref>PMID: 31416831</ref>. Eukaryotic IMPDHs have three nucleotide-binding sites in the Bateman domain that allosterically modulate catalytic activity. These three nucleotide-binding sites bind adenine/guanine dinucleoside polyphosphates, and the affinity for these sites increases for these dinucleoside polyphosphates as the activity of IMPDH increases. Purine dinucleoside polyphosphates compete with purine mononucleotides within these sites, so the Bateman domain sites make IMPDH more sensitive to inhibition<ref>PMID: 31416831</ref>. Enzyme catalysis is able to finish with the energy need reduced as the covalent bond is broken later in the reaction to regenerate the enzyme.

</StructureSection>
== References ==

<references />

Sandbox Reserved 1565

2019-12-09T05:25:54Z

Alyssa Ragner:

{{Sandbox_Reserved_BHall_Chem351_F19}}
=='''Inosine-5'-monophosphate dehydrogenase'''==
<StructureSection load='6rpu' size='340' side='right' caption='Structure of the ternary complex of the IMPDH enzyme from Ashbya gossypii bound to the dinucleoside polyphosphate Ap5G and GDP' scene=''>

== Function(s) and Biological Relevance ==

<scene name='82/823089/Cartoon_view/1'>Inosine-5'-monophosphate dehydrogenase</scene> (IMPDH) is the enzyme that catalyzes the rate-limiting step in the ''de novo'' guanine nucleotide biosynthetic pathway, converting inosine monophosphate (IMP) to xanthosine monophosphate (XMP) with the reduction of nicotinamide adenine dinucleotide (NAD). Organisms that undergo the purine nucleotide biosynthetic pathway have IMPDH, including humans. This particular form of IMPDH described and highlighted comes from the recently studied fungus ''Ashbya gossypii'' <ref>PMID: 31416831</ref>. Additional ligands of IMPDH include nicotinamide adenine dinucleotide (NAD), acetate (ACT), and guanosine-5’ monophosphate (5GP), and guanosine-5'-diphosphate (GDP). IMPDH is a regulator of the intracellular guanine nucleotide pool amount and helps control control cell division and proliferation, and therefore related to malignant transformation, tumor cell proliferation, and intracellular and extracellular pathogenic infections. Purine dinucleoside polyphosphates are found to bind to the Bateman domain of ''Ashbya gossypii'' IMPDH to allosterically regulate the catalytic activity by competing against purine mononucleotides<ref>PMID: 31416831</ref>.

== Broader Implications ==

The disease pathophysiology is extensive as the improper IMPDH regulation may lead to uncontrolled cell division and proliferation, affecting the immune system's ability to fight off pathogens and signal tumor cells to apoptose. Therapeutic studies using dinucleoside polyphosphates may allosterically regulate the inhibition of IMPDH activity. Dinucleoside polyphosphates have physiological functions including cell division, neurotransmission, apoptosis, vasoconstriction, platelet aggregation, and cellular process variety enhancement from DNA replication to repair<ref>PMID: 31416831</ref>. Selected IMPDH inhibitors composed of dinucleoside polyphosphates may be used to make IMPDHs targets for immunosuppressive, antiviral, and anticancer drugs<ref>PMID: 21517780</ref>, with antibacterial and chemotherapeutic strategies feasibile<ref>PMID: 22928911</ref>.

== Structural Highlights and Structure-Function Relationships ==

The <scene name='82/823089/Secondary_structure/1'>secondary structure</scene> shows alpha helices and beta sheets. The ''Ashbya gossypii'' IMPDH is 31% helical and 15% beta sheet, with the other percentages including random coils and residue structures. The active site is located towards the C-terminus within the TIM barrel, containing 8 alpha-helices and 8 beta sheets.

IMPDH quaternary structures include multiunit complexes, such as <scene name='82/823089/Quaternary_view/1'>tetramers</scene>, extended octamers, and compacted octamers. These quaternary structures are created through the binding of multiple subunits of <scene name='82/823089/Tertiary_structure/1'>tertiary</scene> structures, that are strengthened and structurally formed through hydrogen-bonding, Cysteine-Cysteine disulfide bonds, and hydrophobic interactions. Different quaternary forms of IMPDH relate to the kinetic favorability of the IMPDH mechanism as Bateman domain allosteric binding sites and competitive nature changes with unit composition.

This <scene name='82/823089/Space-filled/2'>space-filled view</scene> helps show the Van der Waals interactions and areas for movement within the structure. The ability for monovalent cations to move within the charged tunnel with the phosphate chain directly relates to activation levels. The phosphate chain relates to the ligands that further interact with the binding site to form the covalent intermediate, E-XMP*.

<scene name='82/823089/Hydrophobicity_view/1'>Hydrophobicity view</scene> Purple represents polar molecules and gray represents hydrophobic molecules. The hydrophobicity is within the interior of the molecule as the hydrophilic residues are able to interact in a physiological environment.

<scene name='82/823089/Ligands/1'>Ligand View</scene> In this view the black structures are the ACT molecules. These are the ligands of the IMPDH protein. Other ligands include G5P and GDP.

<scene name='82/823089/Catalytic_triad/1'>Catalytic Triad</scene> The IMPDH triad includes Arg (325), Asn (306), and Asp (272). This is represented by the solid purple structures in the image. This triad is important as it makes cysteine more reactive as a nucleophilic component. This conserved cysteine (Cys331 in human type II IMPDH) induces binding after becoming more reactive.

<scene name='82/823089/Active_site/1'>Active Binding Site</scene> The active binding site includes the Bateman domains, which are components within the TIM barrel. Binding occurs after the catalytic triad makes cysteine more reactive. The cysteines that become more reactive are shown in green in the image, and are closely related to the active binding site. Asp259 (blue) hydrogen bonds with the ribose hydroxyls of NAD (nicotinamide region), and Ser315 (blue) hydrogen bonds to the ribose phosphate through hydroxyl groups. Gly361 and Gly383 (orange) have hydrophobic interactions with the phosphate of the ligand NAD. Other important interactions include Tyr403 hydrogen bonding to ribose phosphate (NAD), and Glu402 and Glu440 hydrogen bonding with the IMP purine ring.

<scene name='82/823089/Charge_view/2'>IMPDH charge</scene> is not strong, as shown by this view. There are positive and negative components within the structure, but a relatively neutral substance is better received in this mechanism due to a physiological environment. Negatively-charged glutamate and positively-charged histidine within this enzyme play a role within the covalent bindings in the mechanism. Covalent binding is necessary to form the covalent intermediate after NAD is reduced (after interacting with the active site residues).

<scene name='82/823089/Composition_view/1'>IMPDH composition</scene> The brown represents a protein, red represents a RNA, and green represents ligands.

== Energy Transformation ==

IMPDH is activated by monovalent cations, such as K+ and Na+, within the triose-phosphate isomerase (TIM) barrel. The Arg325-Asn306-Asp272 catalytic triad (Arg322-Asn303-Asp274 in human type II IMPDH) works inter-dependently and synergistically in the TIM barrel active site to make the nucleophilic component, cysteine, highly reactive to form a temporary covalent bond with the substrate<ref>PMID: 8555204</ref>. Substrates bind randomly to IMPDH as the hydride transfer is quick and NAD is reduced to hydrolyze the covalent intermediate within the enzyme-substrate complex. A covalent intermediate, E-XMP*, is formed, which decreases the energy needed in later nucleophilic and covalent catalysis steps<ref>PMID: 10390600</ref>. Based on normal physiological conditions, the IMPDH mechanism is often not kinetically favorable. The Bateman domains within the TIM barrel are composed of cystathionine beta-synthase motifs that perceive metal ion concentration, cellular energy status, and ionic strength; and will allosterically regulate IMPDH activity<ref>PMID: 31416831</ref>. Eukaryotic IMPDHs have three nucleotide-binding sites in the Bateman domain that allosterically modulate catalytic activity. These three nucleotide-binding sites bind adenine/guanine dinucleoside polyphosphates, and the affinity for these sites increases for these dinucleoside polyphosphates as the activity of IMPDH increases. Purine dinucleoside polyphosphates compete with purine mononucleotides within these sites, so the Bateman domain sites make IMPDH more sensitive to inhibition<ref>PMID: 31416831</ref>. Enzyme catalysis is able to finish with the energy need reduced as the covalent bond is broken later in the reaction to regenerate the enzyme.

</StructureSection>
== References ==

<references />

Sandbox Reserved 1565

2019-12-09T05:24:06Z

Alyssa Ragner:

{{Sandbox_Reserved_BHall_Chem351_F19}}
=='''Inosine-5'-monophosphate dehydrogenase'''==
<StructureSection load='6rpu' size='340' side='right' caption='Structure of the ternary complex of the IMPDH enzyme from Ashbya gossypii bound to the dinucleoside polyphosphate Ap5G and GDP' scene=''>

== Function(s) and Biological Relevance ==

<scene name='82/823089/Cartoon_view/1'>Inosine-5'-monophosphate dehydrogenase</scene> (IMPDH) is the enzyme that catalyzes the rate-limiting step in the ''de novo'' guanine nucleotide biosynthetic pathway, converting inosine monophosphate (IMP) to xanthosine monophosphate (XMP) with the reduction of nicotinamide adenine dinucleotide (NAD). Organisms that undergo the purine nucleotide biosynthetic pathway have IMPDH, including humans. This particular form of IMPDH described and highlighted comes from the recently studied fungus ''Ashbya gossypii'' <ref>PMID: 31416831</ref>. Additional ligands of IMPDH include nicotinamide adenine dinucleotide (NAD), acetate (ACT), and guanosine-5’ monophosphate (5GP), and guanosine-5'-diphosphate (GDP). IMPDH is a regulator of the intracellular guanine nucleotide pool amount and helps control control cell division and proliferation, and therefore related to malignant transformation, tumor cell proliferation, and intracellular and extracellular pathogenic infections. Purine dinucleoside polyphosphates are found to bind to the Bateman domain of ''Ashbya gossypii'' IMPDH to allosterically regulate the catalytic activity by competing against purine mononucleotides<ref>PMID: 31416831</ref>.

== Broader Implications ==

The disease pathophysiology is extensive as the improper IMPDH regulation may lead to uncontrolled cell division and proliferation, affecting the immune system's ability to fight off pathogens and signal tumor cells to apoptose. Therapeutic studies using dinucleoside polyphosphates may allosterically regulate the inhibition of IMPDH activity. Dinucleoside polyphosphates have physiological functions including cell division, neurotransmission, apoptosis, vasoconstriction, platelet aggregation, and cellular process variety enhancement from DNA replication to repair<ref>PMID: 31416831</ref>. Selected IMPDH inhibitors composed of dinucleoside polyphosphates may be used to make IMPDHs targets for immunosuppressive, antiviral, and anticancer drugs<ref>PMID: 21517780</ref>, with antibacterial and chemotherapeutic strategies feasibile<ref>PMID: 22928911</ref>.

== Structural Highlights and Structure-Function Relationships ==

The <scene name='82/823089/Secondary_structure/1'>secondary structure</scene> shows alpha helices and beta sheets. The ''Ashbya gossypii'' IMPDH is 31% helical and 15% beta sheet, with the other percentages including random coils and residue structures. The active site is located towards the C-terminus within the TIM barrel, containing 8 alpha-helices and 8 beta sheets.

IMPDH quaternary structures include multiunit complexes, such as <scene name='82/823089/Quaternary_view/1'>tetramers</scene>, extended octamers, and compacted octamers. These quaternary structures are created through the binding of multiple subunits of <scene name='82/823089/Tertiary_structure/1'>tertiary</scene> structures, that are strengthened and structurally formed through hydrogen-bonding, Cysteine-Cysteine disulfide bonds, and hydrophobic interactions. Different quaternary forms of IMPDH relate to the kinetic favorability of the IMPDH mechanism as Bateman domain allosteric binding sites and competitive nature changes with unit composition.

This <scene name='82/823089/Space-filled/2'>space-filled view</scene> helps show the Van der Waals interactions and areas for movement within the structure. The ability for monovalent cations to move within the charged tunnel with the phosphate chain directly relates to activation levels.

<scene name='82/823089/Hydrophobicity_view/1'>Hydrophobicity view</scene> Purple represents polar molecules and gray represents hydrophobic molecules. The hydrophobicity is within the interior of the molecule as the hydrophilic residues are able to interact in a physiological environment.

<scene name='82/823089/Ligands/1'>Ligand View</scene> In this view the black structures are the ACT molecules. These are the ligands of the IMPDH protein. Other ligands include G5P and GDP.

<scene name='82/823089/Catalytic_triad/1'>Catalytic Triad</scene> The IMPDH triad includes Arg (325), Asn (306), and Asp (272). This is represented by the solid purple structures in the image. This triad is important as it makes cysteine more reactive as a nucleophilic component. This conserved cysteine (Cys331 in human type II IMPDH) induces binding after becoming more reactive.

<scene name='82/823089/Active_site/1'>Active Binding Site</scene> The active binding site includes the Bateman domains, which are components within the TIM barrel. Binding occurs after the catalytic triad makes cysteine more reactive. The cysteines that become more reactive are shown in green in the image, and are closely related to the active binding site. Asp259 (blue) hydrogen bonds with the ribose hydroxyls of NAD (nicotinamide region), and Ser315 (blue) hydrogen bonds to the ribose phosphate through hydroxyl groups. Gly361 and Gly383 (orange) have hydrophobic interactions with the phosphate of the ligand NAD. Other important interactions include Tyr403 hydrogen bonding to ribose phosphate (NAD), and Glu402 and Glu440 hydrogen bonding with the IMP purine ring.

<scene name='82/823089/Charge_view/2'>IMPDH charge</scene> is not strong, as shown by this view. There are positive and negative components within the structure, but a relatively neutral substance is better received in this mechanism due to a physiological environment. Negatively-charged glutamate and positively-charged histidine within this enzyme play a role within the covalent bindings in the mechanism. Covalent binding is necessary to form the covalent intermediate after NAD is reduced (after interacting with the active site residues).

<scene name='82/823089/Composition_view/1'>IMPDH composition</scene> The brown represents a protein, red represents a RNA, and green represents ligands.

== Energy Transformation ==

IMPDH is activated by monovalent cations, such as K+ and Na+, within the triose-phosphate isomerase (TIM) barrel. The Arg325-Asn306-Asp272 catalytic triad (Arg322-Asn303-Asp274 in human type II IMPDH) works inter-dependently and synergistically in the TIM barrel active site to make the nucleophilic component, cysteine, highly reactive to form a temporary covalent bond with the substrate<ref>PMID: 8555204</ref>. Substrates bind randomly to IMPDH as the hydride transfer is quick and NAD is reduced to hydrolyze the covalent intermediate within the enzyme-substrate complex. A covalent intermediate, E-XMP*, is formed, which decreases the energy needed in later nucleophilic and covalent catalysis steps<ref>PMID: 10390600</ref>. Based on normal physiological conditions, the IMPDH mechanism is often not kinetically favorable. The Bateman domains within the TIM barrel are composed of cystathionine beta-synthase motifs that perceive metal ion concentration, cellular energy status, and ionic strength; and will allosterically regulate IMPDH activity<ref>PMID: 31416831</ref>. Eukaryotic IMPDHs have three nucleotide-binding sites in the Bateman domain that allosterically modulate catalytic activity. These three nucleotide-binding sites bind adenine/guanine dinucleoside polyphosphates, and the affinity for these sites increases for these dinucleoside polyphosphates as the activity of IMPDH increases. Purine dinucleoside polyphosphates compete with purine mononucleotides within these sites, so the Bateman domain sites make IMPDH more sensitive to inhibition<ref>PMID: 31416831</ref>. Enzyme catalysis is able to finish with the energy need reduced as the covalent bond is broken later in the reaction to regenerate the enzyme.

</StructureSection>
== References ==

<references />

Sandbox Reserved 1565

2019-12-09T05:22:58Z

Alyssa Ragner:

{{Sandbox_Reserved_BHall_Chem351_F19}}
=='''Inosine-5'-monophosphate dehydrogenase'''==
<StructureSection load='6rpu' size='340' side='right' caption='Structure of the ternary complex of the IMPDH enzyme from Ashbya gossypii bound to the dinucleoside polyphosphate Ap5G and GDP' scene=''>

== Function(s) and Biological Relevance ==

<scene name='82/823089/Cartoon_view/1'>Inosine-5'-monophosphate dehydrogenase</scene> (IMPDH) is the enzyme that catalyzes the rate-limiting step in the ''de novo'' guanine nucleotide biosynthetic pathway, converting inosine monophosphate (IMP) to xanthosine monophosphate (XMP) with the reduction of nicotinamide adenine dinucleotide (NAD). Organisms that undergo the purine nucleotide biosynthetic pathway have IMPDH, including humans. This particular form of IMPDH described and highlighted comes from the recently studied fungus ''Ashbya gossypii'' <ref>PMID: 31416831</ref>. Additional ligands of IMPDH include nicotinamide adenine dinucleotide (NAD), acetate (ACT), and guanosine-5’ monophosphate (5GP), and guanosine-5'-diphosphate (GDP). IMPDH is a regulator of the intracellular guanine nucleotide pool amount and helps control control cell division and proliferation, and therefore related to malignant transformation, tumor cell proliferation, and intracellular and extracellular pathogenic infections. Purine dinucleoside polyphosphates are found to bind to the Bateman domain of ''Ashbya gossypii'' IMPDH to allosterically regulate the catalytic activity by competing against purine mononucleotides<ref>PMID: 31416831</ref>.

== Broader Implications ==

The disease pathophysiology is extensive as the improper IMPDH regulation may lead to uncontrolled cell division and proliferation, affecting the immune system's ability to fight off pathogens and signal tumor cells to apoptose. Therapeutic studies using dinucleoside polyphosphates may allosterically regulate the inhibition of IMPDH activity. Dinucleoside polyphosphates have physiological functions including cell division, neurotransmission, apoptosis, vasoconstriction, platelet aggregation, and cellular process variety enhancement from DNA replication to repair<ref>PMID: 31416831</ref>. Selected IMPDH inhibitors composed of dinucleoside polyphosphates may be used to make IMPDHs targets for immunosuppressive, antiviral, and anticancer drugs<ref>PMID: 21517780</ref>, with antibacterial and chemotherapeutic strategies feasibile<ref>PMID: 22928911</ref>.

== Structural Highlights and Structure-Function Relationships ==

The <scene name='82/823089/Secondary_structure/1'>secondary structure</scene> shows alpha helices and beta sheets. The ''Ashbya gossypii'' IMPDH is 31% helical and 15% beta sheet, with the other percentages including random coils and residue structures. The active site is located towards the C-terminus within the TIM barrel, containing 8 alpha-helices and 8 beta sheets.

IMPDH quaternary structures include multiunit complexes, such as <scene name='82/823089/Quaternary_view/1'>tetramers</scene>, extended octamers, and compacted octamers. These quaternary structures are created through the binding of multiple subunits of <scene name='82/823089/Tertiary_structure/1'>tertiary</scene> structures, that are strengthened and structurally formed through hydrogen-bonding, Cysteine-Cysteine disulfide bonds, and hydrophobic interactions. Different quaternary forms of IMPDH relate to the kinetic favorability of the IMPDH mechanism as Bateman domain allosteric binding sites and competitive nature changes with unit composition.

This <scene name='82/823089/Space-filled/2'>space-filled view</scene> helps show the Van der Waals interactions and areas for movement within the structure. The ability for monovalent cations to move within the charged tunnel with the phosphate chain directly relates to activation levels.

<scene name='82/823089/Hydrophobicity_view/1'>Hydrophobicity view</scene> Purple represents polar molecules and gray represents hydrophobic molecules. The hydrophobicity is within the interior of the molecule as the hydrophilic residues are able to interact in a physiological environment.

<scene name='82/823089/Ligands/1'>Ligand View</scene> In this view the black structures are the ACT molecules. These are the ligands of the IMPDH protein. Other ligands include G5P and GDP.

<scene name='82/823089/Catalytic_triad/1'>Catalytic Triad</scene> The IMPDH triad includes Arg (325), Asn (306), and Asp (272). This is represented by the solid purple structures in the image. This triad is important as it makes cysteine more reactive as a nucleophilic component. This conserved cysteine (Cys331 in human type II IMPDH) induces binding after becoming more reactive.

<scene name='82/823089/Active_site/1'>Active Binding Site</scene> The active binding site includes the Bateman domains, which are components within the TIM barrel. Binding occurs after the catalytic triad makes cysteine more reactive. The cysteines that become more reactive are shown in green in the image, and are closely related to the active binding site. Asp259 (blue) hydrogen bonds with the ribose hydroxyls of NAD (nicotinamide region), and Ser315 (blue) hydrogen bonds to the ribose phosphate through hydroxyl groups. Gly361 and Gly383 (orange) have hydrophobic interactions with the phosphate of the ligand NAD. Other important interactions include Tyr403 hydrogen bonding to ribose phosphate (NAD), and Glu402 and Glu440 hydrogen bonding with the IMP purine ring.

<scene name='82/823089/Charge_view/2'>IMPDH charge</scene> is not strong, as shown by this view. There are positive and negative components within the structure, but a relatively neutral substance is better received in this mechanism due to a physiological environment. Negatively-charged glutamate and positively-charged histidine within this enzyme play a role within the covalent bindings in the mechanism.

<scene name='82/823089/Composition_view/1'>IMPDH composition</scene> The brown represents a protein, red represents a RNA, and green represents ligands.

== Energy Transformation ==

IMPDH is activated by monovalent cations, such as K+ and Na+, within the triose-phosphate isomerase (TIM) barrel. The Arg325-Asn306-Asp272 catalytic triad (Arg322-Asn303-Asp274 in human type II IMPDH) works inter-dependently and synergistically in the TIM barrel active site to make the nucleophilic component, cysteine, highly reactive to form a temporary covalent bond with the substrate<ref>PMID: 8555204</ref>. Substrates bind randomly to IMPDH as the hydride transfer is quick and NAD is reduced to hydrolyze the covalent intermediate within the enzyme-substrate complex. A covalent intermediate, E-XMP*, is formed, which decreases the energy needed in later nucleophilic and covalent catalysis steps<ref>PMID: 10390600</ref>. Based on normal physiological conditions, the IMPDH mechanism is often not kinetically favorable. The Bateman domains within the TIM barrel are composed of cystathionine beta-synthase motifs that perceive metal ion concentration, cellular energy status, and ionic strength; and will allosterically regulate IMPDH activity<ref>PMID: 31416831</ref>. Eukaryotic IMPDHs have three nucleotide-binding sites in the Bateman domain that allosterically modulate catalytic activity. These three nucleotide-binding sites bind adenine/guanine dinucleoside polyphosphates, and the affinity for these sites increases for these dinucleoside polyphosphates as the activity of IMPDH increases. Purine dinucleoside polyphosphates compete with purine mononucleotides within these sites, so the Bateman domain sites make IMPDH more sensitive to inhibition<ref>PMID: 31416831</ref>. Enzyme catalysis is able to finish with the energy need reduced as the covalent bond is broken later in the reaction to regenerate the enzyme.

</StructureSection>
== References ==

<references />

Sandbox Reserved 1565

2019-12-09T05:07:02Z

Alyssa Ragner:

{{Sandbox_Reserved_BHall_Chem351_F19}}
=='''Inosine-5'-monophosphate dehydrogenase'''==
<StructureSection load='6rpu' size='340' side='right' caption='Structure of the ternary complex of the IMPDH enzyme from Ashbya gossypii bound to the dinucleoside polyphosphate Ap5G and GDP' scene=''>

== Function(s) and Biological Relevance ==

<scene name='82/823089/Cartoon_view/1'>Inosine-5'-monophosphate dehydrogenase</scene> (IMPDH) is the enzyme that catalyzes the rate-limiting step in the ''de novo'' guanine nucleotide biosynthetic pathway, converting inosine monophosphate (IMP) to xanthosine monophosphate (XMP) with the reduction of nicotinamide adenine dinucleotide (NAD). Organisms that undergo the purine nucleotide biosynthetic pathway have IMPDH, including humans. This particular form of IMPDH described and highlighted comes from the recently studied fungus ''Ashbya gossypii'' <ref>PMID: 31416831</ref>. Additional ligands of IMPDH include nicotinamide adenine dinucleotide (NAD), acetate (ACT), and guanosine-5’ monophosphate (5GP), and guanosine-5'-diphosphate (GDP). IMPDH is a regulator of the intracellular guanine nucleotide pool amount and helps control control cell division and proliferation, and therefore related to malignant transformation, tumor cell proliferation, and intracellular and extracellular pathogenic infections. Purine dinucleoside polyphosphates are found to bind to the Bateman domain of ''Ashbya gossypii'' IMPDH to allosterically regulate the catalytic activity by competing against purine mononucleotides<ref>PMID: 31416831</ref>.

== Broader Implications ==

The disease pathophysiology is extensive as the improper IMPDH regulation may lead to uncontrolled cell division and proliferation, affecting the immune system's ability to fight off pathogens and signal tumor cells to apoptose. Therapeutic studies using dinucleoside polyphosphates may allosterically regulate the inhibition of IMPDH activity. Dinucleoside polyphosphates have physiological functions including cell division, neurotransmission, apoptosis, vasoconstriction, platelet aggregation, and cellular process variety enhancement from DNA replication to repair<ref>PMID: 31416831</ref>. Selected IMPDH inhibitors composed of dinucleoside polyphosphates may be used to make IMPDHs targets for immunosuppressive, antiviral, and anticancer drugs<ref>PMID: 21517780</ref>, with antibacterial and chemotherapeutic strategies feasibile<ref>PMID: 22928911</ref>.

== Structural Highlights and Structure-Function Relationships ==

The <scene name='82/823089/Secondary_structure/1'>secondary structure</scene> shows alpha helices and beta sheets. The ''Ashbya gossypii'' IMPDH is 31% helical and 15% beta sheet, with the other percentages including random coils and residue structures. The active site is located towards the C-terminus within the TIM barrel, containing 8 alpha-helices and 8 beta sheets.

IMPDH quaternary structures include multiunit complexes, such as <scene name='82/823089/Quaternary_view/1'>tetramers</scene>, extended octamers, and compacted octamers. These quaternary structures are created through the binding of multiple subunits of <scene name='82/823089/Tertiary_structure/1'>tertiary</scene> structures, that are strengthened and structurally formed through hydrogen-bonding, Cysteine-Cysteine disulfide bonds, and hydrophobic interactions. Different quaternary forms of IMPDH relate to the kinetic favorability of the IMPDH mechanism as Bateman domain allosteric binding sites and competitive nature changes with unit composition.

This <scene name='82/823089/Space-filled/2'>space-filled view</scene> helps show the Van der Waals interactions and areas for movement within the structure. The ability for monovalent cations to move within the charged tunnel with the phosphate chain directly relates to activation levels.

<scene name='82/823089/Hydrophobicity_view/1'>Hydrophobicity view</scene> Purple represents polar molecules and gray represents hydrophobic molecules. The hydrophobicity is within the interior of the molecule as the hydrophilic residues are able to interact in a physiological environment.

<scene name='82/823089/Ligands/1'>Ligand View</scene> In this view the black structures are the ACT molecules. These are the ligands of the IMPDH protein. Other ligands include G5P and GDP.

<scene name='82/823089/Catalytic_triad/1'>Catalytic Triad</scene> The IMPDH triad includes Arg (325), Asn (306), and Asp (272). This is represented by the solid red structures in the image. This triad is important as it makes cysteine more reactive, which in turn induces binding.

<scene name='82/823089/Active_site/1'>Active Binding Site</scene> The active binding site includes the Bateman domains, which are components within the TIM barrel. Binding occurs after the catalytic triad makes cysteine more reactive. In the image the cysteines are in white (6 in this sequence).

<scene name='82/823089/Charge_view/2'>IMPDH charge</scene> is not strong, as shown by this view. There are positive and negative components within the structure, but a relatively neutral substance is better received in this mechanism due to a physiological environment. Negatively-charged glutamate and positively-charged histidine within this enzyme play a role within the covalent bindings in the mechanism.

<scene name='82/823089/Composition_view/1'>IMPDH composition</scene> The brown represents a protein, red represents a RNA, and green represents ligands.

== Energy Transformation ==

IMPDH is activated by monovalent cations, such as K+ and Na+, within the triose-phosphate isomerase (TIM) barrel. The Arg325-Asn306-Asp272 catalytic triad (Arg322-Asn303-Asp274 in human type II IMPDH) works inter-dependently and synergistically in the TIM barrel active site to make the nucleophilic component, Cysteine, highly reactive to form a temporary covalent bond with the substrate<ref>PMID: 8555204</ref>. Substrates bind randomly to IMPDH as the hydride transfer is quick and NAD is reduced to hydrolyze the covalent intermediate within the enzyme-substrate complex. A covalent intermediate, E-XMP*, is formed, which decreases the energy needed in later nucleophilic and covalent catalysis steps<ref>PMID: 10390600</ref>. Based on normal physiological conditions, the IMPDH mechanism is often not kinetically favorable. The Bateman domains within the TIM barrel are composed of cystathionine beta-synthase motifs that perceive metal ion concentration, cellular energy status, and ionic strength; and will allosterically regulate IMPDH activity<ref>PMID: 31416831</ref>. Eukaryotic IMPDHs have three nucleotide-binding sites in the Bateman domain that allosterically modulate catalytic activity. These three nucleotide-binding sites bind adenine/guanine dinucleoside polyphosphates, and the affinity for these sites increases for these dinucleoside polyphosphates as the activity of IMPDH increases. Purine dinucleoside polyphosphates compete with purine mononucleotides within these sites, so the Bateman domain sites make IMPDH more sensitive to inhibition<ref>PMID: 31416831</ref>. Enzyme catalysis is able to finish with the energy need reduced as the covalent bond is broken later in the reaction to regenerate the enzyme.

</StructureSection>
== References ==

<references />

Sandbox Reserved 1565

2019-12-09T04:50:07Z

Alyssa Ragner:

{{Sandbox_Reserved_BHall_Chem351_F19}}
=='''Inosine-5'-monophosphate dehydrogenase'''==
<StructureSection load='6rpu' size='340' side='right' caption='Structure of the ternary complex of the IMPDH enzyme from Ashbya gossypii bound to the dinucleoside polyphosphate Ap5G and GDP' scene=''>

== Function(s) and Biological Relevance ==

<scene name='82/823089/Cartoon_view/1'>Inosine-5'-monophosphate dehydrogenase</scene> (IMPDH) is the enzyme that catalyzes the rate-limiting step in the ''de novo'' guanine nucleotide biosynthetic pathway, converting inosine monophosphate (IMP) to xanthosine monophosphate (XMP) with the reduction of nicotinamide adenine dinucleotide (NAD). Organisms that undergo the purine nucleotide biosynthetic pathway have IMPDH, including humans. This particular form of IMPDH described and highlighted comes from the recently studied fungus ''Ashbya gossypii'' <ref>PMID: 31416831</ref>. Additional ligands of IMPDH include nicotinamide adenine dinucleotide (NAD), acetate (ACT), and guanosine-5’ monophosphate (5GP), and guanosine-5'-diphosphate (GDP). IMPDH is a regulator of the intracellular guanine nucleotide pool amount and helps control control cell division and proliferation, and therefore related to malignant transformation, tumor cell proliferation, and intracellular and extracellular pathogenic infections. Purine dinucleoside polyphosphates are found to bind to the Bateman domain of ''Ashbya gossypii'' IMPDH to allosterically regulate the catalytic activity by competing against purine mononucleotides<ref>PMID: 31416831</ref>.

== Broader Implications ==

The disease pathophysiology is extensive as the improper IMPDH regulation may lead to uncontrolled cell division and proliferation, affecting the immune system's ability to fight off pathogens and signal tumor cells to apoptose. Therapeutic studies using dinucleoside polyphosphates may allosterically regulate the inhibition of IMPDH activity. Dinucleoside polyphosphates have physiological functions including cell division, neurotransmission, apoptosis, vasoconstriction, platelet aggregation, and cellular process variety enhancement from DNA replication to repair<ref>PMID: 31416831</ref>. Selected IMPDH inhibitors composed of dinucleoside polyphosphates may be used to make IMPDHs targets for immunosuppressive, antiviral, and anticancer drugs<ref>PMID: 21517780</ref>, with antibacterial and chemotherapeutic strategies feasibile<ref>PMID: 22928911</ref>.

== Structural Highlights and Structure-Function Relationships ==

The <scene name='82/823089/Secondary_structure/1'>secondary structure</scene> shows alpha helices and beta sheets. The ''Ashbya gossypii'' IMPDH is 31% helical and 15% beta sheet, with the other percentages including random coils and residue structures. The active site is located towards the C-terminus within the TIM barrel, containing 8 alpha-helices and 8 beta sheets.

IMPDH quaternary structures include multiunit complexes, such as <scene name='82/823089/Quaternary_view/1'>tetramers</scene>, extended octamers, and compacted octamers. These quaternary structures are created through the binding of multiple subunits of tertiary structures, that are strengthened and structurally formed through hydrogen-bonding, Cysteine-Cysteine disulfide bonds, and hydrophobic interactions. Different quaternary forms of IMPDH relate to the kinetic favorability of the IMPDH mechanism as Bateman domain allosteric binding sites and competitive nature changes with unit composition.

This <scene name='82/823089/Space-filled/2'>space-filled view</scene> helps show the Van der Waals interactions and areas for movement within the structure. The ability for monovalent cations to move within the charged tunnel with the phosphate chain directly relates to activation levels.

<scene name='82/823089/Hydrophobicity_view/1'>Hydrophobicity view</scene> Purple represents polar molecules and gray represents hydrophobic molecules. The hydrophobicity is within the interior of the molecule as the hydrophilic residues are able to interact in a physiological environment.

<scene name='82/823089/Ligands/1'>Ligand View</scene> In this view the black structures are the ACT molecules. These are the ligands of the IMPDH protein. Other ligands include G5P and GDP.

<scene name='82/823089/Catalytic_triad/1'>Catalytic Triad</scene> The IMPDH triad includes Arg (325), Asn (306), and Asp (272). This is represented by the solid red structures in the image. This triad is important as it makes cysteine more reactive, which in turn induces binding.

<scene name='82/823089/Active_site/1'>Active Binding Site</scene> The active binding site includes the Bateman domains, which are components within the TIM barrel. Binding occurs after the catalytic triad makes cysteine more reactive. In the image the cysteines are in white (6 in this sequence).

<scene name='82/823089/Charge_view/2'>IMPDH charge</scene> is not strong, as shown by this view. There are positive and negative components within the structure, but a relatively neutral substance is better received in this mechanism due to a physiological environment. Negatively-charged glutamate and positively-charged histidine within this enzyme play a role within the covalent bindings in the mechanism.

<scene name='82/823089/Composition_view/1'>IMPDH composition</scene> The brown represents a protein, red represents a RNA, and green represents ligands.

== Energy Transformation ==

IMPDH is activated by monovalent cations, such as K+ and Na+, within the triose-phosphate isomerase (TIM) barrel. The Arg325-Asn306-Asp272 catalytic triad (Arg322-Asn303-Asp274 in human type II IMPDH) works inter-dependently and synergistically in the TIM barrel active site to make the nucleophilic component, Cysteine, highly reactive to form a temporary covalent bond with the substrate<ref>PMID: 8555204</ref>. Substrates bind randomly to IMPDH as the hydride transfer is quick and NAD is reduced to hydrolyze the covalent intermediate within the enzyme-substrate complex. A covalent intermediate, E-XMP*, is formed, which decreases the energy needed in later nucleophilic and covalent catalysis steps<ref>PMID: 10390600</ref>. Based on normal physiological conditions, the IMPDH mechanism is often not kinetically favorable. The Bateman domains within the TIM barrel are composed of cystathionine beta-synthase motifs that perceive metal ion concentration, cellular energy status, and ionic strength; and will allosterically regulate IMPDH activity<ref>PMID: 31416831</ref>. Eukaryotic IMPDHs have three nucleotide-binding sites in the Bateman domain that allosterically modulate catalytic activity. These three nucleotide-binding sites bind adenine/guanine dinucleoside polyphosphates, and the affinity for these sites increases for these dinucleoside polyphosphates as the activity of IMPDH increases. Purine dinucleoside polyphosphates compete with purine mononucleotides within these sites, so the Bateman domain sites make IMPDH more sensitive to inhibition<ref>PMID: 31416831</ref>. Enzyme catalysis is able to finish with the energy need reduced as the covalent bond is broken later in the reaction to regenerate the enzyme.

</StructureSection>
== References ==

<references />

Sandbox Reserved 1565

2019-12-09T04:40:09Z

Alyssa Ragner:

{{Sandbox_Reserved_BHall_Chem351_F19}}
=='''Inosine-5'-monophosphate dehydrogenase'''==
<StructureSection load='6rpu' size='340' side='right' caption='Structure of the ternary complex of the IMPDH enzyme from Ashbya gossypii bound to the dinucleoside polyphosphate Ap5G and GDP' scene=''>

== Function(s) and Biological Relevance ==

<scene name='82/823089/Cartoon_view/1'>Inosine-5'-monophosphate dehydrogenase</scene> (IMPDH) is the enzyme that catalyzes the rate-limiting step in the ''de novo'' guanine nucleotide biosynthetic pathway, converting inosine monophosphate (IMP) to xanthosine monophosphate (XMP) with the reduction of nicotinamide adenine dinucleotide (NAD). Organisms that undergo the purine nucleotide biosynthetic pathway have IMPDH, including humans. This particular form of IMPDH described and highlighted comes from the recently studied fungus ''Ashbya gossypii'' <ref>PMID: 31416831</ref>. Additional ligands of IMPDH include nicotinamide adenine dinucleotide (NAD), acetate (ACT), and guanosine-5’ monophosphate (5GP). IMPDH is a regulator of the intracellular guanine nucleotide pool amount and helps control control cell division and proliferation, and therefore related to malignant transformation, tumor cell proliferation, and intracellular and extracellular pathogenic infections. Purine dinucleoside polyphosphates are found to bind to the Bateman domain of ''Ashbya gossypii'' IMPDH to allosterically regulate the catalytic activity by competing against purine mononucleotides<ref>PMID: 31416831</ref>.

== Broader Implications ==

The disease pathophysiology is extensive as the improper IMPDH regulation may lead to uncontrolled cell division and proliferation, affecting the immune system's ability to fight off pathogens and signal tumor cells to apoptose. Therapeutic studies using dinucleoside polyphosphates may allosterically regulate the inhibition of IMPDH activity. Dinucleoside polyphosphates have physiological functions including cell division, neurotransmission, apoptosis, vasoconstriction, platelet aggregation, and cellular process variety enhancement from DNA replication to repair<ref>PMID: 31416831</ref>. Selected IMPDH inhibitors composed of dinucleoside polyphosphates may be used to make IMPDHs targets for immunosuppressive, antiviral, and anticancer drugs<ref>PMID: 21517780</ref>, with antibacterial and chemotherapeutic strategies feasibile<ref>PMID: 22928911</ref>.

== Structural Highlights and Structure-Function Relationships ==

The <scene name='82/823089/Secondary_structure/1'>secondary structure</scene> shows alpha helices and beta sheets. The ''Ashbya gossypii'' IMPDH is 31% helical and 15% beta sheet, with the other percentages including random coils and residue structures. The active site is located towards the C-terminus within the TIM barrel, containing 8 alpha-helices and 8 beta sheets.

IMPDH quaternary structures include multiunit complexes, such as <scene name='82/823089/Quaternary_view/1'>tetramers</scene>, extended octamers, and compacted octamers. These quaternary structures are created through the binding of multiple subunits of tertiary structures, that are strengthened and structurally formed through hydrogen-bonding, Cysteine-Cysteine disulfide bonds, and hydrophobic interactions. Different quaternary forms of IMPDH relate to the kinetic favorability of the IMPDH mechanism as Bateman domain allosteric binding sites and competitive nature changes with unit composition.

This <scene name='82/823089/Space-filled/2'>space-filled view</scene> helps show the Van der Waals interactions and areas for movement within the structure. The ability for monovalent cations to move within the charged tunnel with the phosphate chain directly relates to activation levels.

<scene name='82/823089/Hydrophobicity_view/1'>Hydrophobicity view</scene> Purple represents polar molecules and gray represents hydrophobic molecules. The hydrophobicity is within the interior of the molecule as the hydrophilic residues are able to interact in a physiological environment.

<scene name='82/823089/Ligands/1'>Ligand View</scene> In this view the black structures are the ACT molecules. These are the ligands of the IMPDH protein. Other ligands include G5P and GDP.

<scene name='82/823089/Catalytic_triad/1'>Catalytic Triad</scene> The IMPDH triad includes Arg (325), Asn (306), and Asp (272). This is represented by the solid red structures in the image. This triad is important as it makes cysteine more reactive, which in turn induces binding.

<scene name='82/823089/Active_site/1'>Active Binding Site</scene> The active binding site includes the Bateman domains, which are components within the TIM barrel. Binding occurs after the catalytic triad makes cysteine more reactive. In the image the cysteines are in white (6 in this sequence).

<scene name='82/823089/Charge_view/2'>IMPDH charge</scene> is not strong, as shown by this view. There are positive and negative components within the structure, but a relatively neutral substance is better received in this mechanism due to a physiological environment. Negatively-charged glutamate and positively-charged histidine within this enzyme play a role within the covalent bindings in the mechanism.

<scene name='82/823089/Composition_view/1'>IMPDH composition</scene> The brown represents a protein, red represents a RNA, and green represents ligands.

== Energy Transformation ==

IMPDH is activated by monovalent cations, such as K+ and Na+, within the triose-phosphate isomerase (TIM) barrel. The Arg325-Asn306-Asp272 catalytic triad (Arg322-Asn303-Asp274 in human type II IMPDH) works inter-dependently and synergistically in the TIM barrel active site to make the nucleophilic component, Cysteine, highly reactive to form a temporary covalent bond with the substrate<ref>PMID: 8555204</ref>. Substrates bind randomly to IMPDH as the hydride transfer is quick and NAD is reduced to hydrolyze the covalent intermediate within the enzyme-substrate complex. A covalent intermediate, E-XMP*, is formed, which decreases the energy needed in later nucleophilic and covalent catalysis steps<ref>PMID: 10390600</ref>. Based on normal physiological conditions, the IMPDH mechanism is often not kinetically favorable. The Bateman domains within the TIM barrel are composed of cystathionine beta-synthase motifs that perceive metal ion concentration, cellular energy status, and ionic strength; and will allosterically regulate IMPDH activity<ref>PMID: 31416831</ref>. Eukaryotic IMPDHs have three nucleotide-binding sites in the Bateman domain that allosterically modulate catalytic activity. These three nucleotide-binding sites bind adenine/guanine dinucleoside polyphosphates, and the affinity for these sites increases for these dinucleoside polyphosphates as the activity of IMPDH increases. Purine dinucleoside polyphosphates compete with purine mononucleotides within these sites, so the Bateman domain sites make IMPDH more sensitive to inhibition<ref>PMID: 31416831</ref>. Enzyme catalysis is able to finish with the energy need reduced as the covalent bond is broken later in the reaction to regenerate the enzyme.

</StructureSection>
== References ==

<references />

Sandbox Reserved 1565

2019-12-09T04:28:08Z

Alyssa Ragner:

{{Sandbox_Reserved_BHall_Chem351_F19}}
=='''Inosine-5'-monophosphate dehydrogenase'''==
<StructureSection load='6rpu' size='340' side='right' caption='Structure of the ternary complex of the IMPDH enzyme from Ashbya gossypii bound to the dinucleoside polyphosphate Ap5G and GDP' scene=''>

== Function(s) and Biological Relevance ==

<scene name='82/823089/Cartoon_view/1'>Inosine-5'-monophosphate dehydrogenase</scene> (IMPDH) is the enzyme that catalyzes the rate-limiting step in the ''de novo'' guanine nucleotide biosynthetic pathway, converting inosine monophosphate (IMP) to xanthosine monophosphate (XMP) with the reduction of nicotinamide adenine dinucleotide (NAD). Organisms that undergo the purine nucleotide biosynthetic pathway have IMPDH, including humans. This particular form of IMPDH described and highlighted comes from the recently studied fungus ''Ashbya gossypii'' <ref>PMID: 31416831</ref>. Additional ligands of IMPDH include nicotinamide adenine dinucleotide (NAD), acetate (ACT), and guanosine-5’ monophosphate (5GP). IMPDH is a regulator of the intracellular guanine nucleotide pool amount and helps control control cell division and proliferation, and therefore related to malignant transformation, tumor cell proliferation, and intracellular and extracellular pathogenic infections. Purine dinucleoside polyphosphates are found to bind to the Bateman domain of ''Ashbya gossypii'' IMPDH to allosterically regulate the catalytic activity by competing against purine mononucleotides<ref>PMID: 31416831</ref>.

== Broader Implications ==

The disease pathophysiology is extensive as the improper IMPDH regulation may lead to uncontrolled cell division and proliferation, affecting the immune system's ability to fight off pathogens and signal tumor cells to apoptose. Therapeutic studies using dinucleoside polyphosphates may allosterically regulate the inhibition of IMPDH activity. Dinucleoside polyphosphates have physiological functions including cell division, neurotransmission, apoptosis, vasoconstriction, platelet aggregation, and cellular process variety enhancement from DNA replication to repair<ref>PMID: 31416831</ref>. Selected IMPDH inhibitors composed of dinucleoside polyphosphates may be used to make IMPDHs targets for immunosuppressive, antiviral, and anticancer drugs<ref>PMID: 21517780</ref>, with antibacterial and chemotherapeutic strategies feasibile<ref>PMID: 22928911</ref>.

== Structural Highlights and Structure-Function Relationships ==

The <scene name='82/823089/Secondary_structure/1'>secondary structure</scene> shows alpha helices and beta sheets. The ''Ashbya gossypii'' IMPDH is 31% helical and 15% beta sheet, with the other percentages including random coils and residue structures. The active site is located towards the C-terminus within the TIM barrel, containing 8 alpha-helices and 8 beta sheets.

IMPDH <scene name='82/823087/Impdh_quaternary_structure/1'>quaternary structures</scene> include multiunit complexes, such as tetramers, extended octamers, and compacted octamers. These quaternary structures are created through the binding of multiple subunits of tertiary structures, that are strengthened and structurally formed through hydrogen-bonding, Cysteine-Cysteine disulfide bonds, and hydrophobic interactions. Different quaternary forms of IMPDH relate to the kinetic favorability of the IMPDH mechanism as Bateman domain allosteric binding sites and competitive nature changes with unit composition.

This <scene name='82/823089/Space-filled/2'>space-filled view</scene> helps show the Van der Waals interactions and areas for movement within the structure. The ability for monovalent cations to move within the charged tunnel with the phosphate chain directly relates to activation levels.

<scene name='82/823089/Hydrophobicity_view/1'>Hydrophobicity view</scene> Purple represents polar molecules and gray represents hydrophobic molecules. The hydrophobicity is within the interior of the molecule as the hydrophilic residues are able to interact in a physiological environment.

<scene name='82/823089/Ligands/1'>Ligand View</scene> In this view the black structures are the ACT molecules. These are the ligands of the IMPDH protein. Other ligands include G5P and GDP.

<scene name='82/823089/Catalytic_triad/1'>Catalytic Triad</scene> The IMPDH triad includes Arg (325), Asn (306), and Asp (272). This is represented by the solid red structures in the image. This triad is important as it makes cysteine more reactive, which in turn induces binding.

<scene name='82/823089/Active_site/1'>Active Binding Site</scene> The active binding site includes the Bateman domains, which are components within the TIM barrel. Binding occurs after the catalytic triad makes cysteine more reactive. In the image the cysteines are in white (6 in this sequence).

<scene name='82/823089/Charge_view/2'>IMPDH charge</scene> is not strong, as shown by this view. There are positive and negative components within the structure, but a relatively neutral substance is better received in this mechanism due to a physiological environment. Negatively-charged glutamate and positively-charged histidine within this enzyme play a role within the covalent bindings in the mechanism.

<scene name='82/823089/Composition_view/1'>IMPDH composition</scene> The brown represents a protein, red represents a RNA, and green represents ligands.

== Energy Transformation ==

IMPDH is activated by monovalent cations, such as K+ and Na+, within the triose-phosphate isomerase (TIM) barrel. The Arg325-Asn306-Asp272 catalytic triad (Arg322-Asn303-Asp274 in human type II IMPDH) works inter-dependently and synergistically in the TIM barrel active site to make the nucleophilic component, Cysteine, highly reactive to form a temporary covalent bond with the substrate<ref>PMID: 8555204</ref>. Substrates bind randomly to IMPDH as the hydride transfer is quick and NAD is reduced to hydrolyze the covalent intermediate within the enzyme-substrate complex. A covalent intermediate, E-XMP*, is formed, which decreases the energy needed in later nucleophilic and covalent catalysis steps<ref>PMID: 10390600</ref>. Based on normal physiological conditions, the IMPDH mechanism is often not kinetically favorable. The Bateman domains within the TIM barrel are composed of cystathionine beta-synthase motifs that perceive metal ion concentration, cellular energy status, and ionic strength; and will allosterically regulate IMPDH activity<ref>PMID: 31416831</ref>. Eukaryotic IMPDHs have three nucleotide-binding sites in the Bateman domain that allosterically modulate catalytic activity. These three nucleotide-binding sites bind adenine/guanine dinucleoside polyphosphates, and the affinity for these sites increases for these dinucleoside polyphosphates as the activity of IMPDH increases. Purine dinucleoside polyphosphates compete with purine mononucleotides within these sites, so the Bateman domain sites make IMPDH more sensitive to inhibition<ref>PMID: 31416831</ref>. Enzyme catalysis is able to finish with the energy need reduced as the covalent bond is broken later in the reaction to regenerate the enzyme.

</StructureSection>
== References ==

<references />

Sandbox Reserved 1565

2019-12-09T03:35:48Z

Alyssa Ragner:

{{Sandbox_Reserved_BHall_Chem351_F19}}
=='''Inosine-5'-monophosphate dehydrogenase'''==
<StructureSection load='6rpu' size='340' side='right' caption='Structure of the ternary complex of the IMPDH enzyme from Ashbya gossypii bound to the dinucleoside polyphosphate Ap5G and GDP' scene=''>

== Function(s) and Biological Relevance ==

<scene name='82/823089/Cartoon_view/1'>Inosine-5'-monophosphate dehydrogenase</scene> (IMPDH) is the enzyme that catalyzes the rate-limiting step in the ''de novo'' guanine nucleotide biosynthetic pathway, converting inosine monophosphate (IMP) to xanthosine monophosphate (XMP) with the reduction of nicotinamide adenine dinucleotide (NAD). Organisms that undergo the purine nucleotide biosynthetic pathway have IMPDH, including humans. This particular form of IMPDH described and highlighted comes from the recently studied fungus ''Ashbya gossypii'' <ref>PMID: 31416831</ref>. Additional ligands of IMPDH include nicotinamide adenine dinucleotide (NAD), acetate (ACT), and guanosine-5’ monophosphate (5GP). IMPDH is a regulator of the intracellular guanine nucleotide pool amount and helps control control cell division and proliferation, and therefore related to malignant transformation, tumor cell proliferation, and intracellular and extracellular pathogenic infections. Purine dinucleoside polyphosphates are found to bind to the Bateman domain of ''Ashbya gossypii'' IMPDH to allosterically regulate the catalytic activity by competing against purine mononucleotides<ref>PMID: 31416831</ref>.

== Broader Implications ==

The disease pathophysiology is extensive as the improper IMPDH regulation may lead to uncontrolled cell division and proliferation, affecting the immune system's ability to fight off pathogens and signal tumor cells to apoptose. Therapeutic studies using dinucleoside polyphosphates may allosterically regulate the inhibition of IMPDH activity. Dinucleoside polyphosphates have physiological functions including cell division, neurotransmission, apoptosis, vasoconstriction, platelet aggregation, and cellular process variety enhancement from DNA replication to repair<ref>PMID: 31416831</ref>. Selected IMPDH inhibitors composed of dinucleoside polyphosphates may be used to make IMPDHs targets for immunosuppressive, antiviral, and anticancer drugs<ref>PMID: 21517780</ref>, with antibacterial and chemotherapeutic strategies feasibile<ref>PMID: 22928911</ref>.

== Structural Highlights and Structure-Function Relationships ==

The <scene name='82/823089/Secondary_structure/1'>secondary structure</scene> shows alpha helices and beta sheets. The ''Ashbya gossypii'' IMPDH is 31% helical and 15% beta sheet, with the other percentages including random coils and residue structures. The active site is located towards the C-terminus within the TIM barrel, containing 8 alpha-helices and 8 beta sheets.

IMPDH <scene name='82/823087/Impdh_quaternary_structure/1'>quaternary structures</scene> include multiunit complexes, such as tetramers, extended octamers, and compacted octamers. These quaternary structures are created through the binding of multiple subunits of tertiary structures, that are strengthened and structurally formed through hydrogen-bonding, Cysteine-Cysteine disulfide bonds, and hydrophobic interactions. Different quaternary forms of IMPDH relate to the kinetic favorability of the IMPDH mechanism as Bateman domain allosteric binding sites and competitive nature changes with unit composition.

This <scene name='82/823089/Space-filled/2'>space-filled view</scene> helps show the Van der Waals interactions and areas for movement within the structure. The ability for monovalent cations to move within the charged tunnel with the phosphate chain directly relates to activation levels.

<scene name='82/823089/Hydrophobicity_view/1'>Hydrophobicity view</scene> Purple represents polar molecules and gray represents hydrophobic molecules. The hydrophobicity is within the interior of the molecule as the hydrophilic residues are able to interact in a physiological environment.

<scene name='82/823089/Ligands/1'>Ligand View</scene> In this view the black structures are the ACT molecules. These are the ligands of the IMPDH protein. Other ligands include G5P and GDP.

<scene name='82/823089/Catalytic_triad/1'>Catalytic Triad</scene> The IMPDH triad includes Arg (325), Asn (306), and Asp (272). This is represented by the solid red structures in the image. This triad is important as it makes cysteine more reactive, which in turn induces binding.

<scene name='82/823089/Active_binding_site/1'>IMPDH active binding site</scene> The active binding site includes the Bateman domains, which are components within the TIM barrel. Binding occurs after the catalytic triad makes cysteine more reactive. In the image the cysteines are in white (6 in this sequence).

<scene name='82/823089/Charge_view/2'>IMPDH charge</scene> is not strong, as shown by this view. There are positive and negative components within the structure, but a relatively neutral substance is better received in this mechanism due to a physiological environment. Negatively-charged glutamate and positively-charged histidine within this enzyme play a role within the covalent bindings in the mechanism.

<scene name='82/823089/Composition_view/1'>IMPDH composition</scene> The brown represents a protein, red represents a RNA, and green represents ligands.

== Energy Transformation ==

IMPDH is activated by monovalent cations, such as K+ and Na+, within the triose-phosphate isomerase (TIM) barrel. The Arg325-Asn306-Asp272 catalytic triad (Arg322-Asn303-Asp274 in human type II IMPDH) works inter-dependently and synergistically in the TIM barrel active site to make the nucleophilic component, Cysteine, highly reactive to form a temporary covalent bond with the substrate<ref>PMID: 8555204</ref>. Substrates bind randomly to IMPDH as the hydride transfer is quick and NAD is reduced to hydrolyze the covalent intermediate within the enzyme-substrate complex. A covalent intermediate, E-XMP*, is formed, which decreases the energy needed in later nucleophilic and covalent catalysis steps<ref>PMID: 10390600</ref>. Based on normal physiological conditions, the IMPDH mechanism is often not kinetically favorable. The Bateman domains within the TIM barrel are composed of cystathionine beta-synthase motifs that perceive metal ion concentration, cellular energy status, and ionic strength; and will allosterically regulate IMPDH activity<ref>PMID: 31416831</ref>. Eukaryotic IMPDHs have three nucleotide-binding sites in the Bateman domain that allosterically modulate catalytic activity. These three nucleotide-binding sites bind adenine/guanine dinucleoside polyphosphates, and the affinity for these sites increases for these dinucleoside polyphosphates as the activity of IMPDH increases. Purine dinucleoside polyphosphates compete with purine mononucleotides within these sites, so the Bateman domain sites make IMPDH more sensitive to inhibition<ref>PMID: 31416831</ref>. Enzyme catalysis is able to finish with the energy need reduced as the covalent bond is broken later in the reaction to regenerate the enzyme.

</StructureSection>
== References ==

<references />

Sandbox Reserved 1565

2019-12-09T03:28:43Z

Alyssa Ragner:

{{Sandbox_Reserved_BHall_Chem351_F19}}
=='''Inosine-5'-monophosphate dehydrogenase'''==
<StructureSection load='6rpu' size='340' side='right' caption='Structure of the ternary complex of the IMPDH enzyme from Ashbya gossypii bound to the dinucleoside polyphosphate Ap5G and GDP' scene=''>

== Function(s) and Biological Relevance ==

<scene name='82/823089/Cartoon_view/1'>Inosine-5'-monophosphate dehydrogenase</scene> (IMPDH) is the enzyme that catalyzes the rate-limiting step in the ''de novo'' guanine nucleotide biosynthetic pathway, converting inosine monophosphate (IMP) to xanthosine monophosphate (XMP) with the reduction of nicotinamide adenine dinucleotide (NAD). Organisms that undergo the purine nucleotide biosynthetic pathway have IMPDH, including humans. This particular form of IMPDH described and highlighted comes from the recently studied fungus ''Ashbya gossypii'' <ref>PMID: 31416831</ref>. Additional ligands of IMPDH include nicotinamide adenine dinucleotide (NAD), acetate (ACT), and guanosine-5’ monophosphate (5GP). IMPDH is a regulator of the intracellular guanine nucleotide pool amount and helps control control cell division and proliferation, and therefore related to malignant transformation, tumor cell proliferation, and intracellular and extracellular pathogenic infections. Purine dinucleoside polyphosphates are found to bind to the Bateman domain of ''Ashbya gossypii'' IMPDH to allosterically regulate the catalytic activity by competing against purine mononucleotides<ref>PMID: 31416831</ref>.

== Broader Implications ==

The disease pathophysiology is extensive as the improper IMPDH regulation may lead to uncontrolled cell division and proliferation, affecting the immune system's ability to fight off pathogens and signal tumor cells to apoptose. Therapeutic studies using dinucleoside polyphosphates may allosterically regulate the inhibition of IMPDH activity. Dinucleoside polyphosphates have physiological functions including cell division, neurotransmission, apoptosis, vasoconstriction, platelet aggregation, and cellular process variety enhancement from DNA replication to repair<ref>PMID: 31416831</ref>. Selected IMPDH inhibitors composed of dinucleoside polyphosphates may be used to make IMPDHs targets for immunosuppressive, antiviral, and anticancer drugs<ref>PMID: 21517780</ref>, with antibacterial and chemotherapeutic strategies feasibile<ref>PMID: 22928911</ref>.

== Structural Highlights and Structure-Function Relationships ==

The <scene name='82/823089/Secondary_structure/1'>secondary structure</scene> shows alpha helices and beta sheets. The ''Ashbya gossypii'' IMPDH is 31% helical and 15% beta sheet, with the other percentages including random coils and residue structures. The active site is located towards the C-terminus within the TIM barrel, containing 8 alpha-helices and 8 beta sheets.

IMPDH <scene name='82/823087/Impdh_quaternary_structure/1'>quaternary structures</scene> include multiunit complexes, such as tetramers, extended octamers, and compacted octamers. These quaternary structures are created through the binding of multiple subunits of tertiary structures, that are strengthened and structurally formed through hydrogen-bonding, Cysteine-Cysteine disulfide bonds, and hydrophobic interactions. Different quaternary forms of IMPDH relate to the kinetic favorability of the IMPDH mechanism as Bateman domain allosteric binding sites and competitive nature changes with unit composition.

This <scene name='82/823089/Space-filled/2'>space-filled view</scene> helps show the Van der Waals interactions and areas for movement within the structure. The ability for monovalent cations to move within the charged tunnel with the phosphate chain directly relates to activation levels.

<scene name='82/823089/Hydrophobicity_view/1'>Hydrophobicity view</scene> Purple represents polar molecules and gray represents hydrophobic molecules. The hydrophobicity is within the interior of the molecule as the hydrophilic residues are able to interact in a physiological environment.

<scene name='82/823087/Impdh_ligand_view/1'>IMPDH ligand view
</scene>. In this view the black structures are the ACT molecules. These are the ligands of the IMPDH protein. Other ligands include G5P and GDP.

<scene name='82/823089/Catalytic_triad/1'>Catalytic Triad</scene> The IMPDH triad includes Arg (325), Asn (306), and Asp (272). This is represented by the solid red structures in the image. This triad is important as it makes cysteine more reactive, which in turn induces binding.

<scene name='82/823089/Active_binding_site/1'>IMPDH active binding site</scene> The active binding site includes the Bateman domains, which are components within the TIM barrel. Binding occurs after the catalytic triad makes cysteine more reactive. In the image the cysteines are in white (6 in this sequence).

<scene name='82/823089/Charge_view/2'>IMPDH charge</scene> is not strong, as shown by this view. There are positive and negative components within the structure, but a relatively neutral substance is better received in this mechanism due to a physiological environment. Negatively-charged glutamate and positively-charged histidine within this enzyme play a role within the covalent bindings in the mechanism.

<scene name='82/823089/Composition_view/1'>IMPDH composition</scene> The brown represents a protein, red represents a RNA, and green represents ligands.

== Energy Transformation ==

IMPDH is activated by monovalent cations, such as K+ and Na+, within the triose-phosphate isomerase (TIM) barrel. The Arg325-Asn306-Asp272 catalytic triad (Arg322-Asn303-Asp274 in human type II IMPDH) works inter-dependently and synergistically in the TIM barrel active site to make the nucleophilic component, Cysteine, highly reactive to form a temporary covalent bond with the substrate<ref>PMID: 8555204</ref>. Substrates bind randomly to IMPDH as the hydride transfer is quick and NAD is reduced to hydrolyze the covalent intermediate within the enzyme-substrate complex. A covalent intermediate, E-XMP*, is formed, which decreases the energy needed in later nucleophilic and covalent catalysis steps<ref>PMID: 10390600</ref>. Based on normal physiological conditions, the IMPDH mechanism is often not kinetically favorable. The Bateman domains within the TIM barrel are composed of cystathionine beta-synthase motifs that perceive metal ion concentration, cellular energy status, and ionic strength; and will allosterically regulate IMPDH activity<ref>PMID: 31416831</ref>. Eukaryotic IMPDHs have three nucleotide-binding sites in the Bateman domain that allosterically modulate catalytic activity. These three nucleotide-binding sites bind adenine/guanine dinucleoside polyphosphates, and the affinity for these sites increases for these dinucleoside polyphosphates as the activity of IMPDH increases. Purine dinucleoside polyphosphates compete with purine mononucleotides within these sites, so the Bateman domain sites make IMPDH more sensitive to inhibition<ref>PMID: 31416831</ref>. Enzyme catalysis is able to finish with the energy need reduced as the covalent bond is broken later in the reaction to regenerate the enzyme.

</StructureSection>
== References ==

<references />

Sandbox Reserved 1565

2019-12-09T03:18:44Z

Alyssa Ragner:

{{Sandbox_Reserved_BHall_Chem351_F19}}
=='''Inosine-5'-monophosphate dehydrogenase'''==
<StructureSection load='6rpu' size='340' side='right' caption='Structure of the ternary complex of the IMPDH enzyme from Ashbya gossypii bound to the dinucleoside polyphosphate Ap5G and GDP' scene=''>

== Function(s) and Biological Relevance ==

<scene name='82/823089/Cartoon_view/1'>Inosine-5'-monophosphate dehydrogenase</scene> (IMPDH) is the enzyme that catalyzes the rate-limiting step in the ''de novo'' guanine nucleotide biosynthetic pathway, converting inosine monophosphate (IMP) to xanthosine monophosphate (XMP) with the reduction of nicotinamide adenine dinucleotide (NAD). Organisms that undergo the purine nucleotide biosynthetic pathway have IMPDH, including humans. This particular form of IMPDH described and highlighted comes from the recently studied fungus ''Ashbya gossypii'' <ref>PMID: 31416831</ref>. Additional ligands of IMPDH include nicotinamide adenine dinucleotide (NAD), acetate (ACT), and guanosine-5’ monophosphate (5GP). IMPDH is a regulator of the intracellular guanine nucleotide pool amount and helps control control cell division and proliferation, and therefore related to malignant transformation, tumor cell proliferation, and intracellular and extracellular pathogenic infections. Purine dinucleoside polyphosphates are found to bind to the Bateman domain of ''Ashbya gossypii'' IMPDH to allosterically regulate the catalytic activity by competing against purine mononucleotides<ref>PMID: 31416831</ref>.

== Broader Implications ==

The disease pathophysiology is extensive as the improper IMPDH regulation may lead to uncontrolled cell division and proliferation, affecting the immune system's ability to fight off pathogens and signal tumor cells to apoptose. Therapeutic studies using dinucleoside polyphosphates may allosterically regulate the inhibition of IMPDH activity. Dinucleoside polyphosphates have physiological functions including cell division, neurotransmission, apoptosis, vasoconstriction, platelet aggregation, and cellular process variety enhancement from DNA replication to repair<ref>PMID: 31416831</ref>. Selected IMPDH inhibitors composed of dinucleoside polyphosphates may be used to make IMPDHs targets for immunosuppressive, antiviral, and anticancer drugs<ref>PMID: 21517780</ref>, with antibacterial and chemotherapeutic strategies feasibile<ref>PMID: 22928911</ref>.

== Structural Highlights and Structure-Function Relationships ==

The <scene name='82/823089/Secondary_structure/1'>secondary structure</scene> shows alpha helices and beta sheets. The ''Ashbya gossypii'' IMPDH is 31% helical and 15% beta sheet, with the other percentages including random coils and residue structures. The active site is located towards the C-terminus within the TIM barrel, containing 8 alpha-helices and 8 beta sheets.

IMPDH <scene name='82/823087/Impdh_quaternary_structure/1'>quaternary structures</scene> include multiunit complexes, such as tetramers, extended octamers, and compacted octamers. These quaternary structures are created through the binding of multiple subunits of tertiary structures, that are strengthened and structurally formed through hydrogen-bonding, Cysteine-Cysteine disulfide bonds, and hydrophobic interactions. Different quaternary forms of IMPDH relate to the kinetic favorability of the IMPDH mechanism as Bateman domain allosteric binding sites and competitive nature changes with unit composition.

This <scene name='82/823089/Space-filled/2'>space-filled view</scene> helps show the Van der Waals interactions and areas for movement within the structure. The ability for monovalent cations to move within the charged tunnel with the phosphate chain directly relates to activation levels.

<scene name='82/823089/Hydrophobicity_view/1'>Hydrophobicity view</scene> Purple represents polar molecules and gray represents hydrophobic molecules. The hydrophobicity is within the interior of the molecule as the hydrophilic residues are able to interact in a physiological environment.

<scene name='82/823087/Impdh_ligand_view/1'>IMPDH ligand view
</scene>. In this view the black structures are the ACT molecules. These are the ligands of the IMPDH protein. Other ligands include G5P and GDP.

<scene name='82/823089/Catalytic_triad/1'>Catalytic Triad</scene> The IMPDH triad includes Arg (325), Asn (306), and Asp (272). This is represented by the solid red structures in the image. This triad is important as it makes cysteine more reactive, which in turn induces binding.

<scene name='82/823087/Impdh_triad_active_binding/1'>IMPDH active binding site</scene> The active binding site includes the Bateman domains, which are components within the TIM barrel. Binding occurs after the catalytic triad makes cysteine more reactive. In the image the cysteines are in white (6 in this sequence).

<scene name='82/823089/Charge_view/2'>IMPDH charge</scene> is not strong, as shown by this view. There are positive and negative components within the structure, but a relatively neutral substance is better received in this mechanism due to a physiological environment. Negatively-charged glutamate and positively-charged histidine within this enzyme play a role within the covalent bindings in the mechanism.

<scene name='82/823089/Composition_view/1'>IMPDH composition</scene> The brown represents a protein, red represents a RNA, and green represents ligands.

== Energy Transformation ==

IMPDH is activated by monovalent cations, such as K+ and Na+, within the triose-phosphate isomerase (TIM) barrel. The Arg325-Asn306-Asp272 catalytic triad (Arg322-Asn303-Asp274 in human type II IMPDH) works inter-dependently and synergistically in the TIM barrel active site to make the nucleophilic component, Cysteine, highly reactive to form a temporary covalent bond with the substrate<ref>PMID: 8555204</ref>. Substrates bind randomly to IMPDH as the hydride transfer is quick and NAD is reduced to hydrolyze the covalent intermediate within the enzyme-substrate complex. A covalent intermediate, E-XMP*, is formed, which decreases the energy needed in later nucleophilic and covalent catalysis steps<ref>PMID: 10390600</ref>. Based on normal physiological conditions, the IMPDH mechanism is often not kinetically favorable. The Bateman domains within the TIM barrel are composed of cystathionine beta-synthase motifs that perceive metal ion concentration, cellular energy status, and ionic strength; and will allosterically regulate IMPDH activity<ref>PMID: 31416831</ref>. Eukaryotic IMPDHs have three nucleotide-binding sites in the Bateman domain that allosterically modulate catalytic activity. These three nucleotide-binding sites bind adenine/guanine dinucleoside polyphosphates, and the affinity for these sites increases for these dinucleoside polyphosphates as the activity of IMPDH increases. Purine dinucleoside polyphosphates compete with purine mononucleotides within these sites, so the Bateman domain sites make IMPDH more sensitive to inhibition<ref>PMID: 31416831</ref>. Enzyme catalysis is able to finish with the energy need reduced as the covalent bond is broken later in the reaction to regenerate the enzyme.

</StructureSection>
== References ==

<references />

Sandbox Reserved 1565

2019-12-09T03:03:01Z

Alyssa Ragner:

{{Sandbox_Reserved_BHall_Chem351_F19}}
=='''Inosine-5'-monophosphate dehydrogenase'''==
<StructureSection load='6rpu' size='340' side='right' caption='Structure of the ternary complex of the IMPDH enzyme from Ashbya gossypii bound to the dinucleoside polyphosphate Ap5G and GDP' scene=''>

== Function(s) and Biological Relevance ==

<scene name='82/823089/Cartoon_view/1'>Inosine-5'-monophosphate dehydrogenase</scene> (IMPDH) is the enzyme that catalyzes the rate-limiting step in the ''de novo'' guanine nucleotide biosynthetic pathway, converting inosine monophosphate (IMP) to xanthosine monophosphate (XMP) with the reduction of nicotinamide adenine dinucleotide (NAD). Organisms that undergo the purine nucleotide biosynthetic pathway have IMPDH, including humans. This particular form of IMPDH described and highlighted comes from the recently studied fungus ''Ashbya gossypii'' <ref>PMID: 31416831</ref>. Additional ligands of IMPDH include nicotinamide adenine dinucleotide (NAD), acetate (ACT), and guanosine-5’ monophosphate (5GP). IMPDH is a regulator of the intracellular guanine nucleotide pool amount and helps control control cell division and proliferation, and therefore related to malignant transformation, tumor cell proliferation, and intracellular and extracellular pathogenic infections. Purine dinucleoside polyphosphates are found to bind to the Bateman domain of ''Ashbya gossypii'' IMPDH to allosterically regulate the catalytic activity by competing against purine mononucleotides<ref>PMID: 31416831</ref>.

== Broader Implications ==

The disease pathophysiology is extensive as the improper IMPDH regulation may lead to uncontrolled cell division and proliferation, affecting the immune system's ability to fight off pathogens and signal tumor cells to apoptose. Therapeutic studies using dinucleoside polyphosphates may allosterically regulate the inhibition of IMPDH activity. Dinucleoside polyphosphates have physiological functions including cell division, neurotransmission, apoptosis, vasoconstriction, platelet aggregation, and cellular process variety enhancement from DNA replication to repair<ref>PMID: 31416831</ref>. Selected IMPDH inhibitors composed of dinucleoside polyphosphates may be used to make IMPDHs targets for immunosuppressive, antiviral, and anticancer drugs<ref>PMID: 21517780</ref>, with antibacterial and chemotherapeutic strategies feasibile<ref>PMID: 22928911</ref>.

== Structural Highlights and Structure-Function Relationships ==

The <scene name='82/823089/Secondary_structure/1'>secondary structure</scene> shows alpha helices and beta sheets. The ''Ashbya gossypii'' IMPDH is 31% helical and 15% beta sheet, with the other percentages including random coils and residue structures. The active site is located towards the C-terminus within the TIM barrel, containing 8 alpha-helices and 8 beta sheets.

IMPDH <scene name='82/823087/Impdh_quaternary_structure/1'>quaternary structures</scene> include multiunit complexes, such as tetramers, extended octamers, and compacted octamers. These quaternary structures are created through the binding of multiple subunits of tertiary structures, that are strengthened and structurally formed through hydrogen-bonding, Cysteine-Cysteine disulfide bonds, and hydrophobic interactions. Different quaternary forms of IMPDH relate to the kinetic favorability of the IMPDH mechanism as Bateman domain allosteric binding sites and competitive nature changes with unit composition.

This <scene name='82/823089/Space-filled/2'>space-filled view</scene> helps show the Van der Waals interactions and areas for movement within the structure. The ability for monovalent cations to move within the charged tunnel with the phosphate chain directly relates to activation levels.

<scene name='82/823089/Hydrophobicity_view/1'>Hydrophobicity view</scene> Purple represents polar molecules and gray represents hydrophobic molecules. The hydrophobicity is within the interior of the molecule as the hydrophilic residues are able to interact in a physiological environment.

<scene name='82/823087/Impdh_ligand_view/1'>IMPDH ligand view
</scene>. In this view the black structures are the ACT molecules. These are the ligands of the IMPDH protein. Other ligands include G5P and GDP.

<scene name='82/823087/Impdh_triad/3'>IMPDH Triad</scene> The IMPDH triad includes Arg (325), Asn (306), and Asp (272). This is represented by the solid red structures in the image. This triad is important as it makes cysteine more reactive, which in turn induces binding.

<scene name='82/823087/Impdh_triad_active_binding/1'>IMPDH active binding site</scene> The active binding site includes the Bateman domains, which are components within the TIM barrel. Binding occurs after the catalytic triad makes cysteine more reactive. In the image the cysteines are in white (6 in this sequence).

<scene name='82/823089/Charge_view/2'>IMPDH charge</scene> is not strong, as shown by this view. There are positive and negative components within the structure, but a relatively neutral substance is better received in this mechanism due to a physiological environment. Negatively-charged glutamate and positively-charged histidine within this enzyme play a role within the covalent bindings in the mechanism.

<scene name='82/823089/Composition_view/1'>IMPDH composition</scene> The brown represents a protein, red represents a RNA, and green represents ligands.

== Energy Transformation ==

IMPDH is activated by monovalent cations, such as K+ and Na+, within the triose-phosphate isomerase (TIM) barrel. The Arg325-Asn306-Asp272 catalytic triad (Arg322-Asn303-Asp274 in human type II IMPDH) works inter-dependently and synergistically in the TIM barrel active site to make the nucleophilic component, Cysteine, highly reactive to form a temporary covalent bond with the substrate<ref>PMID: 8555204</ref>. Substrates bind randomly to IMPDH as the hydride transfer is quick and NAD is reduced to hydrolyze the covalent intermediate within the enzyme-substrate complex. A covalent intermediate, E-XMP*, is formed, which decreases the energy needed in later nucleophilic and covalent catalysis steps<ref>PMID: 10390600</ref>. Based on normal physiological conditions, the IMPDH mechanism is often not kinetically favorable. The Bateman domains within the TIM barrel are composed of cystathionine beta-synthase motifs that perceive metal ion concentration, cellular energy status, and ionic strength; and will allosterically regulate IMPDH activity<ref>PMID: 31416831</ref>. Eukaryotic IMPDHs have three nucleotide-binding sites in the Bateman domain that allosterically modulate catalytic activity. These three nucleotide-binding sites bind adenine/guanine dinucleoside polyphosphates, and the affinity for these sites increases for these dinucleoside polyphosphates as the activity of IMPDH increases. Purine dinucleoside polyphosphates compete with purine mononucleotides within these sites, so the Bateman domain sites make IMPDH more sensitive to inhibition<ref>PMID: 31416831</ref>. Enzyme catalysis is able to finish with the energy need reduced as the covalent bond is broken later in the reaction to regenerate the enzyme.

</StructureSection>
== References ==

<references />

Sandbox Reserved 1565

2019-12-09T02:26:30Z

Alyssa Ragner:

{{Sandbox_Reserved_BHall_Chem351_F19}}
=='''Inosine-5'-monophosphate dehydrogenase'''==
<StructureSection load='6rpu' size='340' side='right' caption='Structure of the ternary complex of the IMPDH enzyme from Ashbya gossypii bound to the dinucleoside polyphosphate Ap5G and GDP' scene=''>

== Function(s) and Biological Relevance ==

<scene name='82/823089/Cartoon_view/1'>Inosine-5'-monophosphate dehydrogenase</scene> (IMPDH) is the enzyme that catalyzes the rate-limiting step in the ''de novo'' guanine nucleotide biosynthetic pathway, converting inosine monophosphate (IMP) to xanthosine monophosphate (XMP) with the reduction of nicotinamide adenine dinucleotide (NAD). Organisms that undergo the purine nucleotide biosynthetic pathway have IMPDH, including humans. This particular form of IMPDH described and highlighted comes from the recently studied fungus ''Ashbya gossypii'' <ref>PMID: 31416831</ref>. Additional ligands of IMPDH include nicotinamide adenine dinucleotide (NAD), acetate (ACT), and guanosine-5’ monophosphate (5GP). IMPDH is a regulator of the intracellular guanine nucleotide pool amount and helps control control cell division and proliferation, and therefore related to malignant transformation, tumor cell proliferation, and intracellular and extracellular pathogenic infections. Purine dinucleoside polyphosphates are found to bind to the Bateman domain of ''Ashbya gossypii'' IMPDH to allosterically regulate the catalytic activity by competing against purine mononucleotides<ref>PMID: 31416831</ref>.

== Broader Implications ==

The disease pathophysiology is extensive as the improper IMPDH regulation may lead to uncontrolled cell division and proliferation, affecting the immune system's ability to fight off pathogens and signal tumor cells to apoptose. Therapeutic studies using dinucleoside polyphosphates may allosterically regulate the inhibition of IMPDH activity. Dinucleoside polyphosphates have physiological functions including cell division, neurotransmission, apoptosis, vasoconstriction, platelet aggregation, and cellular process variety enhancement from DNA replication to repair<ref>PMID: 31416831</ref>. Selected IMPDH inhibitors composed of dinucleoside polyphosphates may be used to make IMPDHs targets for immunosuppressive, antiviral, and anticancer drugs<ref>PMID: 21517780</ref>, with antibacterial and chemotherapeutic strategies feasibile<ref>PMID: 22928911</ref>.

== Structural Highlights and Structure-Function Relationships ==

The <scene name='82/823089/Secondary_structure/1'>secondary structure</scene> shows alpha helices and beta sheets. The ''Ashbya gossypii'' IMPDH is 31% helical and 15% beta sheet, with the other percentages including random coils and residue structures. The active site is located towards the C-terminus within the TIM barrel, containing 8 alpha-helices and 8 beta sheets.

IMPDH <scene name='82/823087/Impdh_quaternary_structure/1'>quaternary structures</scene> include multiunit complexes, such as tetramers, extended octamers, and compacted octamers. These quaternary structures are created through the binding of multiple subunits of tertiary structures, that are strengthened and structurally formed through hydrogen-bonding, Cysteine-Cysteine disulfide bonds, and hydrophobic interactions. Different quaternary forms of IMPDH relate to the kinetic favorability of the IMPDH mechanism as Bateman domain allosteric binding sites and competitive nature changes with unit composition.

This <scene name='82/823089/Space-filled/2'>space-filled view</scene> helps show the Van der Waals interactions and areas for movement within the structure. The ability for monovalent cations to move within the charged tunnel with the phosphate chain directly relates to activation levels.

<scene name='82/823089/Hydrophobicity_view/1'>Hydrophobicity view</scene> Purple represents polar molecules and gray represents hydrophobic molecules. The hydrophobicity is within the interior of the molecule as the hydrophilic residues are able to interact in a physiological environment.

<scene name='82/823087/Impdh_ligand_view/1'>IMPDH ligand view
</scene>. In this view the black structures are the ACT molecules. These are the ligands of the IMPDH protein. Other ligands include G5P and GDP.

<scene name='82/823087/Impdh_triad/3'>IMPDH Triad</scene> The IMPDH triad includes Arg (320), Asn (306), and Asp (272). This is represented by the solid red structures in the image. This triad is important as it makes cysteine more reactive, which in turn induces binding.

<scene name='82/823087/Impdh_triad_active_binding/1'>IMPDH active binding site</scene> The active binding site includes the Bateman domains, which are components within the TIM barrel. Binding occurs after the catalytic triad makes cysteine more reactive. In the image the cysteines are in white (6 in this sequence).

<scene name='82/823089/Charge_view/2'>IMPDH charge</scene> is not strong, as shown by this view. There are positive and negative components within the structure, but a relatively neutral substance is better received in this mechanism due to a physiological environment. Negatively-charged glutamate and positively-charged histidine within this enzyme play a role within the covalent bindings in the mechanism.

<scene name='82/823089/Composition_view/1'>IMPDH composition</scene> The brown represents a protein, red represents a RNA, and green represents ligands.

== Energy Transformation ==

IMPDH is activated by monovalent cations, such as K+ and Na+, within the triose-phosphate isomerase (TIM) barrel. The Arg320-Asn306-Asp272 catalytic triad (Arg322-Asn303-Asp274 in human type II IMPDH) works inter-dependently and synergistically in the TIM barrel active site to make the nucleophilic component, Cysteine, highly reactive to form a temporary covalent bond with the substrate<ref>PMID: 8555204</ref>. Substrates bind randomly to IMPDH as the hydride transfer is quick and NAD is reduced to hydrolyze the covalent intermediate within the enzyme-substrate complex. A covalent intermediate, E-XMP*, is formed, which decreases the energy needed in later nucleophilic and covalent catalysis steps<ref>PMID: 10390600</ref>. Based on normal physiological conditions, the IMPDH mechanism is often not kinetically favorable. The Bateman domains within the TIM barrel are composed of cystathionine beta-synthase motifs that perceive metal ion concentration, cellular energy status, and ionic strength; and will allosterically regulate IMPDH activity<ref>PMID: 31416831</ref>. Eukaryotic IMPDHs have three nucleotide-binding sites in the Bateman domain that allosterically modulate catalytic activity. These three nucleotide-binding sites bind adenine/guanine dinucleoside polyphosphates, and the affinity for these sites increases for these dinucleoside polyphosphates as the activity of IMPDH increases. Purine dinucleoside polyphosphates compete with purine mononucleotides within these sites, so the Bateman domain sites make IMPDH more sensitive to inhibition<ref>PMID: 31416831</ref>. Enzyme catalysis is able to finish with the energy need reduced as the covalent bond is broken later in the reaction to regenerate the enzyme.

</StructureSection>
== References ==

<references />

Sandbox Reserved 1565

2019-12-09T02:21:03Z

Alyssa Ragner:

{{Sandbox_Reserved_BHall_Chem351_F19}}
=='''Inosine-5'-monophosphate dehydrogenase'''==
<StructureSection load='6rpu' size='340' side='right' caption='Structure of the ternary complex of the IMPDH enzyme from Ashbya gossypii bound to the dinucleoside polyphosphate Ap5G and GDP' scene=''>

== Function(s) and Biological Relevance ==

<scene name='82/823089/Cartoon_view/1'>Inosine-5'-monophosphate dehydrogenase</scene> (IMPDH) is the enzyme that catalyzes the rate-limiting step in the ''de novo'' guanine nucleotide biosynthetic pathway, converting inosine monophosphate (IMP) to xanthosine monophosphate (XMP) with the reduction of nicotinamide adenine dinucleotide (NAD). Organisms that undergo the purine nucleotide biosynthetic pathway have IMPDH, including humans. This particular form of IMPDH described and highlighted comes from the recently studied fungus ''Ashbya gossypii'' <ref>PMID: 31416831</ref>. Additional ligands of IMPDH include nicotinamide adenine dinucleotide (NAD), acetate (ACT), and guanosine-5’ monophosphate (5GP). IMPDH is a regulator of the intracellular guanine nucleotide pool amount and helps control control cell division and proliferation, and therefore related to malignant transformation, tumor cell proliferation, and intracellular and extracellular pathogenic infections. Purine dinucleoside polyphosphates are found to bind to the Bateman domain of ''Ashbya gossypii'' IMPDH to allosterically regulate the catalytic activity by competing against purine mononucleotides<ref>PMID: 31416831</ref>.

== Broader Implications ==

The disease pathophysiology is extensive as the improper IMPDH regulation may lead to uncontrolled cell division and proliferation, affecting the immune system's ability to fight off pathogens and signal tumor cells to apoptose. Therapeutic studies using dinucleoside polyphosphates may allosterically regulate the inhibition of IMPDH activity. Dinucleoside polyphosphates have physiological functions including cell division, neurotransmission, apoptosis, vasoconstriction, platelet aggregation, and cellular process variety enhancement from DNA replication to repair<ref>PMID: 31416831</ref>. Selected IMPDH inhibitors composed of dinucleoside polyphosphates may be used to make IMPDHs targets for immunosuppressive, antiviral, and anticancer drugs<ref>PMID: 21517780</ref>, with antibacterial and chemotherapeutic strategies feasibile<ref>PMID: 22928911</ref>.

== Structural Highlights and Structure-Function Relationships ==

The <scene name='82/823089/Secondary_structure/1'>secondary structure</scene> shows alpha helices and beta sheets. The ''Ashbya gossypii'' IMPDH is 31% helical and 15% beta sheet, with the other percentages including random coils and residue structures. The active site is located towards the C-terminus within the TIM barrel, containing 8 alpha-helices and 8 beta sheets.

IMPDH <scene name='82/823087/Impdh_quaternary_structure/1'>quaternary structures</scene> include multiunit complexes, such as tetramers, extended octamers, and compacted octamers. These quaternary structures are created through the binding of multiple subunits of tertiary structures, that are strengthened and structurally formed through hydrogen-bonding, Cysteine-Cysteine disulfide bonds, and hydrophobic interactions. Different quaternary forms of IMPDH relate to the kinetic favorability of the IMPDH mechanism as Bateman domain allosteric binding sites and competitive nature changes with unit composition.

This <scene name='82/823089/Space-filled/2'>space-filled view</scene> helps show the Van der Waals interactions and areas for movement within the structure. The ability for monovalent cations to move within the charged tunnel with the phosphate chain directly relates to activation levels.

<scene name='82/823089/Hydrophobicity_view/1'>Hydrophobicity view</scene> Purple represents polar molecules and gray represents hydrophobic molecules. The hydrophobicity is within the interior of the molecule as the hydrophilic residues are able to interact in a physiological environment.

<scene name='82/823087/Impdh_ligand_view/1'>IMPDH ligand view
</scene>. In this view the black structures are the ACT molecules. These are the ligands of the IMPDH protein. Other ligands include G5P and GDP.

<scene name='82/823087/Impdh_triad/3'>IMPDH Triad</scene> The IMPDH triad includes Arg (320), Asn (306), and Asp (272). This is represented by the solid red structures in the image. This triad is important as it makes cysteine more reactive, which in turn induces binding.

<scene name='82/823087/Impdh_triad_active_binding/1'>IMPDH active binding site</scene> The active binding site includes the Bateman domains, which are components within the TIM barrel. Binding occurs after the catalytic triad makes cysteine more reactive. In the image the cysteines are in white (6 in this sequence).

<scene name='82/823089/Charge_view/1'>IMPDH charge</scene> is not strong, as shown by this view. There are positive and negative components within the structure, but a relatively neutral substance is better received in this mechanism due to a physiological environment. Negatively-charged glutamate and positively-charged histidine within this enzyme play a role within the covalent bindings in the mechanism.

<scene name='82/823089/Composition_view/1'>IMPDH composition</scene> The brown represents a protein, red represents a RNA, and green represents ligands.

== Energy Transformation ==

IMPDH is activated by monovalent cations, such as K+ and Na+, within the triose-phosphate isomerase (TIM) barrel. The Arg320-Asn306-Asp272 catalytic triad (Arg322-Asn303-Asp274 in human type II IMPDH) works inter-dependently and synergistically in the TIM barrel active site to make the nucleophilic component, Cysteine, highly reactive to form a temporary covalent bond with the substrate<ref>PMID: 8555204</ref>. Substrates bind randomly to IMPDH as the hydride transfer is quick and NAD is reduced to hydrolyze the covalent intermediate within the enzyme-substrate complex. A covalent intermediate, E-XMP*, is formed, which decreases the energy needed in later nucleophilic and covalent catalysis steps<ref>PMID: 10390600</ref>. Based on normal physiological conditions, the IMPDH mechanism is often not kinetically favorable. The Bateman domains within the TIM barrel are composed of cystathionine beta-synthase motifs that perceive metal ion concentration, cellular energy status, and ionic strength; and will allosterically regulate IMPDH activity<ref>PMID: 31416831</ref>. Eukaryotic IMPDHs have three nucleotide-binding sites in the Bateman domain that allosterically modulate catalytic activity. These three nucleotide-binding sites bind adenine/guanine dinucleoside polyphosphates, and the affinity for these sites increases for these dinucleoside polyphosphates as the activity of IMPDH increases. Purine dinucleoside polyphosphates compete with purine mononucleotides within these sites, so the Bateman domain sites make IMPDH more sensitive to inhibition<ref>PMID: 31416831</ref>. Enzyme catalysis is able to finish with the energy need reduced as the covalent bond is broken later in the reaction to regenerate the enzyme.

</StructureSection>
== References ==

<references />

Sandbox Reserved 1565

2019-12-09T02:15:28Z

Alyssa Ragner:

{{Sandbox_Reserved_BHall_Chem351_F19}}
=='''Inosine-5'-monophosphate dehydrogenase'''==
<StructureSection load='6rpu' size='340' side='right' caption='Structure of the ternary complex of the IMPDH enzyme from Ashbya gossypii bound to the dinucleoside polyphosphate Ap5G and GDP' scene=''>

== Function(s) and Biological Relevance ==

<scene name='82/823089/Cartoon_view/1'>Inosine-5'-monophosphate dehydrogenase</scene> (IMPDH) is the enzyme that catalyzes the rate-limiting step in the ''de novo'' guanine nucleotide biosynthetic pathway, converting inosine monophosphate (IMP) to xanthosine monophosphate (XMP) with the reduction of nicotinamide adenine dinucleotide (NAD). Organisms that undergo the purine nucleotide biosynthetic pathway have IMPDH, including humans. This particular form of IMPDH described and highlighted comes from the recently studied fungus ''Ashbya gossypii'' <ref>PMID: 31416831</ref>. Additional ligands of IMPDH include nicotinamide adenine dinucleotide (NAD), acetate (ACT), and guanosine-5’ monophosphate (5GP). IMPDH is a regulator of the intracellular guanine nucleotide pool amount and helps control control cell division and proliferation, and therefore related to malignant transformation, tumor cell proliferation, and intracellular and extracellular pathogenic infections. Purine dinucleoside polyphosphates are found to bind to the Bateman domain of ''Ashbya gossypii'' IMPDH to allosterically regulate the catalytic activity by competing against purine mononucleotides<ref>PMID: 31416831</ref>.

== Broader Implications ==

The disease pathophysiology is extensive as the improper IMPDH regulation may lead to uncontrolled cell division and proliferation, affecting the immune system's ability to fight off pathogens and signal tumor cells to apoptose. Therapeutic studies using dinucleoside polyphosphates may allosterically regulate the inhibition of IMPDH activity. Dinucleoside polyphosphates have physiological functions including cell division, neurotransmission, apoptosis, vasoconstriction, platelet aggregation, and cellular process variety enhancement from DNA replication to repair<ref>PMID: 31416831</ref>. Selected IMPDH inhibitors composed of dinucleoside polyphosphates may be used to make IMPDHs targets for immunosuppressive, antiviral, and anticancer drugs<ref>PMID: 21517780</ref>, with antibacterial and chemotherapeutic strategies feasibile<ref>PMID: 22928911</ref>.

== Structural Highlights and Structure-Function Relationships ==

The <scene name='82/823089/Secondary_structure/1'>secondary structure</scene> shows alpha helices and beta sheets. The ''Ashbya gossypii'' IMPDH is 31% helical and 15% beta sheet, with the other percentages including random coils and residue structures. The active site is located towards the C-terminus within the TIM barrel, containing 8 alpha-helices and 8 beta sheets.

IMPDH <scene name='82/823087/Impdh_quaternary_structure/1'>quaternary structures</scene> include multiunit complexes, such as tetramers, extended octamers, and compacted octamers. These quaternary structures are created through the binding of multiple subunits of tertiary structures, that are strengthened and structurally formed through hydrogen-bonding, Cysteine-Cysteine disulfide bonds, and hydrophobic interactions. Different quaternary forms of IMPDH relate to the kinetic favorability of the IMPDH mechanism as Bateman domain allosteric binding sites and competitive nature changes with unit composition.

This <scene name='82/823089/Space-filled/2'>space-filled view</scene> helps show the Van der Waals interactions and areas for movement within the structure. The ability for monovalent cations to move within the charged tunnel with the phosphate chain directly relates to activation levels.

<scene name='82/823089/Hydrophobicity_view/1'>Hydrophobicity view</scene> Purple represents polar molecules and gray represents hydrophobic molecules. The hydrophobicity is within the interior of the molecule as the hydrophilic residues are able to interact in a physiological environment.

<scene name='82/823087/Impdh_ligand_view/1'>IMPDH ligand view
</scene>. In this view the black structures are the ACT molecules. These are the ligands of the IMPDH protein. Other ligands include G5P and GDP.

<scene name='82/823087/Impdh_triad/3'>IMPDH Triad</scene> The IMPDH triad includes Arg (320), Asn (306), and Asp (272). This is represented by the solid red structures in the image. This triad is important as it makes cysteine more reactive, which in turn induces binding.

<scene name='82/823087/Impdh_triad_active_binding/1'>IMPDH active binding site</scene> The active binding site includes the Bateman domains, which are components within the TIM barrel. Binding occurs after the catalytic triad makes cysteine more reactive. In the image the cysteines are in white (6 in this sequence).

<scene name='82/823089/Charge_view/1'>IMPDH charge</scene> is not strong, as shown by this view. There are positive and negative components within the structure, but a relatively neutral substance is better received in this mechanism due to a physiological environment. Negatively-charged glutamate and positively-charged histidine within this enzyme play a role within the covalent bindings in the mechanism.

<scene name='82/823087/Impdh_composition/1'>IMPDH Composition</scene> The brown represents a protein, red represents a RNA, and green represents ligands.

== Energy Transformation ==

IMPDH is activated by monovalent cations, such as K+ and Na+, within the triose-phosphate isomerase (TIM) barrel. The Arg320-Asn306-Asp272 catalytic triad (Arg322-Asn303-Asp274 in human type II IMPDH) works inter-dependently and synergistically in the TIM barrel active site to make the nucleophilic component, Cysteine, highly reactive to form a temporary covalent bond with the substrate<ref>PMID: 8555204</ref>. Substrates bind randomly to IMPDH as the hydride transfer is quick and NAD is reduced to hydrolyze the covalent intermediate within the enzyme-substrate complex. A covalent intermediate, E-XMP*, is formed, which decreases the energy needed in later nucleophilic and covalent catalysis steps<ref>PMID: 10390600</ref>. Based on normal physiological conditions, the IMPDH mechanism is often not kinetically favorable. The Bateman domains within the TIM barrel are composed of cystathionine beta-synthase motifs that perceive metal ion concentration, cellular energy status, and ionic strength; and will allosterically regulate IMPDH activity<ref>PMID: 31416831</ref>. Eukaryotic IMPDHs have three nucleotide-binding sites in the Bateman domain that allosterically modulate catalytic activity. These three nucleotide-binding sites bind adenine/guanine dinucleoside polyphosphates, and the affinity for these sites increases for these dinucleoside polyphosphates as the activity of IMPDH increases. Purine dinucleoside polyphosphates compete with purine mononucleotides within these sites, so the Bateman domain sites make IMPDH more sensitive to inhibition<ref>PMID: 31416831</ref>. Enzyme catalysis is able to finish with the energy need reduced as the covalent bond is broken later in the reaction to regenerate the enzyme.

</StructureSection>
== References ==

<references />

Sandbox Reserved 1565

2019-12-09T02:12:22Z

Alyssa Ragner:

{{Sandbox_Reserved_BHall_Chem351_F19}}
=='''Inosine-5'-monophosphate dehydrogenase'''==
<StructureSection load='6rpu' size='340' side='right' caption='Structure of the ternary complex of the IMPDH enzyme from Ashbya gossypii bound to the dinucleoside polyphosphate Ap5G and GDP' scene=''>

== Function(s) and Biological Relevance ==

<scene name='82/823087/Impdh/1'>Inosine-5'-monophosphate dehydrogenase</scene> (IMPDH) is the enzyme that catalyzes the rate-limiting step in the ''de novo'' guanine nucleotide biosynthetic pathway, converting inosine monophosphate (IMP) to xanthosine monophosphate (XMP) with the reduction of nicotinamide adenine dinucleotide (NAD). Organisms that undergo the purine nucleotide biosynthetic pathway have IMPDH, including humans. This particular form of IMPDH described and highlighted comes from the recently studied fungus ''Ashbya gossypii'' <ref>PMID: 31416831</ref>. Additional ligands of IMPDH include nicotinamide adenine dinucleotide (NAD), acetate (ACT), and guanosine-5’ monophosphate (5GP). IMPDH is a regulator of the intracellular guanine nucleotide pool amount and helps control control cell division and proliferation, and therefore related to malignant transformation, tumor cell proliferation, and intracellular and extracellular pathogenic infections. Purine dinucleoside polyphosphates are found to bind to the Bateman domain of ''Ashbya gossypii'' IMPDH to allosterically regulate the catalytic activity by competing against purine mononucleotides<ref>PMID: 31416831</ref>.

== Broader Implications ==

The disease pathophysiology is extensive as the improper IMPDH regulation may lead to uncontrolled cell division and proliferation, affecting the immune system's ability to fight off pathogens and signal tumor cells to apoptose. Therapeutic studies using dinucleoside polyphosphates may allosterically regulate the inhibition of IMPDH activity. Dinucleoside polyphosphates have physiological functions including cell division, neurotransmission, apoptosis, vasoconstriction, platelet aggregation, and cellular process variety enhancement from DNA replication to repair<ref>PMID: 31416831</ref>. Selected IMPDH inhibitors composed of dinucleoside polyphosphates may be used to make IMPDHs targets for immunosuppressive, antiviral, and anticancer drugs<ref>PMID: 21517780</ref>, with antibacterial and chemotherapeutic strategies feasibile<ref>PMID: 22928911</ref>.

== Structural Highlights and Structure-Function Relationships ==

The <scene name='82/823089/Secondary_structure/1'>secondary structure</scene> shows alpha helices and beta sheets. The ''Ashbya gossypii'' IMPDH is 31% helical and 15% beta sheet, with the other percentages including random coils and residue structures. The active site is located towards the C-terminus within the TIM barrel, containing 8 alpha-helices and 8 beta sheets.

IMPDH <scene name='82/823087/Impdh_quaternary_structure/1'>quaternary structures</scene> include multiunit complexes, such as tetramers, extended octamers, and compacted octamers. These quaternary structures are created through the binding of multiple subunits of tertiary structures, that are strengthened and structurally formed through hydrogen-bonding, Cysteine-Cysteine disulfide bonds, and hydrophobic interactions. Different quaternary forms of IMPDH relate to the kinetic favorability of the IMPDH mechanism as Bateman domain allosteric binding sites and competitive nature changes with unit composition.

This <scene name='82/823089/Space-filled/2'>space-filled view</scene> helps show the Van der Waals interactions and areas for movement within the structure. The ability for monovalent cations to move within the charged tunnel with the phosphate chain directly relates to activation levels.

<scene name='82/823089/Hydrophobicity_view/1'>Hydrophobicity view</scene> Purple represents polar molecules and gray represents hydrophobic molecules. The hydrophobicity is within the interior of the molecule as the hydrophilic residues are able to interact in a physiological environment.

<scene name='82/823087/Impdh_ligand_view/1'>IMPDH ligand view
</scene>. In this view the black structures are the ACT molecules. These are the ligands of the IMPDH protein. Other ligands include G5P and GDP.

<scene name='82/823087/Impdh_triad/3'>IMPDH Triad</scene> The IMPDH triad includes Arg (320), Asn (306), and Asp (272). This is represented by the solid red structures in the image. This triad is important as it makes cysteine more reactive, which in turn induces binding.

<scene name='82/823087/Impdh_triad_active_binding/1'>IMPDH active binding site</scene> The active binding site includes the Bateman domains, which are components within the TIM barrel. Binding occurs after the catalytic triad makes cysteine more reactive. In the image the cysteines are in white (6 in this sequence).

<scene name='82/823089/Charge_view/1'>IMPDH charge</scene> is not strong, as shown by this view. There are positive and negative components within the structure, but a relatively neutral substance is better received in this mechanism due to a physiological environment. Negatively-charged glutamate and positively-charged histidine within this enzyme play a role within the covalent bindings in the mechanism.

<scene name='82/823087/Impdh_composition/1'>IMPDH Composition</scene> The brown represents a protein, red represents a RNA, and green represents ligands.

== Energy Transformation ==

IMPDH is activated by monovalent cations, such as K+ and Na+, within the triose-phosphate isomerase (TIM) barrel. The Arg320-Asn306-Asp272 catalytic triad (Arg322-Asn303-Asp274 in human type II IMPDH) works inter-dependently and synergistically in the TIM barrel active site to make the nucleophilic component, Cysteine, highly reactive to form a temporary covalent bond with the substrate<ref>PMID: 8555204</ref>. Substrates bind randomly to IMPDH as the hydride transfer is quick and NAD is reduced to hydrolyze the covalent intermediate within the enzyme-substrate complex. A covalent intermediate, E-XMP*, is formed, which decreases the energy needed in later nucleophilic and covalent catalysis steps<ref>PMID: 10390600</ref>. Based on normal physiological conditions, the IMPDH mechanism is often not kinetically favorable. The Bateman domains within the TIM barrel are composed of cystathionine beta-synthase motifs that perceive metal ion concentration, cellular energy status, and ionic strength; and will allosterically regulate IMPDH activity<ref>PMID: 31416831</ref>. Eukaryotic IMPDHs have three nucleotide-binding sites in the Bateman domain that allosterically modulate catalytic activity. These three nucleotide-binding sites bind adenine/guanine dinucleoside polyphosphates, and the affinity for these sites increases for these dinucleoside polyphosphates as the activity of IMPDH increases. Purine dinucleoside polyphosphates compete with purine mononucleotides within these sites, so the Bateman domain sites make IMPDH more sensitive to inhibition<ref>PMID: 31416831</ref>. Enzyme catalysis is able to finish with the energy need reduced as the covalent bond is broken later in the reaction to regenerate the enzyme.

</StructureSection>
== References ==

<references />

Sandbox Reserved 1565

2019-12-09T02:11:27Z

Alyssa Ragner:

{{Sandbox_Reserved_BHall_Chem351_F19}}
=='''Inosine-5'-monophosphate dehydrogenase'''==
<StructureSection load='6rpu' size='340' side='right' caption='Structure of the ternary complex of the IMPDH enzyme from Ashbya gossypii bound to the dinucleoside polyphosphate Ap5G and GDP' scene=''>

== Function(s) and Biological Relevance ==

<scene name='82/823087/Impdh/1'>Inosine-5'-monophosphate dehydrogenase</scene> (IMPDH) is the enzyme that catalyzes the rate-limiting step in the ''de novo'' guanine nucleotide biosynthetic pathway, converting inosine monophosphate (IMP) to xanthosine monophosphate (XMP) with the reduction of nicotinamide adenine dinucleotide (NAD). Organisms that undergo the purine nucleotide biosynthetic pathway have IMPDH, including humans. This particular form of IMPDH described and highlighted comes from the recently studied fungus ''Ashbya gossypii'' <ref>PMID: 31416831</ref>. Additional ligands of IMPDH include nicotinamide adenine dinucleotide (NAD), acetate (ACT), and guanosine-5’ monophosphate (5GP). IMPDH is a regulator of the intracellular guanine nucleotide pool amount and helps control control cell division and proliferation, and therefore related to malignant transformation, tumor cell proliferation, and intracellular and extracellular pathogenic infections. Purine dinucleoside polyphosphates are found to bind to the Bateman domain of ''Ashbya gossypii'' IMPDH to allosterically regulate the catalytic activity by competing against purine mononucleotides<ref>PMID: 31416831</ref>.

== Broader Implications ==

The disease pathophysiology is extensive as the improper IMPDH regulation may lead to uncontrolled cell division and proliferation, affecting the immune system's ability to fight off pathogens and signal tumor cells to apoptose. Therapeutic studies using dinucleoside polyphosphates may allosterically regulate the inhibition of IMPDH activity. Dinucleoside polyphosphates have physiological functions including cell division, neurotransmission, apoptosis, vasoconstriction, platelet aggregation, and cellular process variety enhancement from DNA replication to repair<ref>PMID: 31416831</ref>. Selected IMPDH inhibitors composed of dinucleoside polyphosphates may be used to make IMPDHs targets for immunosuppressive, antiviral, and anticancer drugs<ref>PMID: 21517780</ref>, with antibacterial and chemotherapeutic strategies feasibile<ref>PMID: 22928911</ref>.

== Structural Highlights and Structure-Function Relationships ==

The <scene name='82/823089/Secondary_structure/1'>secondary structure</scene> shows alpha helices and beta sheets. The ''Ashbya gossypii'' IMPDH is 31% helical and 15% beta sheet, with the other percentages including random coils and residue structures. The active site is located towards the C-terminus within the TIM barrel, containing 8 alpha-helices and 8 beta sheets.

IMPDH <scene name='82/823087/Impdh_quaternary_structure/1'>quaternary structures</scene> include multiunit complexes, such as tetramers, extended octamers, and compacted octamers. These quaternary structures are created through the binding of multiple subunits of tertiary structures, that are strengthened and structurally formed through hydrogen-bonding, Cysteine-Cysteine disulfide bonds, and hydrophobic interactions. Different quaternary forms of IMPDH relate to the kinetic favorability of the IMPDH mechanism as Bateman domain allosteric binding sites and competitive nature changes with unit composition.

This <scene name='82/823089/Space-filled/2'>space-filled view</scene> helps show the Van der Waals interactions and areas for movement within the structure. The ability for monovalent cations to move within the charged tunnel with the phosphate chain directly relates to activation levels.

<scene name='82/823089/Hydrophobicity_view/1'>Hydrophobicity view</scene> Purple represents polar molecules and gray represents hydrophobic molecules. The hydrophobicity is within the interior of the molecule as the hydrophilic residues are able to interact in a physiological environment.

<scene name='82/823087/Impdh_ligand_view/1'>IMPDH ligand view
</scene>. In this view the black structures are the ACT molecules. These are the ligands of the IMPDH protein. Other ligands include G5P and GDP.

<scene name='82/823087/Impdh_triad/3'>IMPDH Triad</scene> The IMPDH triad includes Arg (320), Asn (306), and Asp (272). This is represented by the solid red structures in the image. This triad is important as it makes cysteine more reactive, which in turn induces binding.

<scene name='82/823087/Impdh_triad_active_binding/1'>IMPDH active binding site</scene> The active binding site includes the Bateman domains, which are components within the TIM barrel. Binding occurs after the catalytic triad makes cysteine more reactive. In the image the cysteines are in white (6 in this sequence).

<scene name='82/823089/Charge_view/1'>IMPDH charge</scene> is not strong, as shown by this view. There are positive and negative components within the structure, but a relatively neutral substance is better received in this mechanism. Negatively-charged glutamate and positively-charged histidine within this enzyme are minor components but play a role within the covalent bindings in the mechanism.

<scene name='82/823087/Impdh_composition/1'>IMPDH Composition</scene> The brown represents a protein, red represents a RNA, and green represents ligands.

== Energy Transformation ==

IMPDH is activated by monovalent cations, such as K+ and Na+, within the triose-phosphate isomerase (TIM) barrel. The Arg320-Asn306-Asp272 catalytic triad (Arg322-Asn303-Asp274 in human type II IMPDH) works inter-dependently and synergistically in the TIM barrel active site to make the nucleophilic component, Cysteine, highly reactive to form a temporary covalent bond with the substrate<ref>PMID: 8555204</ref>. Substrates bind randomly to IMPDH as the hydride transfer is quick and NAD is reduced to hydrolyze the covalent intermediate within the enzyme-substrate complex. A covalent intermediate, E-XMP*, is formed, which decreases the energy needed in later nucleophilic and covalent catalysis steps<ref>PMID: 10390600</ref>. Based on normal physiological conditions, the IMPDH mechanism is often not kinetically favorable. The Bateman domains within the TIM barrel are composed of cystathionine beta-synthase motifs that perceive metal ion concentration, cellular energy status, and ionic strength; and will allosterically regulate IMPDH activity<ref>PMID: 31416831</ref>. Eukaryotic IMPDHs have three nucleotide-binding sites in the Bateman domain that allosterically modulate catalytic activity. These three nucleotide-binding sites bind adenine/guanine dinucleoside polyphosphates, and the affinity for these sites increases for these dinucleoside polyphosphates as the activity of IMPDH increases. Purine dinucleoside polyphosphates compete with purine mononucleotides within these sites, so the Bateman domain sites make IMPDH more sensitive to inhibition<ref>PMID: 31416831</ref>. Enzyme catalysis is able to finish with the energy need reduced as the covalent bond is broken later in the reaction to regenerate the enzyme.

</StructureSection>
== References ==

<references />

Sandbox Reserved 1565

2019-12-09T01:54:53Z

Alyssa Ragner:

{{Sandbox_Reserved_BHall_Chem351_F19}}
=='''Inosine-5'-monophosphate dehydrogenase'''==
<StructureSection load='6rpu' size='340' side='right' caption='Structure of the ternary complex of the IMPDH enzyme from Ashbya gossypii bound to the dinucleoside polyphosphate Ap5G and GDP' scene=''>

== Function(s) and Biological Relevance ==

<scene name='82/823087/Impdh/1'>Inosine-5'-monophosphate dehydrogenase</scene> (IMPDH) is the enzyme that catalyzes the rate-limiting step in the ''de novo'' guanine nucleotide biosynthetic pathway, converting inosine monophosphate (IMP) to xanthosine monophosphate (XMP) with the reduction of nicotinamide adenine dinucleotide (NAD). Organisms that undergo the purine nucleotide biosynthetic pathway have IMPDH, including humans. This particular form of IMPDH described and highlighted comes from the recently studied fungus ''Ashbya gossypii'' <ref>PMID: 31416831</ref>. Additional ligands of IMPDH include nicotinamide adenine dinucleotide (NAD), acetate (ACT), and guanosine-5’ monophosphate (5GP). IMPDH is a regulator of the intracellular guanine nucleotide pool amount and helps control control cell division and proliferation, and therefore related to malignant transformation, tumor cell proliferation, and intracellular and extracellular pathogenic infections. Purine dinucleoside polyphosphates are found to bind to the Bateman domain of ''Ashbya gossypii'' IMPDH to allosterically regulate the catalytic activity by competing against purine mononucleotides<ref>PMID: 31416831</ref>.

== Broader Implications ==

The disease pathophysiology is extensive as the improper IMPDH regulation may lead to uncontrolled cell division and proliferation, affecting the immune system's ability to fight off pathogens and signal tumor cells to apoptose. Therapeutic studies using dinucleoside polyphosphates may allosterically regulate the inhibition of IMPDH activity. Dinucleoside polyphosphates have physiological functions including cell division, neurotransmission, apoptosis, vasoconstriction, platelet aggregation, and cellular process variety enhancement from DNA replication to repair<ref>PMID: 31416831</ref>. Selected IMPDH inhibitors composed of dinucleoside polyphosphates may be used to make IMPDHs targets for immunosuppressive, antiviral, and anticancer drugs<ref>PMID: 21517780</ref>, with antibacterial and chemotherapeutic strategies feasibile<ref>PMID: 22928911</ref>.

== Structural Highlights and Structure-Function Relationships ==

The <scene name='82/823089/Secondary_structure/1'>secondary structure</scene> shows alpha helices and beta sheets. The ''Ashbya gossypii'' IMPDH is 31% helical and 15% beta sheet, with the other percentages including random coils and residue structures. The active site is located towards the C-terminus within the TIM barrel, containing 8 alpha-helices and 8 beta sheets.

IMPDH <scene name='82/823087/Impdh_quaternary_structure/1'>quaternary structures</scene> include multiunit complexes, such as tetramers, extended octamers, and compacted octamers. These quaternary structures are created through the binding of multiple subunits of tertiary structures, that are strengthened and structurally formed through hydrogen-bonding, Cysteine-Cysteine disulfide bonds, and hydrophobic interactions. Different quaternary forms of IMPDH relate to the kinetic favorability of the IMPDH mechanism as Bateman domain allosteric binding sites and competitive nature changes with unit composition.

This <scene name='82/823089/Space-filled/2'>space-filled view</scene> helps show the Van der Waals interactions and areas for movement within the structure. The ability for monovalent cations to move within the charged tunnel with the phosphate chain directly relates to activation levels.

<scene name='82/823089/Hydrophobicity_view/1'>Hydrophobicity view</scene> Purple represents polar molecules and gray represents hydrophobic molecules. The hydrophobicity is within the interior of the molecule as the hydrophilic residues are able to interact in a physiological environment.

<scene name='82/823087/Impdh_ligand_view/1'>IMPDH ligand view
</scene>. In this view the black structures are the ACT molecules. These are the ligands of the IMPDH protein. Other ligands include G5P and GDP.

<scene name='82/823087/Impdh_triad/3'>IMPDH Triad</scene> The IMPDH triad includes Arg (320), Asn (306), and Asp (272). This is represented by the solid red structures in the image. This triad is important as it makes cysteine more reactive, which in turn induces binding.

<scene name='82/823087/Impdh_triad_active_binding/1'>IMPDH active binding site</scene> The active binding site includes the Bateman domains, which are components within the TIM barrel. Binding occurs after the catalytic triad makes cysteine more reactive. In the image the cysteines are in white (6 in this sequence).

<scene name='82/823087/Impdh_charge/1'>IMPDH charge</scene> is not strong, as shown by this view. There are positive and negative components within the structure, but a relatively neutral substance is better received in this mechanism. Negatively-charged glutamate and positively-charged histidine within this enzyme are minor components but play a role within the covalent bindings in the mechanism.

<scene name='82/823087/Impdh_composition/1'>IMPDH Composition</scene> The brown represents a protein, red represents a RNA, and green represents ligands.

== Energy Transformation ==

IMPDH is activated by monovalent cations, such as K+ and Na+, within the triose-phosphate isomerase (TIM) barrel. The Arg320-Asn306-Asp272 catalytic triad (Arg322-Asn303-Asp274 in human type II IMPDH) works inter-dependently and synergistically in the TIM barrel active site to make the nucleophilic component, Cysteine, highly reactive to form a temporary covalent bond with the substrate<ref>PMID: 8555204</ref>. Substrates bind randomly to IMPDH as the hydride transfer is quick and NAD is reduced to hydrolyze the covalent intermediate within the enzyme-substrate complex. A covalent intermediate, E-XMP*, is formed, which decreases the energy needed in later nucleophilic and covalent catalysis steps<ref>PMID: 10390600</ref>. Based on normal physiological conditions, the IMPDH mechanism is often not kinetically favorable. The Bateman domains within the TIM barrel are composed of cystathionine beta-synthase motifs that perceive metal ion concentration, cellular energy status, and ionic strength; and will allosterically regulate IMPDH activity<ref>PMID: 31416831</ref>. Eukaryotic IMPDHs have three nucleotide-binding sites in the Bateman domain that allosterically modulate catalytic activity. These three nucleotide-binding sites bind adenine/guanine dinucleoside polyphosphates, and the affinity for these sites increases for these dinucleoside polyphosphates as the activity of IMPDH increases. Purine dinucleoside polyphosphates compete with purine mononucleotides within these sites, so the Bateman domain sites make IMPDH more sensitive to inhibition<ref>PMID: 31416831</ref>. Enzyme catalysis is able to finish with the energy need reduced as the covalent bond is broken later in the reaction to regenerate the enzyme.

</StructureSection>
== References ==

<references />

Sandbox Reserved 1563

2019-12-08T00:25:32Z

Alyssa Ragner:

{{Sandbox_Reserved_BHall_Chem351_F19}}
=='''Inosine-5'-monophosphate dehydrogenase (IMPDH)'''==
<StructureSection load='6rpu' size='340' side='right' caption='Structure of the ternary complex of the IMPDH enzyme from Ashbya gossypii bound to the dinucleoside polyphosphate Ap5G and GDP' scene=''>

== '''Function(s) and Biological Relevance''' ==

<scene name='82/823087/Impdh/1'>Inosine-5'-monophosphate dehydrogenase (IMPDH)</scene> catalyzes the rate limiting step of the de novo guanine nucleotide biosynthetic pathway. NAD is reduced resulting in IMP converting to Xanthosine monophosphate (XMP). Additional ligands include Acetate (ACT) and Guanosine-5'-monophosphate (5GP). IMPDH is found in organisms that go through the purine biosynthetic pathway, this includes humans. IMPDH is used medically to help fight against microbial infections and cancer<ref>PMID: 31416831</ref>.

== '''Broader Implications''' ==

If IMPDH is not regulated correctly it could lead to uncontrolled cell division. Without the regulation of cell division this could lead to cancer.
Dinucleoside polyphosphates could allosterically regulate inhibition of IMPDH. If inhibition of IMPDH is regulated errors would occur less frequently and thus uncontrolled cell division would become less likely. Dinucleoside polyphosphates used as IMPDH inhibitors may contribute as anticancer and antiviral drugs<ref>PMID: 21517780</ref>.

== '''Structural highlights and structure-function relationships''' ==

<scene name='82/823087/Impdh_secondary_structures/2'>IMPDH secondary structures</scene>. Alpha helices in pink. Beta sheets are in orange.

<scene name='82/823087/Impdh_quaternary_structure/2'>Impdh_quaternary_structure</scene>. These quaternary structures include tetramers, compacted and extended octamers, and multiunit complexes. These are created through multiple subunits of tertiary structures. They are formed and reinforced through hydrogen bonding, disulfide bonds, and hydrophobic interactions.

<scene name='82/823087/Impdh_space_fill/1'>Impdh_space_filled</scene>. In the space filled view we can see a better representation of how much space the protein would actually take up. In the image the white is the protein as a whole and the red dots represent hydrogen bonds.

<scene name='82/823087/Impdh_hydrophobicity/1'>IMPDH hydrophobicity view</scene>. For this image purple represent polar molecules and grey represents hydrophobic molecules.

<scene name='82/823087/Impdh_ligand_view/2'>IMPDH ligand view</scene>. In this view the black structures are the ACT molecules. These are the ligands of the IMPDH protein.

<scene name='82/823087/Impdh_triad/3'>IMPDH Triad</scene>. The IMPDH triad includes Arg (320), Asn (306), and Asp (272). This is represented by the solid red structures in the image. This triad is important as it makes cystine more reactive, which in turn induces binding.

<scene name='82/823087/Impdh_triad_active_binding/1'>IMPDH active binding site</scene>. The active binding cite is where the binding takes place after the catalytic triad makes cystine more reactive and binding is induced. In the image the cystines are in white. This is where binding would occur.

<scene name='82/823087/Impdh_charge/1'>IMPDH charge</scene>. IMPDH has no significant charge since it is found in physiological environments. Positively and negatively charged amino acids play a part in intermediate covalent binding steps<ref>PMID: 31416831</ref>.

<scene name='82/823087/Impdh_composition/1'>IMPDH composition</scene>. Brown represents a protein. Red represents a RNA. Green represents ligands.

== '''Energy Transformation''' ==

There are three binding sites within the Bateman domain that regulate catalytic activity. These three sites bind dinucleoside polyphosphates, and the affinity for those binding sites increases as activity with IMPDH increases. Purine dinucleoside polyphosphates compete with purine mononucleotides within the Bateman domain. This requires the Bateman domain to make IMPDH more sensitive to inhibition<ref>PMID: 10390600</ref>. Covalent bonds are broken later in the reaction that allows the system enough energy to complete the process.

</StructureSection>
== References ==

<references />

Sandbox Reserved 1565

2019-12-08T00:18:38Z

Alyssa Ragner:

{{Sandbox_Reserved_BHall_Chem351_F19}}
=='''Inosine-5'-monophosphate dehydrogenase'''==
<StructureSection load='6rpu' size='340' side='right' caption='Structure of the ternary complex of the IMPDH enzyme from Ashbya gossypii bound to the dinucleoside polyphosphate Ap5G and GDP' scene=''>

== Function(s) and Biological Relevance ==

<scene name='82/823087/Impdh/1'>Inosine-5'-monophosphate dehydrogenase</scene> (IMPDH) is the enzyme that catalyzes the rate-limiting step in the ''de novo'' guanine nucleotide biosynthetic pathway, converting inosine monophosphate (IMP) to xanthosine monophosphate (XMP) with the reduction of nicotinamide adenine dinucleotide (NAD). Organisms that undergo the purine nucleotide biosynthetic pathway have IMPDH, including humans. This particular form of IMPDH described and highlighted comes from the recently studied fungus ''Ashbya gossypii'' <ref>PMID: 31416831</ref>. Additional ligands of IMPDH include nicotinamide adenine dinucleotide (NAD), acetate (ACT), and guanosine-5’ monophosphate (5GP). IMPDH is a regulator of the intracellular guanine nucleotide pool amount and helps control control cell division and proliferation, and therefore related to malignant transformation, tumor cell proliferation, and intracellular and extracellular pathogenic infections. Purine dinucleoside polyphosphates are found to bind to the Bateman domain of ''Ashbya gossypii'' IMPDH to allosterically regulate the catalytic activity by competing against purine mononucleotides<ref>PMID: 31416831</ref>.

== Broader Implications ==

The disease pathophysiology is extensive as the improper IMPDH regulation may lead to uncontrolled cell division and proliferation, affecting the immune system's ability to fight off pathogens and signal tumor cells to apoptose. Therapeutic studies using dinucleoside polyphosphates may allosterically regulate the inhibition of IMPDH activity. Dinucleoside polyphosphates have physiological functions including cell division, neurotransmission, apoptosis, vasoconstriction, platelet aggregation, and cellular process variety enhancement from DNA replication to repair<ref>PMID: 31416831</ref>. Selected IMPDH inhibitors composed of dinucleoside polyphosphates may be used to make IMPDHs targets for immunosuppressive, antiviral, and anticancer drugs<ref>PMID: 21517780</ref>, with antibacterial and chemotherapeutic strategies feasibile<ref>PMID: 22928911</ref>.

== Structural Highlights and Structure-Function Relationships ==

The <scene name='82/823089/Secondary_structure/1'>secondary structure</scene> shows alpha helices and beta sheets. The ''Ashbya gossypii'' IMPDH is 31% helical and 15% beta sheet, with the other percentages including random coils and residue structures. The active site is located towards the C-terminus within the TIM barrel, containing 8 alpha-helices and 8 beta sheets.

IMPDH <scene name='82/823087/Impdh_quaternary_structure/1'>quaternary structures</scene> include multiunit complexes, such as tetramers, extended octamers, and compacted octamers. These quaternary structures are created through the binding of multiple subunits of tertiary structures, that are strengthened and structurally formed through hydrogen-bonding, Cysteine-Cysteine disulfide bonds, and hydrophobic interactions. Different quaternary forms of IMPDH relate to the kinetic favorability of the IMPDH mechanism as Bateman domain allosteric binding sites and competitive nature changes with unit composition.

This <scene name='82/823089/Space-filled/2'>space-filled view</scene> helps show the Van der Waals interactions and areas for movement within the structure. The ability for monovalent cations to move within the charged tunnel with the phosphate chain directly relates to activation levels.

<scene name='82/823087/Impdh_hydrophobicity/1'>Hydrophobicity view</scene> Purple represents polar molecules and gray represents hydrophobic molecules. The hydrophobicity is within the interior of the molecule as the hydrophilic residues are able to interact in a physiological environment.

<scene name='82/823087/Impdh_ligand_view/1'>IMPDH ligand view
</scene>. In this view the black structures are the ACT molecules. These are the ligands of the IMPDH protein. Other ligands include G5P and GDP.

<scene name='82/823087/Impdh_triad/3'>IMPDH Triad</scene> The IMPDH triad includes Arg (320), Asn (306), and Asp (272). This is represented by the solid red structures in the image. This triad is important as it makes cysteine more reactive, which in turn induces binding.

<scene name='82/823087/Impdh_triad_active_binding/1'>IMPDH active binding site</scene> The active binding site includes the Bateman domains, which are components within the TIM barrel. Binding occurs after the catalytic triad makes cysteine more reactive. In the image the cysteines are in white (6 in this sequence).

<scene name='82/823087/Impdh_charge/1'>IMPDH charge</scene> is not strong, as shown by this view. There are positive and negative components within the structure, but a relatively neutral substance is better received in this mechanism. Negatively-charged glutamate and positively-charged histidine within this enzyme are minor components but play a role within the covalent bindings in the mechanism.

<scene name='82/823087/Impdh_composition/1'>IMPDH Composition</scene> The brown represents a protein, red represents a RNA, and green represents ligands.

== Energy Transformation ==

IMPDH is activated by monovalent cations, such as K+ and Na+, within the triose-phosphate isomerase (TIM) barrel. The Arg320-Asn306-Asp272 catalytic triad (Arg322-Asn303-Asp274 in human type II IMPDH) works inter-dependently and synergistically in the TIM barrel active site to make the nucleophilic component, Cysteine, highly reactive to form a temporary covalent bond with the substrate<ref>PMID: 8555204</ref>. Substrates bind randomly to IMPDH as the hydride transfer is quick and NAD is reduced to hydrolyze the covalent intermediate within the enzyme-substrate complex. A covalent intermediate, E-XMP*, is formed, which decreases the energy needed in later nucleophilic and covalent catalysis steps<ref>PMID: 10390600</ref>. Based on normal physiological conditions, the IMPDH mechanism is often not kinetically favorable. The Bateman domains within the TIM barrel are composed of cystathionine beta-synthase motifs that perceive metal ion concentration, cellular energy status, and ionic strength; and will allosterically regulate IMPDH activity<ref>PMID: 31416831</ref>. Eukaryotic IMPDHs have three nucleotide-binding sites in the Bateman domain that allosterically modulate catalytic activity. These three nucleotide-binding sites bind adenine/guanine dinucleoside polyphosphates, and the affinity for these sites increases for these dinucleoside polyphosphates as the activity of IMPDH increases. Purine dinucleoside polyphosphates compete with purine mononucleotides within these sites, so the Bateman domain sites make IMPDH more sensitive to inhibition<ref>PMID: 31416831</ref>. Enzyme catalysis is able to finish with the energy need reduced as the covalent bond is broken later in the reaction to regenerate the enzyme.

</StructureSection>
== References ==

<references />

Sandbox Reserved 1565

2019-12-08T00:04:15Z

Alyssa Ragner:

{{Sandbox_Reserved_BHall_Chem351_F19}}
=='''Inosine-5'-monophosphate dehydrogenase'''==
<StructureSection load='6rpu' size='340' side='right' caption='Structure of the ternary complex of the IMPDH enzyme from Ashbya gossypii bound to the dinucleoside polyphosphate Ap5G and GDP' scene=''>

== Function(s) and Biological Relevance ==

<scene name='82/823087/Impdh/1'>Inosine-5'-monophosphate dehydrogenase</scene> (IMPDH) is the enzyme that catalyzes the rate-limiting step in the ''de novo'' guanine nucleotide biosynthetic pathway, converting inosine monophosphate (IMP) to xanthosine monophosphate (XMP) with the reduction of nicotinamide adenine dinucleotide (NAD). Organisms that undergo the purine nucleotide biosynthetic pathway have IMPDH, including humans. This particular form of IMPDH described and highlighted comes from the recently studied fungus ''Ashbya gossypii'' <ref>PMID: 31416831</ref>. Additional ligands of IMPDH include nicotinamide adenine dinucleotide (NAD), acetate (ACT), and guanosine-5’ monophosphate (5GP). IMPDH is a regulator of the intracellular guanine nucleotide pool amount and helps control control cell division and proliferation, and therefore related to malignant transformation, tumor cell proliferation, and intracellular and extracellular pathogenic infections. Purine dinucleoside polyphosphates are found to bind to the Bateman domain of ''Ashbya gossypii'' IMPDH to allosterically regulate the catalytic activity by competing against purine mononucleotides<ref>PMID: 31416831</ref>.

== Broader Implications ==

The disease pathophysiology is extensive as the improper IMPDH regulation may lead to uncontrolled cell division and proliferation, affecting the immune system's ability to fight off pathogens and signal tumor cells to apoptose. Therapeutic studies using dinucleoside polyphosphates may allosterically regulate the inhibition of IMPDH activity. Dinucleoside polyphosphates have physiological functions including cell division, neurotransmission, apoptosis, vasoconstriction, platelet aggregation, and cellular process variety enhancement from DNA replication to repair<ref>PMID: 31416831</ref>. Selected IMPDH inhibitors composed of dinucleoside polyphosphates may be used to make IMPDHs targets for immunosuppressive, antiviral, and anticancer drugs<ref>PMID: 21517780</ref>, with antibacterial and chemotherapeutic strategies feasibile<ref>PMID: 22928911</ref>.

== Structural Highlights and Structure-Function Relationships ==

The <scene name='82/823089/Secondary_structure/1'>secondary structure</scene> shows alpha helices and beta sheets. The ''Ashbya gossypii'' IMPDH is 31% helical and 15% beta sheet, with the other percentages including random coils and residue structures. The active site is located towards the C-terminus within the TIM barrel, containing 8 alpha-helices and 8 beta sheets.

IMPDH <scene name='82/823087/Impdh_quaternary_structure/1'>quaternary structures</scene> include multiunit complexes, such as tetramers, extended octamers, and compacted octamers. These quaternary structures are created through the binding of multiple subunits of tertiary structures, that are strengthened and structurally formed through hydrogen-bonding, Cysteine-Cysteine disulfide bonds, and hydrophobic interactions. Different quaternary forms of IMPDH relate to the kinetic favorability of the IMPDH mechanism as Bateman domain allosteric binding sites and competitive nature changes with unit composition.

This <scene name='82/823089/Space-filled/2'>space-filled view</scene> helps show the Van der Waals interactions and areas for movement within the structure. The ability for monovalent cations to move within the charged tunnel with the phosphate chain directly relates to activation levels.

<scene name='82/823087/Impdh_hydrophobicity/1'>Hydrophobicity view</scene> Purple represents polar molecules and gray represents hydrophobic molecules. The hydrophobicity is within the interior of the molecule as the hydrophilic residues are able to interact in a physiological environment.

<scene name='82/823087/Impdh_ligand_view/1'>IMPDH ligand view
</scene>. In this view the black structures are the ACT molecules. These are the ligands of the IMPDH protein. Other ligands include G5P and GDP.

<scene name='82/823087/Impdh_triad/3'>IMPDH Triad</scene> The IMPDH triad includes Arg (320), Asn (306), and Asp (272). This is represented by the solid red structures in the image. This triad is important as it makes cysteine more reactive, which in turn induces binding.

<scene name='82/823087/Impdh_triad_active_binding/1'>IMPDH active binding site</scene> The active binding site includes the Bateman domains, which are components within the TIM barrel. Binding occurs after the catalytic triad makes cysteine more reactive. In the image the cysteines are in white (6 in this sequence).

<scene name='82/823087/Impdh_charge/1'>IMPDH charge</scene> is not strong, as shown by this view. There are positive and negative components within the structure, but a relatively neutral substance is better received in this mechanism. Negatively-charged glutamine and positively-charged histidine within this enzyme are minor components but play a role within the covalent bindings in the mechanism.

<scene name='82/823087/Impdh_composition/1'>IMPDH Composition</scene> The brown represents a protein, red represents a RNA, and green represents ligands.

== Energy Transformation ==

IMPDH is activated by monovalent cations, such as K+ and Na+, within the triose-phosphate isomerase (TIM) barrel. The Arg320-Asn306-Asp272 catalytic triad (Arg322-Asn303-Asp274 in human type II IMPDH) works inter-dependently and synergistically in the TIM barrel active site to make the nucleophilic component, Cysteine, highly reactive to form a temporary covalent bond with the substrate<ref>PMID: 8555204</ref>. Substrates bind randomly to IMPDH as the hydride transfer is quick and NAD is reduced to hydrolyze the covalent intermediate within the enzyme-substrate complex. A covalent intermediate, E-XMP*, is formed, which decreases the energy needed in later nucleophilic and covalent catalysis steps<ref>PMID: 10390600</ref>. Based on normal physiological conditions, the IMPDH mechanism is often not kinetically favorable. The Bateman domains within the TIM barrel are composed of cystathionine beta-synthase motifs that perceive metal ion concentration, cellular energy status, and ionic strength; and will allosterically regulate IMPDH activity<ref>PMID: 31416831</ref>. Eukaryotic IMPDHs have three nucleotide-binding sites in the Bateman domain that allosterically modulate catalytic activity. These three nucleotide-binding sites bind adenine/guanine dinucleoside polyphosphates, and the affinity for these sites increases for these dinucleoside polyphosphates as the activity of IMPDH increases. Purine dinucleoside polyphosphates compete with purine mononucleotides within these sites, so the Bateman domain sites make IMPDH more sensitive to inhibition<ref>PMID: 31416831</ref>. Enzyme catalysis is able to finish with the energy need reduced as the covalent bond is broken later in the reaction to regenerate the enzyme.

</StructureSection>
== References ==

<references />

Sandbox Reserved 1565

2019-12-07T23:32:20Z

Alyssa Ragner:

{{Sandbox_Reserved_BHall_Chem351_F19}}
=='''Inosine-5'-monophosphate dehydrogenase'''==
<StructureSection load='6rpu' size='340' side='right' caption='Structure of the ternary complex of the IMPDH enzyme from Ashbya gossypii bound to the dinucleoside polyphosphate Ap5G and GDP' scene=''>

== Function(s) and Biological Relevance ==

<scene name='82/823087/Impdh/1'>Inosine-5'-monophosphate dehydrogenase</scene> (IMPDH) is the enzyme that catalyzes the rate-limiting step in the ''de novo'' guanine nucleotide biosynthetic pathway, converting inosine monophosphate (IMP) to xanthosine monophosphate (XMP) with the reduction of nicotinamide adenine dinucleotide (NAD). Organisms that undergo the purine nucleotide biosynthetic pathway have IMPDH, including humans. This particular form of IMPDH described and highlighted comes from the recently studied fungus ''Ashbya gossypii'' <ref>PMID: 31416831</ref>. Additional ligands of IMPDH include nicotinamide adenine dinucleotide (NAD), acetate (ACT), and guanosine-5’ monophosphate (5GP). IMPDH is a regulator of the intracellular guanine nucleotide pool amount and helps control control cell division and proliferation, and therefore related to malignant transformation, tumor cell proliferation, and intracellular and extracellular pathogenic infections. Purine dinucleoside polyphosphates are found to bind to the Bateman domain of ''Ashbya gossypii'' IMPDH to allosterically regulate the catalytic activity by competing against purine mononucleotides<ref>PMID: 31416831</ref>.

== Broader Implications ==

The disease pathophysiology is extensive as the improper IMPDH regulation may lead to uncontrolled cell division and proliferation, affecting the immune system's ability to fight off pathogens and signal tumor cells to apoptose. Therapeutic studies using dinucleoside polyphosphates may allosterically regulate the inhibition of IMPDH activity. Dinucleoside polyphosphates have physiological functions including cell division, neurotransmission, apoptosis, vasoconstriction, platelet aggregation, and cellular process variety enhancement from DNA replication to repair<ref>PMID: 31416831</ref>. Selected IMPDH inhibitors composed of dinucleoside polyphosphates may be used to make IMPDHs targets for immunosuppressive, antiviral, and anticancer drugs<ref>PMID: 21517780</ref>, with antibacterial and chemotherapeutic strategies feasibile<ref>PMID: 22928911</ref>.

== Structural Highlights and Structure-Function Relationships ==

The <scene name='82/823089/Secondary_structure/1'>secondary structure</scene> shows alpha helices and beta sheets. The ''Ashbya gossypii'' IMPDH is 31% helical and 15% beta sheet, with the other percentages including random coils and residue structures. The active site is located towards the C-terminus within the TIM barrel, containing 8 alpha-helices and 8 beta sheets.

IMPDH <scene name='82/823087/Impdh_quaternary_structure/1'>quaternary structures</scene> include multiunit complexes, such as tetramers, extended octamers, and compacted octamers. These quaternary structures are created through the binding of multiple subunits of tertiary structures, that are strengthened and structurally formed through hydrogen-bonding, Cysteine-Cysteine disulfide bonds, and hydrophobic interactions. Different quaternary forms of IMPDH relate to the kinetic favorability of the IMPDH mechanism as Bateman domain allosteric binding sites and competitive nature changes with unit composition.

This <scene name='82/823087/space-filled view/1'>IMPDH space filled view</scene> helps show the Van der Waals interactions and areas for movement within the structure. The ability for monovalent cations to move within the charged tunnel with the phosphate chain directly relates to activation levels.

<scene name='82/823087/Impdh_hydrophobicity/1'>Hydrophobicity view</scene> Purple represents polar molecules and gray represents hydrophobic molecules. The hydrophobicity is within the interior of the molecule as the hydrophilic residues are able to interact in a physiological environment.

<scene name='82/823087/Impdh_ligand_view/1'>IMPDH ligand view
</scene>. In this view the black structures are the ACT molecules. These are the ligands of the IMPDH protein. Other ligands include G5P and GDP.

<scene name='82/823087/Impdh_triad/3'>IMPDH Triad</scene> The IMPDH triad includes Arg (320), Asn (306), and Asp (272). This is represented by the solid red structures in the image. This triad is important as it makes cysteine more reactive, which in turn induces binding.

<scene name='82/823087/Impdh_triad_active_binding/1'>IMPDH active binding site</scene> The active binding site includes the Bateman domains, which are components within the TIM barrel. Binding occurs after the catalytic triad makes cysteine more reactive. In the image the cysteines are in white (6 in this sequence).

<scene name='82/823087/Impdh_charge/1'>IMPDH charge</scene> is not strong, as shown by this view. There are positive and negative components within the structure, but a relatively neutral substance is better received in this mechanism. Negatively-charged glutamine and positively-charged histidine within this enzyme are minor components but play a role within the covalent bindings in the mechanism.

<scene name='82/823087/Impdh_composition/1'>IMPDH Composition</scene> The brown represents a protein, red represents a RNA, and green represents ligands.

== Energy Transformation ==

IMPDH is activated by monovalent cations, such as K+ and Na+, within the triose-phosphate isomerase (TIM) barrel. The Arg320-Asn306-Asp272 catalytic triad (Arg322-Asn303-Asp274 in human type II IMPDH) works inter-dependently and synergistically in the TIM barrel active site to make the nucleophilic component, Cysteine, highly reactive to form a temporary covalent bond with the substrate<ref>PMID: 8555204</ref>. Substrates bind randomly to IMPDH as the hydride transfer is quick and NAD is reduced to hydrolyze the covalent intermediate within the enzyme-substrate complex. A covalent intermediate, E-XMP*, is formed, which decreases the energy needed in later nucleophilic and covalent catalysis steps<ref>PMID: 10390600</ref>. Based on normal physiological conditions, the IMPDH mechanism is often not kinetically favorable. The Bateman domains within the TIM barrel are composed of cystathionine beta-synthase motifs that perceive metal ion concentration, cellular energy status, and ionic strength; and will allosterically regulate IMPDH activity<ref>PMID: 31416831</ref>. Eukaryotic IMPDHs have three nucleotide-binding sites in the Bateman domain that allosterically modulate catalytic activity. These three nucleotide-binding sites bind adenine/guanine dinucleoside polyphosphates, and the affinity for these sites increases for these dinucleoside polyphosphates as the activity of IMPDH increases. Purine dinucleoside polyphosphates compete with purine mononucleotides within these sites, so the Bateman domain sites make IMPDH more sensitive to inhibition<ref>PMID: 31416831</ref>. Enzyme catalysis is able to finish with the energy need reduced as the covalent bond is broken later in the reaction to regenerate the enzyme.

</StructureSection>
== References ==

<references />

Sandbox Reserved 1565

2019-12-07T23:28:24Z

Alyssa Ragner:

{{Sandbox_Reserved_BHall_Chem351_F19}}
=='''Inosine-5'-monophosphate dehydrogenase'''==
<StructureSection load='6rpu' size='340' side='right' caption='Structure of the ternary complex of the IMPDH enzyme from Ashbya gossypii bound to the dinucleoside polyphosphate Ap5G and GDP' scene=''>

== Function(s) and Biological Relevance ==

<scene name='82/823087/Impdh/1'>Inosine-5'-monophosphate dehydrogenase</scene> (IMPDH) is the enzyme that catalyzes the rate-limiting step in the ''de novo'' guanine nucleotide biosynthetic pathway, converting inosine monophosphate (IMP) to xanthosine monophosphate (XMP) with the reduction of nicotinamide adenine dinucleotide (NAD). Organisms that undergo the purine nucleotide biosynthetic pathway have IMPDH, including humans. This particular form of IMPDH described and highlighted comes from the recently studied fungus ''Ashbya gossypii'' <ref>PMID: 31416831</ref>. Additional ligands of IMPDH include nicotinamide adenine dinucleotide (NAD), acetate (ACT), and guanosine-5’ monophosphate (5GP). IMPDH is a regulator of the intracellular guanine nucleotide pool amount and helps control control cell division and proliferation, and therefore related to malignant transformation, tumor cell proliferation, and intracellular and extracellular pathogenic infections. Purine dinucleoside polyphosphates are found to bind to the Bateman domain of ''Ashbya gossypii'' IMPDH to allosterically regulate the catalytic activity by competing against purine mononucleotides<ref>PMID: 31416831</ref>.

== Broader Implications ==

The disease pathophysiology is extensive as the improper IMPDH regulation may lead to uncontrolled cell division and proliferation, affecting the immune system's ability to fight off pathogens and signal tumor cells to apoptose. Therapeutic studies using dinucleoside polyphosphates may allosterically regulate the inhibition of IMPDH activity. Dinucleoside polyphosphates have physiological functions including cell division, neurotransmission, apoptosis, vasoconstriction, platelet aggregation, and cellular process variety enhancement from DNA replication to repair<ref>PMID: 31416831</ref>. Selected IMPDH inhibitors composed of dinucleoside polyphosphates may be used to make IMPDHs targets for immunosuppressive, antiviral, and anticancer drugs<ref>PMID: 21517780</ref>, with antibacterial and chemotherapeutic strategies feasibile<ref>PMID: 22928911</ref>.

== Structural Highlights and Structure-Function Relationships ==

The <scene name='82/823089/Secondary_structure/1'>secondary structure</scene> shows alpha helices and beta sheets. The ''Ashbya gossypii'' IMPDH is 31% helical and 15% beta sheet, which the other percentages including random coils and residue structures. The active site is located towards the C-terminus within the TIM barrel, containing 8 alpha-helices and 8 beta sheets.

IMPDH <scene name='82/823087/Impdh_quaternary_structure/1'>quaternary structures</scene> include multiunit complexes, such as tetramers, extended octamers, and compacted octamers. These quaternary structures are created through the binding of multiple subunits of tertiary structures, that are strengthened and structurally formed through hydrogen-bonding, Cysteine-Cysteine disulfide bonds, and hydrophobic interactions. Different quaternary forms of IMPDH relate to the kinetic favorability of the IMPDH mechanism as Bateman domain allosteric binding sites and competitive nature changes with unit composition.

This <scene name='82/823087/space-filled view/1'>IMPDH space filled view</scene> helps show the Van der Waals interactions and areas for movement within the structure. The ability for monovalent cations to move within the charged tunnel with the phosphate chain directly relates to activation levels.

<scene name='82/823087/Impdh_hydrophobicity/1'>Hydrophobicity view</scene> Purple represents polar molecules and gray represents hydrophobic molecules. The hydrophobicity is within the interior of the molecule as the hydrophilic residues are able to interact in a physiological environment.

<scene name='82/823087/Impdh_ligand_view/1'>IMPDH ligand view
</scene>. In this view the black structures are the ACT molecules. These are the ligands of the IMPDH protein. Other ligands include G5P and GDP.

<scene name='82/823087/Impdh_triad/3'>IMPDH Triad</scene> The IMPDH triad includes Arg (320), Asn (306), and Asp (272). This is represented by the solid red structures in the image. This triad is important as it makes cysteine more reactive, which in turn induces binding.

<scene name='82/823087/Impdh_triad_active_binding/1'>IMPDH active binding site</scene> The active binding site includes the Bateman domains, which are components within the TIM barrel. Binding occurs after the catalytic triad makes cysteine more reactive. In the image the cysteines are in white (6 in this sequence).

<scene name='82/823087/Impdh_charge/1'>IMPDH charge</scene> is not strong, as shown by this view. There are positive and negative components within the structure, but a relatively neutral substance is better received in this mechanism. Negatively-charged glutamine and positively-charged histidine within this enzyme are minor components but play a role within the covalent bindings in the mechanism.

<scene name='82/823087/Impdh_composition/1'>IMPDH Composition</scene> The brown represents a protein, red represents a RNA, and green represents ligands.

== Energy Transformation ==

IMPDH is activated by monovalent cations, such as K+ and Na+, within the triose-phosphate isomerase (TIM) barrel. The Arg320-Asn306-Asp272 catalytic triad (Arg322-Asn303-Asp274 in human type II IMPDH) works inter-dependently and synergistically in the TIM barrel active site to make the nucleophilic component, Cysteine, highly reactive to form a temporary covalent bond with the substrate<ref>PMID: 8555204</ref>. Substrates bind randomly to IMPDH as the hydride transfer is quick and NAD is reduced to hydrolyze the covalent intermediate within the enzyme-substrate complex. A covalent intermediate, E-XMP*, is formed, which decreases the energy needed in later nucleophilic and covalent catalysis steps<ref>PMID: 10390600</ref>. Based on normal physiological conditions, the IMPDH mechanism is often not kinetically favorable. The Bateman domains within the TIM barrel are composed of cystathionine beta-synthase motifs that perceive metal ion concentration, cellular energy status, and ionic strength; and will allosterically regulate IMPDH activity<ref>PMID: 31416831</ref>. Eukaryotic IMPDHs have three nucleotide-binding sites in the Bateman domain that allosterically modulate catalytic activity. These three nucleotide-binding sites bind adenine/guanine dinucleoside polyphosphates, and the affinity for these sites increases for these dinucleoside polyphosphates as the activity of IMPDH increases. Purine dinucleoside polyphosphates compete with purine mononucleotides within these sites, so the Bateman domain sites make IMPDH more sensitive to inhibition<ref>PMID: 31416831</ref>. Enzyme catalysis is able to finish with the energy need reduced as the covalent bond is broken later in the reaction to regenerate the enzyme.

</StructureSection>
== References ==

<references />

Sandbox Reserved 1565

2019-12-07T23:16:40Z

Alyssa Ragner:

{{Sandbox_Reserved_BHall_Chem351_F19}}
=='''Inosine-5'-monophosphate dehydrogenase'''==
<StructureSection load='6rpu' size='340' side='right' caption='Structure of the ternary complex of the IMPDH enzyme from Ashbya gossypii bound to the dinucleoside polyphosphate Ap5G and GDP' scene=''>

== Function(s) and Biological Relevance ==

<scene name='82/823087/Impdh/1'>Inosine-5'-monophosphate dehydrogenase</scene> (IMPDH) is the enzyme that catalyzes the rate-limiting step in the ''de novo'' guanine nucleotide biosynthetic pathway, converting inosine monophosphate (IMP) to xanthosine monophosphate (XMP) with the reduction of nicotinamide adenine dinucleotide (NAD). Organisms that undergo the purine nucleotide biosynthetic pathway have IMPDH, including humans. This particular form of IMPDH described and highlighted comes from the recently studied fungus ''Ashbya gossypii'' <ref>PMID: 31416831</ref>. Additional ligands of IMPDH include nicotinamide adenine dinucleotide (NAD), acetate (ACT), and guanosine-5’ monophosphate (5GP). IMPDH is a regulator of the intracellular guanine nucleotide pool amount and helps control control cell division and proliferation, and therefore related to malignant transformation, tumor cell proliferation, and intracellular and extracellular pathogenic infections. Purine dinucleoside polyphosphates are found to bind to the Bateman domain of ''Ashbya gossypii'' IMPDH to allosterically regulate the catalytic activity by competing against purine mononucleotides<ref>PMID: 31416831</ref>.

== Broader Implications ==

The disease pathophysiology is extensive as the improper IMPDH regulation may lead to uncontrolled cell division and proliferation, affecting the immune system's ability to fight off pathogens and signal tumor cells to apoptose. Therapeutic studies using dinucleoside polyphosphates may allosterically regulate the inhibition of IMPDH activity. Dinucleoside polyphosphates have physiological functions including cell division, neurotransmission, apoptosis, vasoconstriction, platelet aggregation, and cellular process variety enhancement from DNA replication to repair<ref>PMID: 31416831</ref>. Selected IMPDH inhibitors composed of dinucleoside polyphosphates may be used to make IMPDHs targets for immunosuppressive, antiviral, and anticancer drugs<ref>PMID: 21517780</ref>, with antibacterial and chemotherapeutic strategies feasibile<ref>PMID: 22928911</ref>.

== Structural Highlights and Structure-Function Relationships ==

The <scene name='82/823087/Impdh_secondary_structure/1'>secondary structure</scene> shows alpha helices and beta sheets. The ''Ashbya gossypii'' IMPDH is 31% helical and 15% beta sheet, which the other percentages including random coils and residue structures. The active site is located towards the C-terminus within the TIM barrel, containing 8 alpha-helices and 8 beta sheets.

IMPDH <scene name='82/823087/Impdh_quaternary_structure/1'>quaternary structures</scene> include multiunit complexes, such as tetramers, extended octamers, and compacted octamers. These quaternary structures are created through the binding of multiple subunits of tertiary structures, that are strengthened and structurally formed through hydrogen-bonding, Cysteine-Cysteine disulfide bonds, and hydrophobic interactions. Different quaternary forms of IMPDH relate to the kinetic favorability of the IMPDH mechanism as Bateman domain allosteric binding sites and competitive nature changes with unit composition.

This <scene name='82/823087/space-filled view/1'>IMPDH space filled view</scene> helps show the Van der Waals interactions and areas for movement within the structure. The ability for monovalent cations to move within the charged tunnel with the phosphate chain directly relates to activation levels.

<scene name='82/823087/Impdh_hydrophobicity/1'>Hydrophobicity view</scene> Purple represents polar molecules and gray represents hydrophobic molecules. The hydrophobicity is within the interior of the molecule as the hydrophilic residues are able to interact in a physiological environment.

<scene name='82/823087/Impdh_ligand_view/1'>IMPDH ligand view
</scene>. In this view the black structures are the ACT molecules. These are the ligands of the IMPDH protein. Other ligands include G5P and GDP.

<scene name='82/823087/Impdh_triad/3'>IMPDH Triad</scene> The IMPDH triad includes Arg (320), Asn (306), and Asp (272). This is represented by the solid red structures in the image. This triad is important as it makes cysteine more reactive, which in turn induces binding.

<scene name='82/823087/Impdh_triad_active_binding/1'>IMPDH active binding site</scene> The active binding site includes the Bateman domains, which are components within the TIM barrel. Binding occurs after the catalytic triad makes cysteine more reactive. In the image the cysteines are in white (6 in this sequence).

<scene name='82/823087/Impdh_charge/1'>IMPDH charge</scene> is not strong, as shown by this view. There are positive and negative components within the structure, but a relatively neutral substance is better received in this mechanism. Negatively-charged glutamine and positively-charged histidine within this enzyme are minor components but play a role within the covalent bindings in the mechanism.

<scene name='82/823087/Impdh_composition/1'>IMPDH Composition</scene> The brown represents a protein, red represents a RNA, and green represents ligands.

== Energy Transformation ==

IMPDH is activated by monovalent cations, such as K+ and Na+, within the triose-phosphate isomerase (TIM) barrel. The Arg320-Asn306-Asp272 catalytic triad (Arg322-Asn303-Asp274 in human type II IMPDH) works inter-dependently and synergistically in the TIM barrel active site to make the nucleophilic component, Cysteine, highly reactive to form a temporary covalent bond with the substrate<ref>PMID: 8555204</ref>. Substrates bind randomly to IMPDH as the hydride transfer is quick and NAD is reduced to hydrolyze the covalent intermediate within the enzyme-substrate complex. A covalent intermediate, E-XMP*, is formed, which decreases the energy needed in later nucleophilic and covalent catalysis steps<ref>PMID: 10390600</ref>. Based on normal physiological conditions, the IMPDH mechanism is often not kinetically favorable. The Bateman domains within the TIM barrel are composed of cystathionine beta-synthase motifs that perceive metal ion concentration, cellular energy status, and ionic strength; and will allosterically regulate IMPDH activity<ref>PMID: 31416831</ref>. Eukaryotic IMPDHs have three nucleotide-binding sites in the Bateman domain that allosterically modulate catalytic activity. These three nucleotide-binding sites bind adenine/guanine dinucleoside polyphosphates, and the affinity for these sites increases for these dinucleoside polyphosphates as the activity of IMPDH increases. Purine dinucleoside polyphosphates compete with purine mononucleotides within these sites, so the Bateman domain sites make IMPDH more sensitive to inhibition<ref>PMID: 31416831</ref>. Enzyme catalysis is able to finish with the energy need reduced as the covalent bond is broken later in the reaction to regenerate the enzyme.

</StructureSection>
== References ==

<references />

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Alyssa Ragner:

{{Sandbox_Reserved_BHall_Chem351_F19}}
=='''Inosine-5'-monophosphate dehydrogenase'''==
<StructureSection load='6rpu' size='340' side='right' caption='Structure of the ternary complex of the IMPDH enzyme from Ashbya gossypii bound to the dinucleoside polyphosphate Ap5G and GDP' scene=''>

== Function(s) and Biological Relevance ==

<scene name='82/823087/Impdh/1'>Inosine-5'-monophosphate dehydrogenase</scene> (IMPDH) is the enzyme that catalyzes the rate-limiting step in the ''de novo'' guanine nucleotide biosynthetic pathway, converting inosine monophosphate (IMP) to xanthosine monophosphate (XMP) with the reduction of nicotinamide adenine dinucleotide (NAD). Organisms that undergo the purine nucleotide biosynthetic pathway have IMPDH, including humans. This particular form of IMPDH described and highlighted comes from the recently studied fungus ''Ashbya gossypii'' <ref>PMID: 31416831</ref>. Additional ligands of IMPDH include nicotinamide adenine dinucleotide (NAD), acetate (ACT), and guanosine-5’ monophosphate (5GP). IMPDH is a regulator of the intracellular guanine nucleotide pool amount and helps control control cell division and proliferation, and therefore related to malignant transformation, tumor cell proliferation, and intracellular and extracellular pathogenic infections. Purine dinucleoside polyphosphates are found to bind to the Bateman domain of ''Ashbya gossypii'' IMPDH to allosterically regulate the catalytic activity by competing against purine mononucleotides<ref>PMID: 31416831</ref>.

== Broader Implications ==

The disease pathophysiology is extensive as the improper IMPDH regulation may lead to uncontrolled cell division and proliferation, affecting the immune system's ability to fight off pathogens and signal tumor cells to apoptose. Therapeutic studies using dinucleoside polyphosphates may allosterically regulate the inhibition of IMPDH activity. Dinucleoside polyphosphates have physiological functions including cell division, neurotransmission, apoptosis, vasoconstriction, platelet aggregation, and cellular process variety enhancement from DNA replication to repair<ref>PMID: 31416831</ref>. Selected IMPDH inhibitors composed of dinucleoside polyphosphates may be used to make IMPDHs targets for immunosuppressive, antiviral, and anticancer drugs<ref>PMID: 21517780</ref>, with antibacterial and chemotherapeutic strategies feasibile<ref>PMID: 22928911</ref>.

== Structural Highlights and Structure-Function Relationships ==

The <scene name='82/823087/Impdh_secondary_structure/1'>secondary structure</scene> shows alpha helices (pink) and beta sheets (orange). The ''Ashbya gossypii'' IMPDH is 31% helical and 15% beta sheet, which the other percentages including random coils and residue structures. The active site is located towards the C-terminus within the TIM barrel, containing 8 alpha-helices and 8 beta sheets.

IMPDH <scene name='82/823087/Impdh_quaternary_structure/1'>quaternary structures</scene> include multiunit complexes, such as tetramers, extended octamers, and compacted octamers. These quaternary structures are created through the binding of multiple subunits of tertiary structures, that are strengthened and structurally formed through hydrogen-bonding, Cysteine-Cysteine disulfide bonds, and hydrophobic interactions. Different quaternary forms of IMPDH relate to the kinetic favorability of the IMPDH mechanism as Bateman domain allosteric binding sites and competitive nature changes with unit composition.

This <scene name='82/823087/space-filled view/1'>IMPDH space filled view</scene> helps show the Van der Waals interactions and areas for movement within the structure. The ability for monovalent cations to move within the charged tunnel with the phosphate chain directly relates to activation levels.

<scene name='82/823087/Impdh_hydrophobicity/1'>Hydrophobicity view</scene> Purple represents polar molecules and gray represents hydrophobic molecules. The hydrophobicity is within the interior of the molecule as the hydrophilic residues are able to interact in a physiological environment.

<scene name='82/823087/Impdh_ligand_view/1'>IMPDH ligand view
</scene>. In this view the black structures are the ACT molecules. These are the ligands of the IMPDH protein. Other ligands include G5P and GDP.

<scene name='82/823087/Impdh_triad/3'>IMPDH Triad</scene> The IMPDH triad includes Arg (320), Asn (306), and Asp (272). This is represented by the solid red structures in the image. This triad is important as it makes cysteine more reactive, which in turn induces binding.

<scene name='82/823087/Impdh_triad_active_binding/1'>IMPDH active binding site</scene> The active binding site includes the Bateman domains, which are components within the TIM barrel. Binding occurs after the catalytic triad makes cysteine more reactive. In the image the cysteines are in white (6 in this sequence).

<scene name='82/823087/Impdh_charge/1'>IMPDH charge</scene> is not strong, as shown by this view. There are positive and negative components within the structure, but a relatively neutral substance is better received in this mechanism. Negatively-charged glutamine and positively-charged histidine within this enzyme are minor components but play a role within the covalent bindings in the mechanism.

<scene name='82/823087/Impdh_composition/1'>IMPDH Composition</scene> The brown represents a protein, red represents a RNA, and green represents ligands.

== Energy Transformation ==

IMPDH is activated by monovalent cations, such as K+ and Na+, within the triose-phosphate isomerase (TIM) barrel. The Arg320-Asn306-Asp272 catalytic triad (Arg322-Asn303-Asp274 in human type II IMPDH) works inter-dependently and synergistically in the TIM barrel active site to make the nucleophilic component, Cysteine, highly reactive to form a temporary covalent bond with the substrate<ref>PMID: 8555204</ref>. Substrates bind randomly to IMPDH as the hydride transfer is quick and NAD is reduced to hydrolyze the covalent intermediate within the enzyme-substrate complex. A covalent intermediate, E-XMP*, is formed, which decreases the energy needed in later nucleophilic and covalent catalysis steps<ref>PMID: 10390600</ref>. Based on normal physiological conditions, the IMPDH mechanism is often not kinetically favorable. The Bateman domains within the TIM barrel are composed of cystathionine beta-synthase motifs that perceive metal ion concentration, cellular energy status, and ionic strength; and will allosterically regulate IMPDH activity<ref>PMID: 31416831</ref>. Eukaryotic IMPDHs have three nucleotide-binding sites in the Bateman domain that allosterically modulate catalytic activity. These three nucleotide-binding sites bind adenine/guanine dinucleoside polyphosphates, and the affinity for these sites increases for these dinucleoside polyphosphates as the activity of IMPDH increases. Purine dinucleoside polyphosphates compete with purine mononucleotides within these sites, so the Bateman domain sites make IMPDH more sensitive to inhibition<ref>PMID: 31416831</ref>. Enzyme catalysis is able to finish with the energy need reduced as the covalent bond is broken later in the reaction to regenerate the enzyme.

</StructureSection>
== References ==

<references />

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Alyssa Ragner:

{{Sandbox_Reserved_BHall_Chem351_F19}}
=='''Inosine-5'-monophosphate dehydrogenase'''==
<StructureSection load='6rpu' size='340' side='right' caption='Structure of the ternary complex of the IMPDH enzyme from Ashbya gossypii bound to the dinucleoside polyphosphate Ap5G and GDP' scene=''>

== Function(s) and Biological Relevance ==

<scene name='82/823087/Impdh/1'>Inosine-5'-monophosphate dehydrogenase</scene> (IMPDH) is the enzyme that catalyzes the rate-limiting step in the ''de novo'' guanine nucleotide biosynthetic pathway, converting inosine monophosphate (IMP) to xanthosine monophosphate (XMP) with the reduction of nicotinamide adenine dinucleotide (NAD). Organisms that undergo the purine nucleotide biosynthetic pathway have IMPDH, including humans. This particular form of IMPDH described and highlighted comes from the recently studied fungus ''Ashbya gossypii'' <ref>PMID: 31416831</ref>. Additional ligands of IMPDH include nicotinamide adenine dinucleotide (NAD), acetate (ACT), and guanosine-5’ monophosphate (5GP). IMPDH is a regulator of the intracellular guanine nucleotide pool amount and helps control control cell division and proliferation, and therefore related to malignant transformation, tumor cell proliferation, and intracellular and extracellular pathogenic infections. Purine dinucleoside polyphosphates are found to bind to the Bateman domain of ''Ashbya gossypii'' IMPDH to allosterically regulate the catalytic activity by competing against purine mononucleotides<ref>PMID: 31416831</ref>.

== Broader Implications ==

The disease pathophysiology is extensive as the improper IMPDH regulation may lead to uncontrolled cell division and proliferation, affecting the immune system's ability to fight off pathogens and signal tumor cells to apoptose. Therapeutic studies using dinucleoside polyphosphates may allosterically regulate the inhibition of IMPDH activity. Dinucleoside polyphosphates have physiological functions including cell division, neurotransmission, apoptosis, vasoconstriction, platelet aggregation, and cellular process variety enhancement from DNA replication to repair<ref>PMID: 31416831</ref>. Selected IMPDH inhibitors composed of dinucleoside polyphosphates may be used to make IMPDHs targets for immunosuppressive, antiviral, and anticancer drugs<ref>PMID: 21517780</ref>, with antibacterial and chemotherapeutic strategies feasibile<ref>PMID: 22928911</ref>.

== Structural Highlights and Structure-Function Relationships ==

The <scene name='82/823087/Impdh_secondary_structure/1'>secondary structure</scene> shows alpha helices (pink) and beta sheets (orange). The ''Ashbya gossypii'' IMPDH is 31% helical and 15% beta sheet, which the other percentages including random coils and residue structures. The active site is located towards the C-terminus within the TIM barrel, containing 8 alpha-helices and 8 beta sheets.

IMPDH <scene name='82/823087/Impdh_quaternary_structure/1'>quaternary structures</scene> include multiunit complexes, such as tetramers, extended octamers, and compacted octamers. These quaternary structures are created through the binding of multiple subunits of tertiary structures, that are strengthened and structurally formed through hydrogen-bonding, Cysteine-Cysteine disulfide bonds, and hydrophobic interactions. Different quaternary forms of IMPDH relate to the kinetic favorability of the IMPDH mechanism as Bateman domain allosteric binding sites and competitive nature changes with unit composition.

This <scene name='82/823087/space-filled view/1'>IMPDH space filled view</scene> helps show the Van der Waals interactions and areas for movement within the structure. The ability for monovalent cations to move within the charged tunnel with the phosphate chain directly relates to activation levels.

<scene name='82/823087/Impdh_hydrophobicity/1'>Hydrophobicity view</scene> Purple represents polar molecules and gray represents hydrophobic molecules. The hydrophobicity is within the interior of the molecule as the hydrophilic residues are able to interact in a physiological environment.

<scene name='82/823087/Impdh_ligand_view/1'>IMPDH ligand view
</scene>.

<scene name='82/823087/Impdh_triad/3'>IMPDH Triad</scene> The IMPDH triad includes Arg (320), Asn (306), and Asp (272). This is represented by the solid red structures in the image. This triad is important as it makes cysteine more reactive, which in turn induces binding.

<scene name='82/823087/Impdh_triad_active_binding/1'>IMPDH active binding site</scene> The active binding site includes the Bateman domains, which are components within the TIM barrel. Binding occurs after the catalytic triad makes cysteine more reactive. In the image the cysteines are in white (6 in this sequence).

<scene name='82/823087/Impdh_charge/1'>IMPDH charge</scene> is not strong, as shown by this view. There are positive and negative components within the structure, but a relatively neutral substance is better received in this mechanism. Negatively-charged glutamine and positively-charged histidine within this enzyme are minor components but play a role within the covalent bindings in the mechanism.

<scene name='82/823087/Impdh_composition/1'>IMPDH Composition</scene> The brown represents a protein, red represents a RNA, and green represents ligands.

== Energy Transformation ==

IMPDH is activated by monovalent cations, such as K+ and Na+, within the triose-phosphate isomerase (TIM) barrel. The Arg320-Asn306-Asp272 catalytic triad (Arg322-Asn303-Asp274 in human type II IMPDH) works inter-dependently and synergistically in the TIM barrel active site to make the nucleophilic component, Cysteine, highly reactive to form a temporary covalent bond with the substrate<ref>PMID: 8555204</ref>. Substrates bind randomly to IMPDH as the hydride transfer is quick and NAD is reduced to hydrolyze the covalent intermediate within the enzyme-substrate complex. A covalent intermediate, E-XMP*, is formed, which decreases the energy needed in later nucleophilic and covalent catalysis steps<ref>PMID: 10390600</ref>. Based on normal physiological conditions, the IMPDH mechanism is often not kinetically favorable. The Bateman domains within the TIM barrel are composed of cystathionine beta-synthase motifs that perceive metal ion concentration, cellular energy status, and ionic strength; and will allosterically regulate IMPDH activity<ref>PMID: 31416831</ref>. Eukaryotic IMPDHs have three nucleotide-binding sites in the Bateman domain that allosterically modulate catalytic activity. These three nucleotide-binding sites bind adenine/guanine dinucleoside polyphosphates, and the affinity for these sites increases for these dinucleoside polyphosphates as the activity of IMPDH increases. Purine dinucleoside polyphosphates compete with purine mononucleotides within these sites, so the Bateman domain sites make IMPDH more sensitive to inhibition<ref>PMID: 31416831</ref>. Enzyme catalysis is able to finish with the energy need reduced as the covalent bond is broken later in the reaction to regenerate the enzyme.

</StructureSection>
== References ==

<references />

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