User:Abbey Wells/Sandbox 1: Difference between revisions

(10 intermediate revisions by the same user not shown)

Line 3:

== Introduction ==

Stearoyl-CoA Desaturase is an enzyme essential for the biosynthesis of monosaturated fatty acids from saturated fatty acids <ref name="Paton">doi: 10.1152/ajpendo.90897.2008</ref>. SCD catalyzes the rate-limiting step in the conversion of [http://en.wikipedia.org/wiki/Stearoyl-CoA Stearoyl-CoA] to [http://en.wikipedia.org/wiki/Oleic_acid oleic acid], an essential substrate in the biosynthesis of phospholipids, triacyclglycerols, and cholesterol <ref name="Bai">PMID:26098370</ref>. SCD is highly conserved in eukaryotes and has different gene isoforms. Mice have four isoforms: SCD1, SCD2, SCD3, and SCD4. Humans have two different isoforms: SCD1 and SCD5. The SCD isoform discussed in this page is [http://en.wikipedia.org/wiki/Stearoyl-CoA_desaturase-1 Stearoyl-CoA Desaturase 1 (SCD1)] found in mice. SCD is believed to have once been an anaerobic pathway found in cartilaginous fish about 450 million years ago <ref name="Filipe">doi: 10.1186/1471-2148-11-132</ref>. The enzyme’s mechanism is now aerobic and ~~this aerobic pathway is favored~~. The structure of SCD1 was found using X-ray crystallography <ref name="Bai">PMID:26098370</ref>.

Stearoyl-CoA Desaturase is an enzyme essential for the biosynthesis of monosaturated fatty acids from saturated fatty acids <ref name="Paton">doi: 10.1152/ajpendo.90897.2008</ref>. SCD catalyzes the rate-limiting step in the conversion of [http://en.wikipedia.org/wiki/Stearoyl-CoA Stearoyl-CoA] to [http://en.wikipedia.org/wiki/Oleic_acid oleic acid], an essential substrate in the biosynthesis of phospholipids, triacyclglycerols, and cholesterol <ref name="Bai">PMID:26098370</ref>. SCD is highly conserved in eukaryotes and has different gene isoforms. Mice have four isoforms: SCD1, SCD2, SCD3, and SCD4. Humans have two different isoforms: SCD1 and SCD5 <ref name="Bai">PMID:26098370</ref>. The SCD isoform discussed in this page is [http://en.wikipedia.org/wiki/Stearoyl-CoA_desaturase-1 Stearoyl-CoA Desaturase 1 (SCD1)] found in mice. SCD is believed to have once been an anaerobic pathway found in cartilaginous fish about 450 million years ago <ref name="Filipe">doi: 10.1186/1471-2148-11-132</ref>. The enzyme’s mechanism is now aerobic and favorable. The structure of SCD1 was found using X-ray crystallography <ref name="Bai">PMID:26098370</ref>.

~~== Function ==~~

== Structure ==

=== Overall Structure ===

SCD1 is an integral membrane protein embedded within the [http://micro.magnet.fsu.edu/cells/endoplasmicreticulum/endoplasmicreticulum.html endoplasmic reticulum] and consists of 4 transmembrane ~~[http://en.wikipedia.org/wiki/Alpha_helix~~ alpha helices], arranged in a cone-like shape. The cytosolic domain of the enzyme consists of 11 alpha helices and contains the carboxy and amino termini <ref name="Bai">PMID:26098370</ref>. Its substrate, Stearoyl-CoA, binds to the cytosolic region which contains a "kink" that properly orients Stearoyl-CoA to undergo a [http://en.wikipedia.org/wiki/Dehydrogenation#:~:text=Dehydrogenation%20is%20the%20a%20chemical,reaction%20and%20a%20serious%20problem.&text=Enzymes%20that%20catalyze%20dehydrogenation%20are%20called%20dehydrogenases. dehydrogenation] reaction between the <scene name='87/877602/C9_and_c103'>carbon 9 and carbon 10</scene> of Stearoyl-CoA.

SCD1 is an integral membrane protein embedded within the [http://micro.magnet.fsu.edu/cells/endoplasmicreticulum/endoplasmicreticulum.html endoplasmic reticulum] and consists of 4 transmembrane alpha helices, arranged in a cone-like shape. The cytosolic domain of the enzyme consists of 11 alpha helices and contains the carboxy and amino termini <ref name="Bai">PMID:26098370</ref>. Its substrate, Stearoyl-CoA, binds to the cytosolic region which contains a "kink" that properly orients Stearoyl-CoA to undergo a [http://en.wikipedia.org/wiki/Dehydrogenation#:~:text=Dehydrogenation%20is%20the%20a%20chemical,reaction%20and%20a%20serious%20problem.&text=Enzymes%20that%20catalyze%20dehydrogenation%20are%20called%20dehydrogenases. dehydrogenation] reaction between the <scene name='87/877602/C9_and_c103'>carbon 9 and carbon 10</scene> of Stearoyl-CoA <ref name="Bai">PMID:26098370</ref>.

=== Binding of Substrate ===

[http://en.wikipedia.org/wiki/Stearoyl-CoA Stearoyl-CoA] is the substrate that binds to the enzyme, SCD1. The binding of the substrate is stabilized by specific residues on the exterior and interior of the protein. Stearoyl-CoA is a long-chain fatty [http://en.wikipedia.org/wiki/Acyl-CoA#:~:text=Acyl%2DCoA%20is%20a%20group,forming%20several%20equivalents%20of%20ATP. acyl-CoA]. The head group of the substrate is composed of an adenine, ribose, phosphate groups, and ~~[http://en.wikipedia.org/wiki/Chemical_polarity#:~:text=In%20chemistry%2C%20polarity%20is%20a,electronegativity%20between%20the%20bonded%20atoms~~ polar atoms] such as of nitrogen, oxygen, and sulfur. The head of stearoyl-CoA is attached to the exterior of the protein by polar residues. The adenine, ribose, and phosphate are attached by the residues <scene name='87/877602/Hydrophillic_top_t/3'>R151, D152, K185</scene>. The remaining exterior of the substrate is attached by the residues <scene name='87/877602/Hydrophillic_bottom_labeled_t/4'>N144, N71, R184</scene>. All the conserved residues are attached to the Stearoyl-CoA via ~~[http://en.wikipedia.org/wiki/Hydrogen_bond#:~:text=A%20hydrogen%20bond%20(often%20informally,donor%20(Dn)%E2%80%94and%20another~~ hydrogen bonds]. The fatty acid tail of Stearoyl-CoA is a 17-carbon chain which reaches into the interior of the protein. The fatty acid chain dives into the interior hydrophobic tunnel which is long, narrow, and approximately 24 Angstroms long <ref name="Bai">PMID:26098370</ref>. The geometry of the tunnel and formation of bound acyl chain are the structural basis for the stereospecificity of the desaturation reaction <ref name="Bai">PMID:26098370</ref>.

[http://en.wikipedia.org/wiki/Stearoyl-CoA Stearoyl-CoA] is the substrate that binds to the enzyme, SCD1. The binding of the substrate is stabilized by specific residues on the exterior and interior of the protein. Stearoyl-CoA is a long-chain fatty [http://en.wikipedia.org/wiki/Acyl-CoA#:~:text=Acyl%2DCoA%20is%20a%20group,forming%20several%20equivalents%20of%20ATP. acyl-CoA]. The head group of the substrate is composed of an adenine, ribose, phosphate groups, and polar atoms such as of nitrogen, oxygen, and sulfur. The head of stearoyl-CoA is attached to the exterior of the protein by polar residues. The adenine, ribose, and phosphate are attached by the residues <scene name='87/877602/Hydrophillic_top_t/4'>R151, D152, K185</scene>. The remaining exterior of the substrate is attached by the residues <scene name='87/877602/Hydrophillic_bottom_labeled_t/5'>N144, N71, R184</scene> <ref name="Bai">PMID:26098370</ref>. All the conserved residues are attached to the Stearoyl-CoA via hydrogen bonds. The fatty acid tail of Stearoyl-CoA is a 17-carbon chain which reaches into the interior of the protein. The fatty acid chain dives into the interior hydrophobic tunnel which is long, narrow, and approximately 24 Angstroms long <ref name="Bai">PMID:26098370</ref>. The geometry of the tunnel and formation of bound acyl chain are the structural basis for the stereospecificity of the desaturation reaction <ref name="Bai">PMID:26098370</ref>.

=== Kink of ~~Chain~~ ===

=== Kink of Substrate ===

The chain is kinked at <scene name='87/877602/C9_and_c10/3'>carbon 9 and carbon 10</scene> where the double bond is generated. The kink is induced through the interactions of four conserved residues. Three out of four of these residues are not bound to the chain, but are hydrogen bonded to each other: <scene name='87/877602/Kink_build/2'>T257, Q143, W149</scene>. T257 is hydrogen bonded to Q143, and Q143 is hydrogen bonded to W149 <ref name="Bai">PMID:26098370</ref>. These residues are directly below the kink and will be hydrolyzed when the enzymatic product is ready to be released. Specifically, if the hydrogen bond between T257 and Q143 is broken, a large opening would allow for the product to be released into the bilayer <ref name="Bai">PMID:26098370</ref>. The residue that is directly hydrogen bonded to the chain is <scene name='87/877602/W258/3'>W258</scene>. This residue is highly conserved and stabilizes the chain so it will be in the correct orientation in the active site. The enzyme will be effective on acyl chains that are between 17 to 19 carbons long. The residue that has a role in determining substrate length is <scene name='87/877602/Cap/4'>Y104</scene>. Y104 is a capping residue that has approximately 4 [http://en.wikipedia.org/wiki/Angstrom Angstroms] between its' hydroxyl oxygen and the end of the chain <ref name="Bai">PMID:26098370</ref>.

The chain is kinked at <scene name='87/877602/C9_and_c10/3'>carbon 9 and carbon 10</scene> where the double bond is generated. The kink is induced through the interactions of four conserved residues. Three out of four of these residues are not bound to the chain, but are hydrogen bonded to each other: <scene name='87/877602/Kink_build/4'>T257, Q143, W149</scene>. T257 is hydrogen bonded to Q143, and Q143 is hydrogen bonded to W149 <ref name="Bai">PMID:26098370</ref>. These residues are directly below the kink and will be hydrolyzed when the enzymatic product is ready to be released. Specifically, if the hydrogen bond between T257 and Q143 is broken, a large opening would allow for the product to be released into the bilayer <ref name="Bai">PMID:26098370</ref>. The residue that is directly hydrogen bonded to the chain is <scene name='87/877602/W258/4'>W258</scene>. This residue is highly conserved and stabilizes the chain so it will be in the correct orientation in the active site. The enzyme will be effective on acyl chains that are between 17 to 19 carbons long. The residue that has a role in determining substrate length is <scene name='87/877602/Cap/5'>Y104</scene>. Y104 is a capping residue that has approximately 4 [http://en.wikipedia.org/wiki/Angstrom Angstroms] between its' hydroxyl oxygen and the end of the chain <ref name="Bai">PMID:26098370</ref>.

=== Active Site ===

Line 20:

Line 19:

[[Image:SCDMech.jpg|300px|thumb|left|]]

== Disease ==

One common mutation that leads to the loss of function SCD1 is a mutation at any of the histidine residues within the <scene name='87/877627/His_box2/1'>his box.</scene> A mutation at any of these 9 histidine residues interrupts the active site. This knockout of SCD1 has been known to combat obesity and lead to liver disease.

Another common mutation with SCD is the insertion of a proline at position <scene name='87/877627/R279/1'>279.</scene> This is due to an insertion of a 'CCC' codon at position 835 in exon 5 of the SCD1 gene. This mutation results in a loss of function of SCD1. This study was done using a mouse model. In mice with this mutation, hair loss, similar to alopecia, occurs. The mice were also found to be lean throughout their lifespan due to reduced triglyceride synthesis due to loss of SCD1 function.

</StructureSection>

== References ==

User:Abbey Wells/Sandbox 1: Difference between revisions

Navigation menu

Page actions

Page actions

Personal tools

Navigation

Search

Tools

@@ Line 3: / Line 3: @@
 == Introduction ==
-Stearoyl-CoA Desaturase is an enzyme essential for the biosynthesis of monosaturated fatty acids from saturated fatty acids <ref name="Paton">doi: 10.1152/ajpendo.90897.2008</ref>. SCD catalyzes the rate-limiting step in the conversion of [http://en.wikipedia.org/wiki/Stearoyl-CoA Stearoyl-CoA] to [http://en.wikipedia.org/wiki/Oleic_acid oleic acid], an essential substrate in the biosynthesis of phospholipids, triacyclglycerols, and cholesterol <ref name="Bai">PMID:26098370</ref>. SCD is highly conserved in eukaryotes and has different gene isoforms. Mice have four isoforms: SCD1, SCD2, SCD3, and SCD4. Humans have two different isoforms: SCD1 and SCD5. The SCD isoform discussed in this page is [http://en.wikipedia.org/wiki/Stearoyl-CoA_desaturase-1 Stearoyl-CoA Desaturase 1 (SCD1)] found in mice. SCD is believed to have once been an anaerobic pathway found in cartilaginous fish about 450 million years ago <ref name="Filipe">doi: 10.1186/1471-2148-11-132</ref>. The enzyme’s mechanism is now aerobic and this aerobic pathway is favored. The structure of SCD1 was found using X-ray crystallography <ref name="Bai">PMID:26098370</ref>.
+Stearoyl-CoA Desaturase is an enzyme essential for the biosynthesis of monosaturated fatty acids from saturated fatty acids <ref name="Paton">doi: 10.1152/ajpendo.90897.2008</ref>. SCD catalyzes the rate-limiting step in the conversion of [http://en.wikipedia.org/wiki/Stearoyl-CoA Stearoyl-CoA] to [http://en.wikipedia.org/wiki/Oleic_acid oleic acid], an essential substrate in the biosynthesis of phospholipids, triacyclglycerols, and cholesterol <ref name="Bai">PMID:26098370</ref>. SCD is highly conserved in eukaryotes and has different gene isoforms. Mice have four isoforms: SCD1, SCD2, SCD3, and SCD4. Humans have two different isoforms: SCD1 and SCD5 <ref name="Bai">PMID:26098370</ref>. The SCD isoform discussed in this page is [http://en.wikipedia.org/wiki/Stearoyl-CoA_desaturase-1 Stearoyl-CoA Desaturase 1 (SCD1)] found in mice. SCD is believed to have once been an anaerobic pathway found in cartilaginous fish about 450 million years ago <ref name="Filipe">doi: 10.1186/1471-2148-11-132</ref>. The enzyme’s mechanism is now aerobic and favorable. The structure of SCD1 was found using X-ray crystallography <ref name="Bai">PMID:26098370</ref>.
-== Function ==
 == Structure ==
 === Overall Structure ===
-SCD1 is an integral membrane protein embedded within the [http://micro.magnet.fsu.edu/cells/endoplasmicreticulum/endoplasmicreticulum.html endoplasmic reticulum] and consists of 4 transmembrane [http://en.wikipedia.org/wiki/Alpha_helix alpha helices], arranged in a cone-like shape. The cytosolic domain of the enzyme consists of 11 alpha helices and contains the carboxy and amino termini <ref name="Bai">PMID:26098370</ref>. Its substrate, Stearoyl-CoA, binds to the cytosolic region which contains a "kink" that properly orients Stearoyl-CoA to undergo a [http://en.wikipedia.org/wiki/Dehydrogenation#:~:text=Dehydrogenation%20is%20the%20a%20chemical,reaction%20and%20a%20serious%20problem.&text=Enzymes%20that%20catalyze%20dehydrogenation%20are%20called%20dehydrogenases. dehydrogenation] reaction between the <scene name='87/877602/C9_and_c103'>carbon 9 and carbon 10</scene> of Stearoyl-CoA.
+SCD1 is an integral membrane protein embedded within the [http://micro.magnet.fsu.edu/cells/endoplasmicreticulum/endoplasmicreticulum.html endoplasmic reticulum] and consists of 4 transmembrane alpha helices, arranged in a cone-like shape. The cytosolic domain of the enzyme consists of 11 alpha helices and contains the carboxy and amino termini <ref name="Bai">PMID:26098370</ref>. Its substrate, Stearoyl-CoA, binds to the cytosolic region which contains a "kink" that properly orients Stearoyl-CoA to undergo a [http://en.wikipedia.org/wiki/Dehydrogenation#:~:text=Dehydrogenation%20is%20the%20a%20chemical,reaction%20and%20a%20serious%20problem.&text=Enzymes%20that%20catalyze%20dehydrogenation%20are%20called%20dehydrogenases. dehydrogenation] reaction between the <scene name='87/877602/C9_and_c103'>carbon 9 and carbon 10</scene> of Stearoyl-CoA <ref name="Bai">PMID:26098370</ref>.
 === Binding of Substrate ===
-[http://en.wikipedia.org/wiki/Stearoyl-CoA Stearoyl-CoA] is the substrate that binds to the enzyme, SCD1. The binding of the substrate is stabilized by specific residues on the exterior and interior of the protein. Stearoyl-CoA is a long-chain fatty [http://en.wikipedia.org/wiki/Acyl-CoA#:~:text=Acyl%2DCoA%20is%20a%20group,forming%20several%20equivalents%20of%20ATP. acyl-CoA]. The head group of the substrate is composed of an adenine, ribose, phosphate groups, and [http://en.wikipedia.org/wiki/Chemical_polarity#:~:text=In%20chemistry%2C%20polarity%20is%20a,electronegativity%20between%20the%20bonded%20atoms polar atoms] such as of nitrogen, oxygen, and sulfur. The head of stearoyl-CoA is attached to the exterior of the protein by polar residues. The adenine, ribose, and phosphate  are attached by the residues <scene name='87/877602/Hydrophillic_top_t/3'>R151, D152, K185</scene>. The remaining exterior of the substrate is attached by the residues <scene name='87/877602/Hydrophillic_bottom_labeled_t/4'>N144, N71, R184</scene>. All the conserved residues are attached to the Stearoyl-CoA via [http://en.wikipedia.org/wiki/Hydrogen_bond#:~:text=A%20hydrogen%20bond%20(often%20informally,donor%20(Dn)%E2%80%94and%20another hydrogen bonds]. The fatty acid tail of Stearoyl-CoA is a 17-carbon chain which reaches into the interior of the protein.  The fatty acid chain dives into the interior hydrophobic tunnel which is long, narrow, and approximately 24 Angstroms long <ref name="Bai">PMID:26098370</ref>. The geometry of the tunnel and formation of bound acyl chain are the structural basis for the stereospecificity of the desaturation reaction <ref name="Bai">PMID:26098370</ref>.
+[http://en.wikipedia.org/wiki/Stearoyl-CoA Stearoyl-CoA] is the substrate that binds to the enzyme, SCD1. The binding of the substrate is stabilized by specific residues on the exterior and interior of the protein. Stearoyl-CoA is a long-chain fatty [http://en.wikipedia.org/wiki/Acyl-CoA#:~:text=Acyl%2DCoA%20is%20a%20group,forming%20several%20equivalents%20of%20ATP. acyl-CoA]. The head group of the substrate is composed of an adenine, ribose, phosphate groups, and polar atoms such as of nitrogen, oxygen, and sulfur. The head of stearoyl-CoA is attached to the exterior of the protein by polar residues. The adenine, ribose, and phosphate  are attached by the residues <scene name='87/877602/Hydrophillic_top_t/4'>R151, D152, K185</scene>. The remaining exterior of the substrate is attached by the residues <scene name='87/877602/Hydrophillic_bottom_labeled_t/5'>N144, N71, R184</scene> <ref name="Bai">PMID:26098370</ref>. All the conserved residues are attached to the Stearoyl-CoA via hydrogen bonds. The fatty acid tail of Stearoyl-CoA is a 17-carbon chain which reaches into the interior of the protein.  The fatty acid chain dives into the interior hydrophobic tunnel which is long, narrow, and approximately 24 Angstroms long <ref name="Bai">PMID:26098370</ref>. The geometry of the tunnel and formation of bound acyl chain are the structural basis for the stereospecificity of the desaturation reaction <ref name="Bai">PMID:26098370</ref>.
-=== Kink of Chain ===
+=== Kink of Substrate ===
-The chain is kinked at <scene name='87/877602/C9_and_c10/3'>carbon 9 and carbon 10</scene> where the double bond is generated. The kink is induced through the interactions of four conserved residues. Three out of four of these residues are not bound to the chain, but are hydrogen bonded to each other: <scene name='87/877602/Kink_build/2'>T257, Q143, W149</scene>. T257 is hydrogen bonded to Q143, and Q143 is hydrogen bonded to W149 <ref name="Bai">PMID:26098370</ref>. These residues are directly below the kink and will be hydrolyzed when the enzymatic product is ready to be released. Specifically, if the hydrogen bond between T257 and Q143 is broken, a large opening would allow for the product to be released into the bilayer <ref name="Bai">PMID:26098370</ref>. The residue that is directly hydrogen bonded to the chain is <scene name='87/877602/W258/3'>W258</scene>. This residue is highly conserved and stabilizes the chain so it will be in the correct orientation in the active site. The enzyme will be effective on acyl chains that are between 17 to 19 carbons long. The residue that has a role in determining substrate length is <scene name='87/877602/Cap/4'>Y104</scene>. Y104 is a capping residue that has approximately 4 [http://en.wikipedia.org/wiki/Angstrom Angstroms] between its' hydroxyl oxygen and the end of the chain <ref name="Bai">PMID:26098370</ref>.
+The chain is kinked at <scene name='87/877602/C9_and_c10/3'>carbon 9 and carbon 10</scene> where the double bond is generated. The kink is induced through the interactions of four conserved residues. Three out of four of these residues are not bound to the chain, but are hydrogen bonded to each other: <scene name='87/877602/Kink_build/4'>T257, Q143, W149</scene>. T257 is hydrogen bonded to Q143, and Q143 is hydrogen bonded to W149 <ref name="Bai">PMID:26098370</ref>. These residues are directly below the kink and will be hydrolyzed when the enzymatic product is ready to be released. Specifically, if the hydrogen bond between T257 and Q143 is broken, a large opening would allow for the product to be released into the bilayer <ref name="Bai">PMID:26098370</ref>. The residue that is directly hydrogen bonded to the chain is <scene name='87/877602/W258/4'>W258</scene>. This residue is highly conserved and stabilizes the chain so it will be in the correct orientation in the active site. The enzyme will be effective on acyl chains that are between 17 to 19 carbons long. The residue that has a role in determining substrate length is <scene name='87/877602/Cap/5'>Y104</scene>. Y104 is a capping residue that has approximately 4 [http://en.wikipedia.org/wiki/Angstrom Angstroms] between its' hydroxyl oxygen and the end of the chain <ref name="Bai">PMID:26098370</ref>.
 === Active Site ===
@@ Line 20: / Line 19: @@
 [[Image:SCDMech.jpg|300px|thumb|left|]]
 == Disease ==
-One common mutation that leads to the loss of function SCD1 is a mutation at any of the histidine residues within the  <scene name='87/877627/His_box2/1'>his box.</scene> A mutation at any of these 9 histidine residues interrupts the active site. This knockout of SCD1 has been known to combat obesity and lead to liver disease.
-Another common mutation with SCD is the insertion of a proline at position <scene name='87/877627/R279/1'>279.</scene> This is due to an insertion of a 'CCC' codon at position 835 in exon 5 of the SCD1 gene. This mutation results in a loss of function of SCD1. This study was done using a mouse model. In mice with this mutation, hair loss, similar to alopecia, occurs. The mice were also found to be lean throughout their lifespan due to reduced triglyceride synthesis due to loss of SCD1 function.
 </StructureSection>
 == References ==