https://proteopedia.org/api.php?action=feedcontributions&feedformat=atom&user=Anna+PostnikovaProteopedia - User contributions [en]2026-09-14T23:11:48ZUser contributionsMediaWiki 1.43.8https://proteopedia.org/index.php?title=Methionine_adenosyltransferase&diff=3554979Methionine adenosyltransferase2022-05-02T01:16:41Z<p>Anna Postnikova: </p>
<hr />
<div>[[Methionine adenosyltransferase]] (MAT) or S-adenosylmethionine synthetase (SAM synthetase) synthesizes S-adenosylmethionine (SAM or AdoMet) from the substrates adenosine triphosphate (ATP) and methionine. ATP isn’t used only as a source of energy like it is in other reactions but gets a methionine added onto the 5' carbon while the three phosphate groups are broken down and released from the active site. This enzyme is conserved and found in many organisms, so it is essential for life. Importantly, the production of SAM by MAT provides methyl for methylation of nucleic acids, allowing for epigenetic modification. Problems with this enzyme have been shown to cause diseases including various cancers.<br />
<br />
== Relevance ==<br />
The product of this enzymatic reaction, SAM, is the universal methyl donor of metabolism. DNA methyltransferases can transfer a methyl group from SAM to the 5th carbon of cytosine residues <ref>DOI:10.1038/npp.2012.112</ref>. In this way, MAT is indirectly important for regulation of gene expression by providing methyl through SAM. SAM is also involved in N-methylation, O-methylation and C-methylation, yielding S-adenosyl homocysteine as a product that gets recycled by the [[one-carbon metabolism]]. Radical SAM enzymes break down SAM into an adenosyl radical and methionine, enabling a host of otherwise difficult to achieve reactions, e.g. in molybdenum cofactors biosynthesis<ref>DOI:10.1073/pnas.0404624101</ref>. Accumulation of S-adenosyl homocysteine (or homocysteine itself) indicates an imbalance in supply and demand for SAM in the organism. Methionine metabolism impairment in liver diseases is related in alteration in MAT<ref>PMID:7741002</ref>.<br />
<br />
<br />
== Function and reaction mechanism ==<br />
'''S-adenosylmethionine synthetase''' or '''S-adenosylmethionine synthase''' or '''S-adenosylmethionine transferase''' or '''methionine adenosyltransferase''' (MAT) catalyzes the conversion of methionine and ATP to S-adenosylmethionine (AdoMet), pyrophosphate (PPi) and orthophosphate (Pi). The catalytic entity of MAT is a dimer. MAT cofactors are Mg+2 (or Co+2) and K+ ions<ref>PMID:8611562</ref>. <br />
<br />
[[Image:Sam rxn 2.jpg|800px]]<br />
<br />
The nucleophilic sulfur atom of methionine attacks the slightly positive 5' carbon of the adenosine sugar unit. Following this, the bond from the 5' carbon to the oxygen breaks, separating the tripolyphosphate from the newly formed S-adenosylmethionine (SAM) <ref name="Murray et al.">Murray B, Antonyuk SV, Marina A, Lu SC, Mato JM, Hasnain SS, Rojas Al. Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes. PNAS. 2016 Feb 8;113 (8) 2104-2109. doi: https://doi.org/10.1073/pnas.1510959113</ref>. This is an example of an SN2 reaction, where the substrates move through a transition state to then form the products. The products are only released after the methionine binds and the C-O bond breaks.<br />
<br />
== Structure ==<br />
<StructureSection load='5a1i' size='400' side='right' caption='MAT dimer in complex with methionine, PPNP, and adenosine (PBD 5a1i)' scene=''><br />
Mammalian MAT consists of α and β subunits. The MATα1 and MATα2 subunits are catalytic subunits while MATβ is a regulatory subunit. Human MATα2 subunits can form <scene name='49/493038/Tetramer/1'>tetramers</scene>, where the active site is found <scene name='49/493038/Tetramer/2'>between two of the subunits</scene>. (For comparison, here is the <scene name='49/493038/Cv/13'>overall structure</scene> and the <scene name='49/493038/Cv/12'>active site</scene> of the rat enzyme.<ref>PMID:12888348</ref>)<br />
<br />
The <scene name='49/493038/Tetramer/4'>substrates</scene> used by the enzyme are methionine and ATP. Notably, ATP is not used as a source of energy in this reaction like it is for many other processes. Instead, it is used as a substrate in the synthesis reaction. Methionine and ATP enter the active site and are stabilized by residues present there, including lysine and histidine. Once the reaction begins to take place, methionine flips toward the 5' carbon of the adenosine sugar<ref>doi:10.1042/BJ20121580</ref>. The C-O bond between the phosphates and the carbon breaks, and the <scene name='49/493038/Product/5'>products</scene> are formed (tripolyphosphate not pictured). SAM is released from the active site first. MAT also catalyzes hydrolysis of the tripolyphosphate into pyrophosphate and orthophosphate, which are then released from the active site <ref>Niland CN, Ghosh A, Cahill SM, Schramm VL. Mechanism and Inhibition of Human Methionine Adenosyltransferase 2A. ACS Biochemistry. 2021 Mar 3;60 (10) 791-801. doi: https://doi.org/10.1021/acs.biochem.0c00998</ref>.<br />
<br />
The subunits are encoded on different genes in humans, so they are created separately and can then come together to form various complexes, such as MATαβ or MATα2 dimers <ref name="Murray et al." />. Not much is currently known about the function of this regulatory subunit and how it regulates the function of the enzyme, but a structure of the <scene name='49/493038/Complex/2'>complex</scene> shows how the C-terminal tail of the regulatory subunit reaches into the dimer interface of the catalytic subunit<ref>DOI:10.1107/S2052252514012585</ref>. Murray et al.<ref name="Murray et al." /> show that even in the absence of the regulatory subunit, the active site found in the catalytic subunit remains functional.<br />
<br />
== Gating Loop ==<br />
MAT has been shown to have a <scene name='49/493038/Loop/6'>gating loop</scene> next to the active site <ref name="Murray et al." />. <br />
<br />
<jmol><br />
<jmolRadioGroup><br />
<item><br />
<script>model 1</script><br />
<text>ordered with SAM</text><br />
<checked>true</checked><br />
</item><br />
<item><br />
<script>model 2</script><br />
<text>disordered apo</text><br />
<checked>false</checked><br />
</item><br />
<item><br />
<script>model 0</script><br />
<text>both</text><br />
<checked>false</checked><br />
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<script>model 1; delay 0.5;model 2; delay 0.5;model 1; delay 0.5;model 2; delay 0.5;model 1; delay 0.5;model 2;</script><br />
<text>animate 3 cycles</text><br />
<checked>false</checked><br />
</item><br />
</jmolRadioGroup><br />
</jmol><br />
<br />
This structure is thought to allow access to the active site, becoming ordered or disordered. When the loop is ordered, the active site is closed, and it is opened again when the loop is disordered. Murray et al. <ref name="Murray et al." /> found that when SAM or adenosine is bound to the active site the gate is closed, and when PPNP (tripolyphosphate in the body) is bound to the active site the gate is open. It is still unknown what causes the gating loop to open and what triggers the release of products, but it is not caused by hydrolysis of tripolyphosphate <ref name="Murray et al." />. This finding shows that hydrolysis of tripolyphosphate does not provide energy for the opening of the gating loop, nor does ATP provide energy for any part of this reaction.<br />
</StructureSection><br />
<br />
==3D structures of S-adenosylmethionine synthetase==<br />
<br />
[[S-adenosylmethionine synthetase 3D structures]]<br />
<br />
{{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}<br />
{{#tree:id=OrganizedByTopic|openlevels=0|<br />
<br />
*S-adenosylmethionine synthetase<br />
<br />
**[[1fug]] – EcMAT – ''Escherichia coli''<br /><br />
**[[3iml]] – MAT – ''Burkholderia pseudomallei''<br /><br />
**[[2ydy]] – hMAT II subunit β – human<br /><br />
**[[4le5]] – MAT- ''Campylobacter jejuni''<br /><br />
**[[4hpv]] - SsMAT – ''Sulfolobus solfataricus''<br /><br />
**[[3tde]] – MAT- ''Mycobacterium tuberculosis''<br /><br />
**[[3s82]] – MAT- ''Mycobacterium avium''<br /><br />
**[[3rv2]] – MAT- ''Mycobacterium marinum''<br /><br />
<br />
<br />
*S-adenosylmethionine synthetase complexes<br />
<br />
**[[1xra]], [[1xrb]] – EcMAT + Pi + K + Mg <br /><br />
**[[1xrc]] - EcMAT + Pi + Co + K<br /><br />
**[[1mxa]] - EcMAT + Pi + PPi + Mg + K<br /><br />
**[[1mxb]] - EcMAT + Pi + ADP + Mg + K<br /><br />
**[[1mxc]] - EcMAT + Pi + Br-ADP + Mg + K<br /><br />
**[[1p7l]] – EcMAT + methionine + AdoMet + AMPPNP + Mg + K<br /><br />
**[[1rg9]] - EcMAT + AdoMet + AMPPNP + Mg + K<br /><br />
**[[1qm4]] - rMAT+ methionine analog + K + Mg – rat<br /><br />
**[[1o90]] - rMAT + Pi + Mg + K<br /><br />
**[[1o92]] – rMAT + methionine analog + ADP + Mg + K<br /><br />
**[[1o93]] – rMAT + methionine analog + ATP + Mg + K<br /><br />
**[[1o9t]] – rMAT + methionine + ADP + Mg + K<br /><br />
**[[2obv]] – hMAT I + AdoMet + Na <br /><br />
**[[2p02]] - hMAT II + AdoMet<br /><br />
**[[2ydx]] – MAT + resveratrol + NADP + Ca + ADP derivative<br /><br />
**[[4l2z]], [[4k0b]] - SsMAT + Pi + PPi + Mg + SAM derivative <br /><br />
}}<br />
<br />
==Acknowledgements==<br />
Big thank you to Dr. Karsten Theis, Kia, Mike, and Shaylie for all the help and support in editing the page and images. Thank you to Dr. Joel Sussman as well for the feedback on improving the 3D images.<br />
<br />
== References ==<br />
<references/><br />
[[Category:Topic Page]][[Category:One-carbon metabolism]]</div>Anna Postnikovahttps://proteopedia.org/index.php?title=Methionine_adenosyltransferase&diff=3553680Methionine adenosyltransferase2022-04-27T15:06:57Z<p>Anna Postnikova: </p>
<hr />
<div>[[Methionine adenosyltransferase]] (MAT) or S-adenosylmethionine synthetase (SAM synthetase) synthesizes S-adenosylmethionine (SAM or AdoMet) from the substrates adenosine triphosphate (ATP) and methionine. ATP isn’t used only as a source of energy like it is in other reactions but gets a methionine added onto the 5' carbon while the three phosphate groups are broken down and released from the active site. This enzyme is conserved and found in many organisms, so it is essential for life. Importantly, the production of SAM by MAT provides methyl for methylation of nucleic acids, allowing for epigenetic modification. Problems with this enzyme have been shown to cause diseases including various cancers.<br />
<br />
== Relevance ==<br />
The product of this enzymatic reaction, SAM, is the universal methyl donor of metabolism. DNA methyltransferases can transfer a methyl group from SAM to the 5th carbon of cytosine residues <ref>DOI:10.1038/npp.2012.112</ref>. In this way, MAT is indirectly important for regulation of gene expression by providing methyl through SAM. SAM is also involved in N-methylation, O-methylation and C-methylation, yielding S-adenosyl homocysteine as a product that gets recycled by the [[one-carbon metabolism]]. Radical SAM enzymes break down SAM into an adenosyl radical and methionine, enabling a host of otherwise difficult to achieve reactions, e.g. in molybdenum cofactors biosynthesis<ref>DOI:10.1073/pnas.0404624101</ref>. Accumulation of S-adenosyl homocysteine (or homocysteine itself) indicates an imbalance in supply and demand for SAM in the organism. Methionine metabolism impairment in liver diseases is related in alteration in MAT<ref>PMID:7741002</ref>.<br />
<br />
<br />
== Function and reaction mechanism ==<br />
'''S-adenosylmethionine synthetase''' or '''S-adenosylmethionine synthase''' or '''S-adenosylmethionine transferase''' or '''methionine adenosyltransferase''' (MAT) catalyzes the conversion of methionine and ATP to S-adenosylmethionine (AdoMet), pyrophosphate (PPi) and orthophosphate (Pi). The catalytic entity of MAT is a dimer. MAT cofactors are Mg+2 (or Co+2) and K+ ions<ref>PMID:8611562</ref>. <br />
<br />
[[Image:Sam rxn 2.jpg|800px]]<br />
<br />
The nucleophilic sulfur atom of methionine attacks the slightly positive 5' carbon of the adenosine sugar unit. Following this, the bond from the 5' carbon to the oxygen breaks, separating the tripolyphosphate from the newly formed S-adenosylmethionine (SAM) <ref name="Murray et al.">Murray B, Antonyuk SV, Marina A, Lu SC, Mato JM, Hasnain SS, Rojas Al. Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes. PNAS. 2016 Feb 8;113 (8) 2104-2109. doi: https://doi.org/10.1073/pnas.1510959113</ref>. This is an example of an SN2 reaction, where the substrates move through a transition state to then form the products. The products are only released after the methionine binds and the C-O bond breaks.<br />
<br />
== Structure ==<br />
<scene name='49/493038/Complex/1'>complex</scene><br />
<br />
<StructureSection load='5a1i' size='400' side='right' caption='MAT dimer in complex with methionine, PPNP, and adenosine (PBD 5a1i)' scene=''><br />
Mammalian MAT consists of α and β subunits. The MATα1 and MATα2 subunits are catalytic subunits while MATβ is a regulatory subunit. Human MATα2 subunits can form <scene name='49/493038/Tetramer/1'>tetramers</scene>, where the active site is found <scene name='49/493038/Tetramer/2'>between two of the subunits</scene>. (For comparison, here is the <scene name='49/493038/Cv/13'>overall structure</scene> and the <scene name='49/493038/Cv/12'>active site</scene> of the rat enzyme.<ref>PMID:12888348</ref>)<br />
<br />
The <scene name='49/493038/Tetramer/4'>substrates</scene> used by the enzyme are methionine and ATP. Notably, ATP is not used as a source of energy in this reaction like it is for many other processes. Instead, it is used as a substrate in the synthesis reaction. Methionine and ATP enter the active site and are stabilized by residues present there, including lysine and histidine. Once the reaction begins to take place, methionine flips toward the 5' carbon of the adenosine sugar<ref>doi:10.1042/BJ20121580</ref>. The C-O bond between the phosphates and the carbon breaks, and the <scene name='49/493038/Product/5'>products</scene> are formed (tripolyphosphate not pictured). SAM is released from the active site first. MAT also catalyzes hydrolysis of the tripolyphosphate into pyrophosphate and orthophosphate, which are then released from the active site <ref>Niland CN, Ghosh A, Cahill SM, Schramm VL. Mechanism and Inhibition of Human Methionine Adenosyltransferase 2A. ACS Biochemistry. 2021 Mar 3;60 (10) 791-801. doi: https://doi.org/10.1021/acs.biochem.0c00998</ref>.<br />
<br />
The subunits are encoded on different genes in humans, so they are created separately and can then come together to form various complexes, such as MATαβ or MATα2 dimers <ref name="Murray et al." />. Not much is currently known about the function of this regulatory subunit and how it regulates the function of the enzyme<ref>DOI:10.1107/S2052252514012585</ref>. However, Murray et al.<ref name="Murray et al." /> show that even in the absence of the regulatory subunit, the active site found in the catalytic subunit remains functional.<br />
<br />
== Gating Loop ==<br />
MAT has been shown to have a <scene name='49/493038/Loop/6'>gating loop</scene> next to the active site <ref name="Murray et al." />. <br />
<br />
<jmol><br />
<jmolRadioGroup><br />
<item><br />
<script>model 1</script><br />
<text>ordered with SAM</text><br />
<checked>true</checked><br />
</item><br />
<item><br />
<script>model 2</script><br />
<text>disordered apo</text><br />
<checked>false</checked><br />
</item><br />
<item><br />
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</item><br />
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<script>model 1; delay 0.5;model 2; delay 0.5;model 1; delay 0.5;model 2; delay 0.5;model 1; delay 0.5;model 2;</script><br />
<text>animate 3 cycles</text><br />
<checked>false</checked><br />
</item><br />
</jmolRadioGroup><br />
</jmol><br />
<br />
This structure is thought to allow access to the active site, becoming ordered or disordered. When the loop is ordered, the active site is closed, and it is opened again when the loop is disordered. Murray et al. <ref name="Murray et al." /> found that when SAM or adenosine is bound to the active site the gate is closed, and when PPNP (tripolyphosphate in the body) is bound to the active site the gate is open. It is still unknown what causes the gating loop to open and what triggers the release of products, but it is not caused by hydrolysis of tripolyphosphate <ref name="Murray et al." />. This finding shows that hydrolysis of tripolyphosphate does not provide energy for the opening of the gating loop, nor does ATP provide energy for any part of this reaction.<br />
</StructureSection><br />
<br />
==3D structures of S-adenosylmethionine synthetase==<br />
<br />
[[S-adenosylmethionine synthetase 3D structures]]<br />
<br />
{{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}<br />
{{#tree:id=OrganizedByTopic|openlevels=0|<br />
<br />
*S-adenosylmethionine synthetase<br />
<br />
**[[1fug]] – EcMAT – ''Escherichia coli''<br /><br />
**[[3iml]] – MAT – ''Burkholderia pseudomallei''<br /><br />
**[[2ydy]] – hMAT II subunit β – human<br /><br />
**[[4le5]] – MAT- ''Campylobacter jejuni''<br /><br />
**[[4hpv]] - SsMAT – ''Sulfolobus solfataricus''<br /><br />
**[[3tde]] – MAT- ''Mycobacterium tuberculosis''<br /><br />
**[[3s82]] – MAT- ''Mycobacterium avium''<br /><br />
**[[3rv2]] – MAT- ''Mycobacterium marinum''<br /><br />
<br />
<br />
*S-adenosylmethionine synthetase complexes<br />
<br />
**[[1xra]], [[1xrb]] – EcMAT + Pi + K + Mg <br /><br />
**[[1xrc]] - EcMAT + Pi + Co + K<br /><br />
**[[1mxa]] - EcMAT + Pi + PPi + Mg + K<br /><br />
**[[1mxb]] - EcMAT + Pi + ADP + Mg + K<br /><br />
**[[1mxc]] - EcMAT + Pi + Br-ADP + Mg + K<br /><br />
**[[1p7l]] – EcMAT + methionine + AdoMet + AMPPNP + Mg + K<br /><br />
**[[1rg9]] - EcMAT + AdoMet + AMPPNP + Mg + K<br /><br />
**[[1qm4]] - rMAT+ methionine analog + K + Mg – rat<br /><br />
**[[1o90]] - rMAT + Pi + Mg + K<br /><br />
**[[1o92]] – rMAT + methionine analog + ADP + Mg + K<br /><br />
**[[1o93]] – rMAT + methionine analog + ATP + Mg + K<br /><br />
**[[1o9t]] – rMAT + methionine + ADP + Mg + K<br /><br />
**[[2obv]] – hMAT I + AdoMet + Na <br /><br />
**[[2p02]] - hMAT II + AdoMet<br /><br />
**[[2ydx]] – MAT + resveratrol + NADP + Ca + ADP derivative<br /><br />
**[[4l2z]], [[4k0b]] - SsMAT + Pi + PPi + Mg + SAM derivative <br /><br />
}}<br />
== References ==<br />
<references/><br />
[[Category:Topic Page]][[Category:One-carbon metabolism]]</div>Anna Postnikovahttps://proteopedia.org/index.php?title=Methionine_adenosyltransferase&diff=3550773Methionine adenosyltransferase2022-04-25T15:12:33Z<p>Anna Postnikova: </p>
<hr />
<div>[[Methionine adenosyltransferase]] (MAT) or S-adenosylmethionine synthetase (SAM synthetase) synthesizes S-adenosylmethionine (SAM or AdoMet) from the substrates adenosine triphosphate (ATP) and methionine. ATP isn’t used only as a source of energy like it is in other reactions but gets a methionine added onto the 5' carbon while the three phosphate groups are broken down and released from the active site. This enzyme is conserved and found in many organisms, so it is essential for life. Importantly, the production of SAM by MAT provides methyl for methylation of nucleic acids, allowing for epigenetic modification. Problems with this enzyme have been shown to cause diseases including various cancers.<br />
<br />
== Relevance ==<br />
The product of this enzymatic reaction, SAM, is the universal methyl donor of metabolism. DNA methyltransferases can transfer a methyl group from SAM to the 5th carbon of cytosine residues <ref>DOI:10.1038/npp.2012.112</ref>. In this way, MAT is indirectly important for regulation of gene expression by providing methyl through SAM. SAM is also involved in N-methylation, O-methylation and C-methylation, yielding S-adenosyl homocysteine as a product that gets recycled by the [[one-carbon metabolism]]. Radical SAM enzymes break down SAM into an adenosyl radical and methionine, enabling a host of otherwise difficult to achieve reactions, e.g. in molybdenum cofactors biosynthesis<ref>DOI:10.1073/pnas.0404624101</ref>. Accumulation of S-adenosyl homocysteine (or homocysteine itself) indicates an imbalance in supply and demand for SAM in the organism. Methionine metabolism impairment in liver diseases is related in alteration in MAT<ref>PMID:7741002</ref>.<br />
<br />
<br />
== Function and reaction mechanism ==<br />
'''S-adenosylmethionine synthetase''' or '''S-adenosylmethionine synthase''' or '''S-adenosylmethionine transferase''' or '''methionine adenosyltransferase''' (MAT) catalyzes the conversion of methionine and ATP to S-adenosylmethionine (AdoMet), pyrophosphate (PPi) and orthophosphate (Pi). The catalytic entity of MAT is a dimer. MAT cofactors are Mg+2 (or Co+2) and K+ ions<ref>PMID:8611562</ref>. <br />
<br />
[[Image:Sam rxn 2.jpg|800px]]<br />
<br />
The nucleophilic sulfur atom of methionine attacks the slightly positive 5' carbon of the adenosine sugar unit. Following this, the bond from the 5' carbon to the oxygen breaks, separating the tripolyphosphate from the newly formed S-adenosylmethionine (SAM) <ref name="Murray et al.">Murray B, Antonyuk SV, Marina A, Lu SC, Mato JM, Hasnain SS, Rojas Al. Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes. PNAS. 2016 Feb 8;113 (8) 2104-2109. doi: https://doi.org/10.1073/pnas.1510959113</ref>. This is an example of an SN2 reaction, where the substrates move through a transition state to then form the products. The products are only released after the methionine binds and the C-O bond breaks.<br />
<br />
== Structure ==<br />
<StructureSection load='5a1i' size='400' side='right' caption='MAT dimer in complex with methionine, PPNP, and adenosine (PBD 5a1i)' scene=''><br />
MAT consists of α and β subunits. The MATα1 and MATα2 subunits are catalytic subunits while MATβ is a regulatory subunit. MATα2 subunits can form <scene name='49/493038/Tetramer/1'>tetramers</scene>, where the active site is found <scene name='49/493038/Tetramer/2'>between two of the subunits</scene>. The subunits are encoded on different genes in humans, so they are created separately and can then come together to form various complexes, such as MATαβ or MATα2 dimers <ref name="Murray et al." />. Not much is currently known about the function of this regulatory subunit and how it regulates the function of the enzyme<ref>DOI:10.1107/S2052252514012585</ref>. However, Murray et al.<ref name="Murray et al." /> show that even in the absence of the regulatory subunit, the active site found in the catalytic subunit remains functional. <br />
<br />
The biological assembly of rat S-adenosylmethionine synthetase is a <scene name='49/493038/Cv/11'>homotetramer</scene>. The <scene name='49/493038/Cv/10'>active site of MAT is located between adjacent subunits</scene><ref>PMID:12888348</ref>. The <scene name='49/493038/Substrates/4'>substrates</scene> used by the enzyme are methionine and ATP. Notably, ATP is not used as a source of energy in this reaction like it is for many other processes. Instead, it is used as a substrate in the synthesis reaction. Methionine and ATP enter the active site and are stabilized by residues present there, including lysine and histidine. Once the reaction begins to take place, methionine flips toward the 5' carbon of the adenosine sugar<ref>doi:10.1042/BJ20121580</ref>. Following nucleophilic attack of the sulfur on the carbon, the C-O bond between the phosphates and the carbon breaks, and the <scene name='49/493038/Product/4'>products</scene> are formed (tripolyphosphate not pictured). SAM is released from the active site first. MAT also catalyzes hydrolysis of the tripolyphosphate into pyrophosphate and orthophosphate, which are then released from the active site <ref>Niland CN, Ghosh A, Cahill SM, Schramm VL. Mechanism and Inhibition of Human Methionine Adenosyltransferase 2A. ACS Biochemistry. 2021 Mar 3;60 (10) 791-801. doi: https://doi.org/10.1021/acs.biochem.0c00998</ref>.<br />
<br />
== Gating Loop ==<br />
MAT has been shown to have a <scene name='49/493038/Loop/6'>gating loop</scene> next to the active site <ref name="Murray et al." />. <br />
<br />
<jmol><br />
<jmolRadioGroup><br />
<item><br />
<script>model 1</script><br />
<text>ordered with SAM</text><br />
<checked>true</checked><br />
</item><br />
<item><br />
<script>model 2</script><br />
<text>disordered apo</text><br />
<checked>false</checked><br />
</item><br />
<item><br />
<script>model 0</script><br />
<text>both</text><br />
<checked>false</checked><br />
</item><br />
<item><br />
<script>model 1; delay 0.5;model 2; delay 0.5;model 1; delay 0.5;model 2; delay 0.5;model 1; delay 0.5;model 2;</script><br />
<text>animate 3 cycles</text><br />
<checked>false</checked><br />
</item><br />
</jmolRadioGroup><br />
</jmol><br />
<br />
This structure is thought to allow access to the active site, becoming ordered or disordered. When the loop is ordered, the active site is closed, and it is opened again when the loop is disordered. Murray et al. <ref name="Murray et al." /> found that when SAM or adenosine is bound to the active site the gate is closed, and when PPNP (tripolyphosphate in the body) is bound to the active site the gate is open. It is still unknown what causes the gating loop to open and what triggers the release of products, but it is not caused by hydrolysis of tripolyphosphate <ref name="Murray et al." />. This finding shows that hydrolysis of tripolyphosphate does not provide energy for the opening of the gating loop, nor does ATP provide energy for any part of this reaction.<br />
</StructureSection><br />
<br />
==3D structures of S-adenosylmethionine synthetase==<br />
<br />
[[S-adenosylmethionine synthetase 3D structures]]<br />
<br />
{{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}<br />
{{#tree:id=OrganizedByTopic|openlevels=0|<br />
<br />
*S-adenosylmethionine synthetase<br />
<br />
**[[1fug]] – EcMAT – ''Escherichia coli''<br /><br />
**[[3iml]] – MAT – ''Burkholderia pseudomallei''<br /><br />
**[[2ydy]] – hMAT II subunit β – human<br /><br />
**[[4le5]] – MAT- ''Campylobacter jejuni''<br /><br />
**[[4hpv]] - SsMAT – ''Sulfolobus solfataricus''<br /><br />
**[[3tde]] – MAT- ''Mycobacterium tuberculosis''<br /><br />
**[[3s82]] – MAT- ''Mycobacterium avium''<br /><br />
**[[3rv2]] – MAT- ''Mycobacterium marinum''<br /><br />
<br />
<br />
*S-adenosylmethionine synthetase complexes<br />
<br />
**[[1xra]], [[1xrb]] – EcMAT + Pi + K + Mg <br /><br />
**[[1xrc]] - EcMAT + Pi + Co + K<br /><br />
**[[1mxa]] - EcMAT + Pi + PPi + Mg + K<br /><br />
**[[1mxb]] - EcMAT + Pi + ADP + Mg + K<br /><br />
**[[1mxc]] - EcMAT + Pi + Br-ADP + Mg + K<br /><br />
**[[1p7l]] – EcMAT + methionine + AdoMet + AMPPNP + Mg + K<br /><br />
**[[1rg9]] - EcMAT + AdoMet + AMPPNP + Mg + K<br /><br />
**[[1qm4]] - rMAT+ methionine analog + K + Mg – rat<br /><br />
**[[1o90]] - rMAT + Pi + Mg + K<br /><br />
**[[1o92]] – rMAT + methionine analog + ADP + Mg + K<br /><br />
**[[1o93]] – rMAT + methionine analog + ATP + Mg + K<br /><br />
**[[1o9t]] – rMAT + methionine + ADP + Mg + K<br /><br />
**[[2obv]] – hMAT I + AdoMet + Na <br /><br />
**[[2p02]] - hMAT II + AdoMet<br /><br />
**[[2ydx]] – MAT + resveratrol + NADP + Ca + ADP derivative<br /><br />
**[[4l2z]], [[4k0b]] - SsMAT + Pi + PPi + Mg + SAM derivative <br /><br />
}}<br />
== References ==<br />
<references/><br />
[[Category:Topic Page]][[Category:One-carbon metabolism]]</div>Anna Postnikovahttps://proteopedia.org/index.php?title=Methionine_adenosyltransferase&diff=3550767Methionine adenosyltransferase2022-04-25T15:01:39Z<p>Anna Postnikova: </p>
<hr />
<div>[[Methionine adenosyltransferase]] (MAT) or S-adenosylmethionine synthetase (SAM synthetase) synthesizes S-adenosylmethionine (SAM or AdoMet) from the substrates adenosine triphosphate (ATP) and methionine. ATP isn’t used only as a source of energy like it is in other reactions but gets a methionine added onto the 5' carbon while the three phosphate groups are broken down and released from the active site. This enzyme is conserved and found in many organisms, so it is essential for life. Importantly, the production of SAM by MAT provides methyl for methylation of nucleic acids, allowing for epigenetic modification. Problems with this enzyme have been shown to cause diseases including various cancers.<br />
<br />
== Relevance ==<br />
The product of this enzymatic reaction, SAM, is the universal methyl donor of metabolism. DNA methyltransferases can transfer a methyl group from SAM to the 5th carbon of cytosine residues <ref>DOI:10.1038/npp.2012.112</ref>. In this way, MAT is indirectly important for regulation of gene expression by providing methyl through SAM. SAM is also involved in N-methylation, O-methylation and C-methylation, yielding S-adenosyl homocysteine as a product that gets recycled by the [[one-carbon metabolism]]. Radical SAM enzymes break down SAM into an adenosyl radical and methionine, enabling a host of otherwise difficult to achieve reactions, e.g. in molybdenum cofactors biosynthesis<ref>DOI:10.1073/pnas.0404624101</ref>. Accumulation of S-adenosyl homocysteine (or homocysteine itself) indicates an imbalance in supply and demand for SAM in the organism. Methionine metabolism impairment in liver diseases is related in alteration in MAT<ref>PMID:7741002</ref>.<br />
<br />
<br />
== Function and reaction mechanism ==<br />
'''S-adenosylmethionine synthetase''' or '''S-adenosylmethionine synthase''' or '''S-adenosylmethionine transferase''' or '''methionine adenosyltransferase''' (MAT) catalyzes the conversion of methionine and ATP to S-adenosylmethionine (AdoMet), pyrophosphate (PPi) and orthophosphate (Pi). The catalytic entity of MAT is a dimer. MAT cofactors are Mg+2 (or Co+2) and K+ ions<ref>PMID:8611562</ref>. <br />
<br />
[[Image:Sam rxn 2.jpg|800px]]<br />
<br />
The nucleophilic sulfur atom of methionine attacks the slightly positive 5' carbon of the adenosine sugar unit. Following this, the bond from the 5' carbon to the oxygen breaks, separating the tripolyphosphate from the newly formed S-adenosylmethionine (SAM) <ref name="Murray et al.">Murray B, Antonyuk SV, Marina A, Lu SC, Mato JM, Hasnain SS, Rojas Al. Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes. PNAS. 2016 Feb 8;113 (8) 2104-2109. doi: https://doi.org/10.1073/pnas.1510959113</ref>. This is an example of an SN2 reaction, where the substrates move through a transition state to then form the products. The products are only released after the methionine binds and the C-O bond breaks.<br />
<br />
== Structure ==<br />
<StructureSection load='5a1i' size='400' side='right' caption='MAT dimer in complex with methionine, PPNP, and adenosine (PBD 5a1i)' scene=''><br />
MAT consists of α and β subunits. The MATα1 and <scene name='90/907472/Mat2a/4'>MATα2</scene> subunits are catalytic subunits while MATβ is a regulatory subunit. MATα2 subunits can form <scene name='49/493038/Tetramer/1'>tetramers</scene>, where the active site is found <scene name='49/493038/Tetramer/2'>between two of the subunits</scene>. The subunits are encoded on different genes in humans, so they are created separately and can then come together to form various complexes, such as MATαβ or MATα2 dimers <ref name="Murray et al." />. Not much is currently known about the function of this regulatory subunit and how it regulates the function of the enzyme<ref>DOI:10.1107/S2052252514012585</ref>. However, Murray et al.<ref name="Murray et al." /> show that even in the absence of the regulatory subunit, the active site found in the catalytic subunit remains functional. <br />
<br />
The biological assembly of rat S-adenosylmethionine synthetase is a <scene name='49/493038/Cv/7'>homotetramer</scene>. The <scene name='49/493038/Cv/8'>active site of MAT is located between adjacent subunits</scene><ref>PMID:12888348</ref>. The <scene name='49/493038/Substrates/2'>substrates</scene> used by the enzyme are methionine and ATP. Notably, ATP is not used as a source of energy in this reaction like it is for many other processes. Instead, it is used as a substrate in the synthesis reaction. Methionine and ATP enter the active site and are stabilized by residues present there, including lysine and histidine. Once the reaction begins to take place, methionine flips toward the 5' carbon of the adenosine sugar<ref>doi:10.1042/BJ20121580</ref>. Following nucleophilic attack of the sulfur on the carbon, the C-O bond between the phosphates and the carbon breaks, and the <scene name='49/493038/Product/3'>products</scene> are formed (tripolyphosphate not pictured). SAM is released from the active site first. MAT also catalyzes hydrolysis of the tripolyphosphate into pyrophosphate and orthophosphate, which are then released from the active site <ref>Niland CN, Ghosh A, Cahill SM, Schramm VL. Mechanism and Inhibition of Human Methionine Adenosyltransferase 2A. ACS Biochemistry. 2021 Mar 3;60 (10) 791-801. doi: https://doi.org/10.1021/acs.biochem.0c00998</ref>.<br />
<br />
== Gating Loop ==<br />
MAT has been shown to have a <scene name='49/493038/Loop/2'>gating loop</scene> next to the active site <ref name="Murray et al." />. <br />
<br />
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This structure is thought to allow access to the active site, becoming ordered or disordered. When the loop is ordered, the active site is closed, and it is opened again when the loop is disordered. Murray et al. <ref name="Murray et al." /> found that when SAM or adenosine is bound to the active site the gate is closed, and when PPNP (tripolyphosphate in the body) is bound to the active site the gate is open. It is still unknown what causes the gating loop to open and what triggers the release of products, but it is not caused by hydrolysis of tripolyphosphate <ref name="Murray et al." />. This finding shows that hydrolysis of tripolyphosphate does not provide energy for the opening of the gating loop, nor does ATP provide energy for any part of this reaction.<br />
</StructureSection><br />
<br />
==3D structures of S-adenosylmethionine synthetase==<br />
<br />
[[S-adenosylmethionine synthetase 3D structures]]<br />
<br />
{{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}<br />
{{#tree:id=OrganizedByTopic|openlevels=0|<br />
<br />
*S-adenosylmethionine synthetase<br />
<br />
**[[1fug]] – EcMAT – ''Escherichia coli''<br /><br />
**[[3iml]] – MAT – ''Burkholderia pseudomallei''<br /><br />
**[[2ydy]] – hMAT II subunit β – human<br /><br />
**[[4le5]] – MAT- ''Campylobacter jejuni''<br /><br />
**[[4hpv]] - SsMAT – ''Sulfolobus solfataricus''<br /><br />
**[[3tde]] – MAT- ''Mycobacterium tuberculosis''<br /><br />
**[[3s82]] – MAT- ''Mycobacterium avium''<br /><br />
**[[3rv2]] – MAT- ''Mycobacterium marinum''<br /><br />
<br />
<br />
*S-adenosylmethionine synthetase complexes<br />
<br />
**[[1xra]], [[1xrb]] – EcMAT + Pi + K + Mg <br /><br />
**[[1xrc]] - EcMAT + Pi + Co + K<br /><br />
**[[1mxa]] - EcMAT + Pi + PPi + Mg + K<br /><br />
**[[1mxb]] - EcMAT + Pi + ADP + Mg + K<br /><br />
**[[1mxc]] - EcMAT + Pi + Br-ADP + Mg + K<br /><br />
**[[1p7l]] – EcMAT + methionine + AdoMet + AMPPNP + Mg + K<br /><br />
**[[1rg9]] - EcMAT + AdoMet + AMPPNP + Mg + K<br /><br />
**[[1qm4]] - rMAT+ methionine analog + K + Mg – rat<br /><br />
**[[1o90]] - rMAT + Pi + Mg + K<br /><br />
**[[1o92]] – rMAT + methionine analog + ADP + Mg + K<br /><br />
**[[1o93]] – rMAT + methionine analog + ATP + Mg + K<br /><br />
**[[1o9t]] – rMAT + methionine + ADP + Mg + K<br /><br />
**[[2obv]] – hMAT I + AdoMet + Na <br /><br />
**[[2p02]] - hMAT II + AdoMet<br /><br />
**[[2ydx]] – MAT + resveratrol + NADP + Ca + ADP derivative<br /><br />
**[[4l2z]], [[4k0b]] - SsMAT + Pi + PPi + Mg + SAM derivative <br /><br />
}}<br />
== References ==<br />
<references/><br />
[[Category:Topic Page]][[Category:One-carbon metabolism]]</div>Anna Postnikovahttps://proteopedia.org/index.php?title=Methionine_adenosyltransferase&diff=3550761Methionine adenosyltransferase2022-04-25T14:54:41Z<p>Anna Postnikova: </p>
<hr />
<div>[[Methionine adenosyltransferase]] (MAT) or S-adenosylmethionine synthetase (SAM synthetase) synthesizes S-adenosylmethionine (SAM or AdoMet) from the substrates adenosine triphosphate (ATP) and methionine. ATP isn’t used only as a source of energy like it is in other reactions but gets a methionine added onto the 5' carbon while the three phosphate groups are broken down and released from the active site. This enzyme is conserved and found in many organisms, so it is essential for life. Importantly, the production of SAM by MAT provides methyl for methylation of nucleic acids, allowing for epigenetic modification. Problems with this enzyme have been shown to cause diseases including various cancers.<br />
<br />
== Relevance ==<br />
The product of this enzymatic reaction, SAM, is the universal methyl donor of metabolism. DNA methyltransferases can transfer a methyl group from SAM to the 5th carbon of cytosine residues <ref>DOI:10.1038/npp.2012.112</ref>. In this way, MAT is indirectly important for regulation of gene expression by providing methyl through SAM. SAM is also involved in N-methylation, O-methylation and C-methylation, yielding S-adenosyl homocysteine as a product that gets recycled by the [[one-carbon metabolism]]. Radical SAM enzymes break down SAM into an adenosyl radical and methionine, enabling a host of otherwise difficult to achieve reactions, e.g. in molybdenum cofactors biosynthesis<ref>DOI:10.1073/pnas.0404624101</ref>. Accumulation of S-adenosyl homocysteine (or homocysteine itself) indicates an imbalance in supply and demand for SAM in the organism. Methionine metabolism impairment in liver diseases is related in alteration in MAT<ref>PMID:7741002</ref>.<br />
<br />
<br />
== Function and reaction mechanism ==<br />
'''S-adenosylmethionine synthetase''' or '''S-adenosylmethionine synthase''' or '''S-adenosylmethionine transferase''' or '''methionine adenosyltransferase''' (MAT) catalyzes the conversion of methionine and ATP to S-adenosylmethionine (AdoMet), pyrophosphate (PPi) and orthophosphate (Pi). The catalytic entity of MAT is a dimer. MAT cofactors are Mg+2 (or Co+2) and K+ ions<ref>PMID:8611562</ref>. <br />
<br />
[[Image:Sam rxn 2.jpg|800px]]<br />
<br />
The nucleophilic sulfur atom of methionine attacks the slightly positive 5' carbon of the adenosine sugar unit. Following this, the bond from the 5' carbon to the oxygen breaks, separating the tripolyphosphate from the newly formed S-adenosylmethionine (SAM) <ref name="Murray et al.">Murray B, Antonyuk SV, Marina A, Lu SC, Mato JM, Hasnain SS, Rojas Al. Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes. PNAS. 2016 Feb 8;113 (8) 2104-2109. doi: https://doi.org/10.1073/pnas.1510959113</ref>. This is an example of an SN2 reaction, where the substrates move through a transition state to then form the products. The products are only released after the methionine binds and the C-O bond breaks.<br />
<br />
== Structure ==<br />
<StructureSection load='5a1i' size='400' side='right' caption='MAT dimer in complex with methionine, PPNP, and adenosine' scene=''><br />
MAT consists of α and β subunits. The MATα1 and <scene name='90/907472/Mat2a/4'>MATα2</scene> subunits are catalytic subunits while MATβ is a regulatory subunit. The subunits are encoded on different genes in humans, so they are created separately and can then come together to form various complexes, such as MATαβ or MATα2 dimers <ref name="Murray et al." />. Not much is currently known about the function of this regulatory subunit and how it regulates the function of the enzyme<ref>DOI:10.1107/S2052252514012585</ref>. However, Murray et al.<ref name="Murray et al." /> show that even in the absence of the regulatory subunit, the active site found in the catalytic subunit remains functional. <br />
<br />
The biological assembly of rat S-adenosylmethionine synthetase is a <scene name='49/493038/Cv/7'>homotetramer</scene>. The <scene name='49/493038/Cv/8'>active site of MAT is located between adjacent subunits</scene><ref>PMID:12888348</ref>. The <scene name='90/907472/Substrates/2'>substrates</scene> used by the enzyme are methionine and ATP. Notably, ATP is not used as a source of energy in this reaction like it is for many other processes. Instead, it is used as a substrate in the synthesis reaction. Methionine and ATP enter the active site and are stabilized by residues present there, including lysine and histidine. Once the reaction begins to take place, methionine flips toward the 5' carbon of the adenosine sugar<ref>doi:10.1042/BJ20121580</ref>. Following nucleophilic attack of the sulfur on the carbon, the C-O bond between the phosphates and the carbon breaks, and the <scene name='90/907472/Product/3'>products</scene> are formed (tripolyphosphate not pictured). SAM is released from the active site first. MAT also catalyzes hydrolysis of the tripolyphosphate into pyrophosphate and orthophosphate, which are then released from the active site <ref>Niland CN, Ghosh A, Cahill SM, Schramm VL. Mechanism and Inhibition of Human Methionine Adenosyltransferase 2A. ACS Biochemistry. 2021 Mar 3;60 (10) 791-801. doi: https://doi.org/10.1021/acs.biochem.0c00998</ref>.<br />
<br />
== Gating Loop ==<br />
MAT has been shown to have a <scene name='49/493038/Loop/2'>gating loop</scene> next to the active site <ref name="Murray et al." />. <br />
<br />
<jmol><br />
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<script>model 1</script><br />
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<br />
This structure is thought to allow access to the active site, becoming ordered or disordered. When the loop is ordered, the active site is closed, and it is opened again when the loop is disordered. Murray et al. <ref name="Murray et al." /> found that when SAM or adenosine is bound to the active site the gate is closed, and when PPNP (tripolyphosphate in the body) is bound to the active site the gate is open. It is still unknown what causes the gating loop to open and what triggers the release of products, but it is not caused by hydrolysis of tripolyphosphate <ref name="Murray et al." />. This finding shows that hydrolysis of tripolyphosphate does not provide energy for the opening of the gating loop, nor does ATP provide energy for any part of this reaction.<br />
</StructureSection><br />
<br />
==3D structures of S-adenosylmethionine synthetase==<br />
Scene 1: <scene name='49/493038/Tetramer/1'>tetramer</scene><br />
Scene 2:<scene name='49/493038/Tetramer/2'>binding site detail</scene><br />
<br />
[[S-adenosylmethionine synthetase 3D structures]]<br />
<br />
{{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}<br />
{{#tree:id=OrganizedByTopic|openlevels=0|<br />
<br />
*S-adenosylmethionine synthetase<br />
<br />
**[[1fug]] – EcMAT – ''Escherichia coli''<br /><br />
**[[3iml]] – MAT – ''Burkholderia pseudomallei''<br /><br />
**[[2ydy]] – hMAT II subunit β – human<br /><br />
**[[4le5]] – MAT- ''Campylobacter jejuni''<br /><br />
**[[4hpv]] - SsMAT – ''Sulfolobus solfataricus''<br /><br />
**[[3tde]] – MAT- ''Mycobacterium tuberculosis''<br /><br />
**[[3s82]] – MAT- ''Mycobacterium avium''<br /><br />
**[[3rv2]] – MAT- ''Mycobacterium marinum''<br /><br />
<br />
<br />
*S-adenosylmethionine synthetase complexes<br />
<br />
**[[1xra]], [[1xrb]] – EcMAT + Pi + K + Mg <br /><br />
**[[1xrc]] - EcMAT + Pi + Co + K<br /><br />
**[[1mxa]] - EcMAT + Pi + PPi + Mg + K<br /><br />
**[[1mxb]] - EcMAT + Pi + ADP + Mg + K<br /><br />
**[[1mxc]] - EcMAT + Pi + Br-ADP + Mg + K<br /><br />
**[[1p7l]] – EcMAT + methionine + AdoMet + AMPPNP + Mg + K<br /><br />
**[[1rg9]] - EcMAT + AdoMet + AMPPNP + Mg + K<br /><br />
**[[1qm4]] - rMAT+ methionine analog + K + Mg – rat<br /><br />
**[[1o90]] - rMAT + Pi + Mg + K<br /><br />
**[[1o92]] – rMAT + methionine analog + ADP + Mg + K<br /><br />
**[[1o93]] – rMAT + methionine analog + ATP + Mg + K<br /><br />
**[[1o9t]] – rMAT + methionine + ADP + Mg + K<br /><br />
**[[2obv]] – hMAT I + AdoMet + Na <br /><br />
**[[2p02]] - hMAT II + AdoMet<br /><br />
**[[2ydx]] – MAT + resveratrol + NADP + Ca + ADP derivative<br /><br />
**[[4l2z]], [[4k0b]] - SsMAT + Pi + PPi + Mg + SAM derivative <br /><br />
}}<br />
== References ==<br />
<references/><br />
[[Category:Topic Page]][[Category:One-carbon metabolism]]</div>Anna Postnikovahttps://proteopedia.org/index.php?title=Methionine_adenosyltransferase&diff=3550707Methionine adenosyltransferase2022-04-25T00:40:28Z<p>Anna Postnikova: </p>
<hr />
<div>[[Methionine adenosyltransferase]] (MAT) or S-adenosylmethionine synthetase (SAM synthetase) synthesizes S-adenosylmethionine (SAM or AdoMet) from the substrates adenosine triphosphate (ATP) and methionine. ATP isn’t used only as a source of energy like it is in other reactions but gets a methionine added onto the 5' carbon while the three phosphate groups are broken down and released from the active site. This enzyme is conserved and found in many organisms, so it is essential for life. Importantly, the production of SAM by MAT provides methyl for methylation of nucleic acids, allowing for epigenetic modification. Problems with this enzyme have been shown to cause diseases including various cancers.<br />
<br />
== Relevance ==<br />
The product of this enzymatic reaction, SAM, is the universal methyl donor of metabolism. DNA methyltransferases can transfer a methyl group from SAM to the 5th carbon of cytosine residues <ref>DOI:10.1038/npp.2012.112</ref>. In this way, MAT is indirectly important for regulation of gene expression by providing methyl through SAM. SAM is also involved in N-methylation, O-methylation and C-methylation, yielding S-adenosyl homocysteine as a product that gets recycled by the [[one-carbon metabolism]]. Radical SAM enzymes break down SAM into an adenosyl radical and methionine, enabling a host of otherwise difficult to achieve reactions, e.g. in molybdenum cofactors biosynthesis<ref>DOI:10.1073/pnas.0404624101</ref>. Accumulation of S-adenosyl homocysteine (or homocysteine itself) indicates an imbalance in supply and demand for SAM in the organism. Methionine metabolism impairment in liver diseases is related in alteration in MAT<ref>PMID:7741002</ref>.<br />
<br />
<br />
== Function and reaction mechanism ==<br />
'''S-adenosylmethionine synthetase''' or '''S-adenosylmethionine synthase''' or '''S-adenosylmethionine transferase''' or '''methionine adenosyltransferase''' (MAT) catalyzes the conversion of methionine and ATP to S-adenosylmethionine (AdoMet), pyrophosphate (PPi) and orthophosphate (Pi). The catalytic entity of MAT is a dimer. MAT cofactors are Mg+2 (or Co+2) and K+ ions<ref>PMID:8611562</ref>. <br />
<br />
[[Image:Sam rxn 2.jpg|800px]]<br />
<br />
The nucleophilic sulfur atom of methionine attacks the slightly positive 5' carbon of the adenosine sugar unit. Following this, the bond from the 5' carbon to the oxygen breaks, separating the tripolyphosphate from the newly formed S-adenosylmethionine (SAM) <ref name="Murray et al.">Murray B, Antonyuk SV, Marina A, Lu SC, Mato JM, Hasnain SS, Rojas Al. Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes. PNAS. 2016 Feb 8;113 (8) 2104-2109. doi: https://doi.org/10.1073/pnas.1510959113</ref>. This is an example of an SN2 reaction, where the substrates move through a transition state to then form the products. The products are only released after the methionine binds and the C-O bond breaks.<br />
<br />
== Structure ==<br />
<StructureSection load='5a1i' size='400' side='right' caption='MAT dimer in complex with methionine, PPNP, and adenosine' scene=''><br />
MAT consists of α and β subunits. The MATα1 and <scene name='90/907472/Mat2a/4'>MATα2</scene> subunits are catalytic subunits while MATβ is a regulatory subunit. The subunits are encoded on different genes in humans, so they are created separately and can then come together to form various complexes, such as MATαβ or MATα2 dimers <ref name="Murray et al." />. Not much is currently known about the function of this regulatory subunit and how it regulates the function of the enzyme<ref>DOI:10.1107/S2052252514012585</ref>. However, Murray et al.<ref name="Murray et al." /> show that even in the absence of the regulatory subunit, the active site found in the catalytic subunit remains functional. <br />
<br />
The biological assembly of rat S-adenosylmethionine synthetase is a <scene name='49/493038/Cv/7'>homotetramer</scene>. The <scene name='49/493038/Cv/8'>active site of MAT is located between adjacent subunits</scene><ref>PMID:12888348</ref>. The <scene name='90/907472/Substrates/1'>substrates</scene> used by the enzyme are methionine and ATP. Notably, ATP is not used as a source of energy in this reaction like it is for many other processes. Instead, it is used as a substrate in the synthesis reaction. Methionine and ATP enter the active site and are stabilized by residues present there, including lysine and histidine. Once the reaction begins to take place, methionine flips toward the 5' carbon of the adenosine sugar<ref>doi:10.1042/BJ20121580</ref>. Following nucleophilic attack of the sulfur on the carbon, the C-O bond between the phosphates and the carbon breaks, and the <scene name='90/907472/Product/2'>products</scene> are formed (tripolyphosphate not pictured). SAM is released from the active site first. MAT also catalyzes hydrolysis of the tripolyphosphate into pyrophosphate and orthophosphate, which are then released from the active site <ref>Niland CN, Ghosh A, Cahill SM, Schramm VL. Mechanism and Inhibition of Human Methionine Adenosyltransferase 2A. ACS Biochemistry. 2021 Mar 3;60 (10) 791-801. doi: https://doi.org/10.1021/acs.biochem.0c00998</ref>.<br />
<br />
== Gating Loop ==<br />
MAT has been shown to have a <scene name='49/493038/Loop/2'>gating loop</scene> next to the active site <ref name="Murray et al." />. <br />
<br />
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</jmol><br />
<br />
This structure is thought to allow access to the active site, becoming ordered or disordered. When the loop is ordered, the active site is closed, and it is opened again when the loop is disordered. Murray et al. <ref name="Murray et al." /> found that when SAM or adenosine is bound to the active site the gate is closed, and when PPNP (tripolyphosphate in the body) is bound to the active site the gate is open. It is still unknown what causes the gating loop to open and what triggers the release of products, but it is not caused by hydrolysis of tripolyphosphate <ref name="Murray et al." />. This finding shows that hydrolysis of tripolyphosphate does not provide energy for the opening of the gating loop, nor does ATP provide energy for any part of this reaction.<br />
</StructureSection><br />
<br />
==3D structures of S-adenosylmethionine synthetase==<br />
<br />
[[S-adenosylmethionine synthetase 3D structures]]<br />
<br />
{{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}<br />
{{#tree:id=OrganizedByTopic|openlevels=0|<br />
<br />
*S-adenosylmethionine synthetase<br />
<br />
**[[1fug]] – EcMAT – ''Escherichia coli''<br /><br />
**[[3iml]] – MAT – ''Burkholderia pseudomallei''<br /><br />
**[[2ydy]] – hMAT II subunit β – human<br /><br />
**[[4le5]] – MAT- ''Campylobacter jejuni''<br /><br />
**[[4hpv]] - SsMAT – ''Sulfolobus solfataricus''<br /><br />
**[[3tde]] – MAT- ''Mycobacterium tuberculosis''<br /><br />
**[[3s82]] – MAT- ''Mycobacterium avium''<br /><br />
**[[3rv2]] – MAT- ''Mycobacterium marinum''<br /><br />
<br />
<br />
*S-adenosylmethionine synthetase complexes<br />
<br />
**[[1xra]], [[1xrb]] – EcMAT + Pi + K + Mg <br /><br />
**[[1xrc]] - EcMAT + Pi + Co + K<br /><br />
**[[1mxa]] - EcMAT + Pi + PPi + Mg + K<br /><br />
**[[1mxb]] - EcMAT + Pi + ADP + Mg + K<br /><br />
**[[1mxc]] - EcMAT + Pi + Br-ADP + Mg + K<br /><br />
**[[1p7l]] – EcMAT + methionine + AdoMet + AMPPNP + Mg + K<br /><br />
**[[1rg9]] - EcMAT + AdoMet + AMPPNP + Mg + K<br /><br />
**[[1qm4]] - rMAT+ methionine analog + K + Mg – rat<br /><br />
**[[1o90]] - rMAT + Pi + Mg + K<br /><br />
**[[1o92]] – rMAT + methionine analog + ADP + Mg + K<br /><br />
**[[1o93]] – rMAT + methionine analog + ATP + Mg + K<br /><br />
**[[1o9t]] – rMAT + methionine + ADP + Mg + K<br /><br />
**[[2obv]] – hMAT I + AdoMet + Na <br /><br />
**[[2p02]] - hMAT II + AdoMet<br /><br />
**[[2ydx]] – MAT + resveratrol + NADP + Ca + ADP derivative<br /><br />
**[[4l2z]], [[4k0b]] - SsMAT + Pi + PPi + Mg + SAM derivative <br /><br />
}}<br />
== References ==<br />
<references/><br />
[[Category:Topic Page]][[Category:One-carbon metabolism]]</div>Anna Postnikovahttps://proteopedia.org/index.php?title=Methionine_adenosyltransferase&diff=3550706Methionine adenosyltransferase2022-04-25T00:36:19Z<p>Anna Postnikova: </p>
<hr />
<div>[[Methionine adenosyltransferase]] (MAT) or S-adenosylmethionine synthetase (SAM synthetase) synthesizes S-adenosylmethionine (SAM or AdoMet) from the substrates adenosine triphosphate (ATP) and methionine. ATP isn’t used only as a source of energy like it is in other reactions but gets a methionine added onto the 5' carbon while the three phosphate groups are broken down and released from the active site. This enzyme is conserved and found in many organisms, so it is essential for life. Importantly, the production of SAM by MAT provides methyl for methylation of nucleic acids, allowing for epigenetic modification. Problems with this enzyme have been shown to cause diseases including various cancers.<br />
<br />
== Relevance ==<br />
The product of this enzymatic reaction, SAM, is the universal methyl donor of metabolism. DNA methyltransferases can transfer a methyl group from SAM to the 5th carbon of cytosine residues <ref>DOI:10.1038/npp.2012.112</ref>. In this way, MAT is indirectly important for regulation of gene expression by providing methyl through SAM. SAM is also involved in N-methylation, O-methylation and C-methylation, yielding S-adenosyl homocysteine as a product that gets recycled by the [[one-carbon metabolism]]. Radical SAM enzymes break down SAM into an adenosyl radical and methionine, enabling a host of otherwise difficult to achieve reactions, e.g. in molybdenum cofactors biosynthesis<ref>DOI:10.1073/pnas.0404624101</ref>. Accumulation of S-adenosyl homocysteine (or homocysteine itself) indicates an imbalance in supply and demand for SAM in the organism. Methionine metabolism impairment in liver diseases is related in alteration in MAT<ref>PMID:7741002</ref>.<br />
<br />
<br />
== Function and reaction mechanism ==<br />
'''S-adenosylmethionine synthetase''' or '''S-adenosylmethionine synthase''' or '''S-adenosylmethionine transferase''' or '''methionine adenosyltransferase''' (MAT) catalyzes the conversion of methionine and ATP to S-adenosylmethionine (AdoMet), pyrophosphate (PPi) and orthophosphate (Pi). The catalytic entity of MAT is a dimer. MAT cofactors are Mg+2 (or Co+2) and K+ ions<ref>PMID:8611562</ref>. <br />
<br />
[[Image:Sam rxn 2.jpg|800px]]<br />
<br />
The nucleophilic sulfur atom of methionine attacks the slightly positive 5' carbon of the adenosine sugar unit. Following this, the bond from the 5' carbon to the oxygen breaks, separating the tripolyphosphate from the newly formed S-adenosylmethionine (SAM) <ref name="Murray et al.">Murray B, Antonyuk SV, Marina A, Lu SC, Mato JM, Hasnain SS, Rojas Al. Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes. PNAS. 2016 Feb 8;113 (8) 2104-2109. doi: https://doi.org/10.1073/pnas.1510959113</ref>. This is an example of an SN2 reaction, where the substrates move through a transition state to then form the products. The products are only released after the methionine binds and the C-O bond breaks.<br />
<br />
== Structure ==<br />
<StructureSection load='5a1i' size='400' side='right' caption='Caption for this structure' scene=''><br />
MAT consists of α and β subunits. The MATα1 and <scene name='90/907472/Mat2a/4'>MATα2</scene> subunits are catalytic subunits while MATβ is a regulatory subunit. The subunits are encoded on different genes in humans, so they are created separately and can then come together to form various complexes, such as MATαβ or MATα2 dimers <ref name="Murray et al." />. Not much is currently known about the function of this regulatory subunit and how it regulates the function of the enzyme<ref>DOI:10.1107/S2052252514012585</ref>. However, Murray et al.<ref name="Murray et al." /> show that even in the absence of the regulatory subunit, the active site found in the catalytic subunit remains functional. <br />
<br />
The biological assembly of rat S-adenosylmethionine synthetase is <scene name='49/493038/Cv/7'>homotetramer</scene>. The <scene name='49/493038/Cv/8'>active site of MAT is located between adjacent subunits</scene><ref>PMID:12888348</ref>. The <scene name='90/907472/Substrates/1'>substrates</scene> used by the enzyme are methionine and ATP. Notably, ATP is not used as a source of energy in this reaction like it is for many other processes. Instead, it is used as a substrate in the synthesis reaction. Methionine and ATP enter the active site and are stabilized by residues present there, including lysine and histidine. Once the reaction begins to take place, methionine flips toward the 5' carbon of the adenosine sugar<ref>doi:10.1042/BJ20121580</ref>. Following nucleophilic attack of the sulfur on the carbon, the C-O bond between the phosphates and the carbon breaks, and the <scene name='90/907472/Product/2'>products</scene> are formed (tripolyphosphate not pictured). SAM is released from the active site first. MAT also catalyzes hydrolysis of the tripolyphosphate into pyrophosphate and orthophosphate, which are then released from the active site <ref>Niland CN, Ghosh A, Cahill SM, Schramm VL. Mechanism and Inhibition of Human Methionine Adenosyltransferase 2A. ACS Biochemistry. 2021 Mar 3;60 (10) 791-801. doi: https://doi.org/10.1021/acs.biochem.0c00998</ref>.<br />
<br />
== Gating Loop ==<br />
MAT has been shown to have a <scene name='49/493038/Loop/2'>gating loop</scene> next to the active site <ref name="Murray et al." />. <br />
<br />
<jmol><br />
<jmolRadioGroup><br />
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<br />
This structure is thought to allow access to the active site, becoming ordered or disordered. When the loop is ordered, the active site is closed, and it is opened again when the loop is disordered. Murray et al. <ref name="Murray et al." /> found that when SAM or adenosine is bound to the active site the gate is closed, and when PPNP (tripolyphosphate in the body) is bound to the active site the gate is open. It is still unknown what causes the gating loop to open and what triggers the release of products, but it is not caused by hydrolysis of tripolyphosphate <ref name="Murray et al." />. This finding shows that hydrolysis of tripolyphosphate does not provide energy for the opening of the gating loop, nor does ATP provide energy for any part of this reaction.<br />
</StructureSection><br />
<br />
==3D structures of S-adenosylmethionine synthetase==<br />
<br />
[[S-adenosylmethionine synthetase 3D structures]]<br />
<br />
{{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}<br />
{{#tree:id=OrganizedByTopic|openlevels=0|<br />
<br />
*S-adenosylmethionine synthetase<br />
<br />
**[[1fug]] – EcMAT – ''Escherichia coli''<br /><br />
**[[3iml]] – MAT – ''Burkholderia pseudomallei''<br /><br />
**[[2ydy]] – hMAT II subunit β – human<br /><br />
**[[4le5]] – MAT- ''Campylobacter jejuni''<br /><br />
**[[4hpv]] - SsMAT – ''Sulfolobus solfataricus''<br /><br />
**[[3tde]] – MAT- ''Mycobacterium tuberculosis''<br /><br />
**[[3s82]] – MAT- ''Mycobacterium avium''<br /><br />
**[[3rv2]] – MAT- ''Mycobacterium marinum''<br /><br />
<br />
<br />
*S-adenosylmethionine synthetase complexes<br />
<br />
**[[1xra]], [[1xrb]] – EcMAT + Pi + K + Mg <br /><br />
**[[1xrc]] - EcMAT + Pi + Co + K<br /><br />
**[[1mxa]] - EcMAT + Pi + PPi + Mg + K<br /><br />
**[[1mxb]] - EcMAT + Pi + ADP + Mg + K<br /><br />
**[[1mxc]] - EcMAT + Pi + Br-ADP + Mg + K<br /><br />
**[[1p7l]] – EcMAT + methionine + AdoMet + AMPPNP + Mg + K<br /><br />
**[[1rg9]] - EcMAT + AdoMet + AMPPNP + Mg + K<br /><br />
**[[1qm4]] - rMAT+ methionine analog + K + Mg – rat<br /><br />
**[[1o90]] - rMAT + Pi + Mg + K<br /><br />
**[[1o92]] – rMAT + methionine analog + ADP + Mg + K<br /><br />
**[[1o93]] – rMAT + methionine analog + ATP + Mg + K<br /><br />
**[[1o9t]] – rMAT + methionine + ADP + Mg + K<br /><br />
**[[2obv]] – hMAT I + AdoMet + Na <br /><br />
**[[2p02]] - hMAT II + AdoMet<br /><br />
**[[2ydx]] – MAT + resveratrol + NADP + Ca + ADP derivative<br /><br />
**[[4l2z]], [[4k0b]] - SsMAT + Pi + PPi + Mg + SAM derivative <br /><br />
}}<br />
== References ==<br />
<references/><br />
[[Category:Topic Page]][[Category:One-carbon metabolism]]</div>Anna Postnikovahttps://proteopedia.org/index.php?title=Methionine_adenosyltransferase&diff=3550705Methionine adenosyltransferase2022-04-25T00:09:13Z<p>Anna Postnikova: </p>
<hr />
<div>[[Methionine adenosyltransferase]] (MAT) or S-adenosylmethionine synthetase (SAM synthetase) synthesizes S-adenosylmethionine (SAM or AdoMet) from the substrates adenosine triphosphate (ATP) and methionine. ATP isn’t used only as a source of energy like it is in other reactions but gets a methionine added onto the 5' carbon while the three phosphate groups are broken down and released from the active site. This enzyme is conserved and found in many organisms, so it is essential for life. Importantly, the production of SAM by MAT provides methyl for methylation of nucleic acids, allowing for epigenetic modification. Problems with this enzyme have been shown to cause diseases including various cancers.<br />
<br />
== Relevance ==<br />
The product of this enzymatic reaction, SAM, is the universal methyl donor of metabolism. DNA methyltransferases can transfer a methyl group from SAM to the 5th carbon of cytosine residues <ref>DOI:10.1038/npp.2012.112</ref>. In this way, MAT is indirectly important for regulation of gene expression by providing methyl through SAM. SAM is also involved in N-methylation, O-methylation and C-methylation, yielding S-adenosyl homocysteine as a product that gets recycled by the [[one-carbon metabolism]]. Radical SAM enzymes break down SAM into an adenosyl radical and methionine, enabling a host of otherwise difficult to achieve reactions, e.g. in molybdenum cofactors biosynthesis<ref>DOI:10.1073/pnas.0404624101</ref>. Accumulation of S-adenosyl homocysteine (or homocysteine itself) indicates an imbalance in supply and demand for SAM in the organism. Methionine metabolism impairment in liver diseases is related in alteration in MAT<ref>PMID:7741002</ref>.<br />
<br />
<br />
== Function and reaction mechanism ==<br />
'''S-adenosylmethionine synthetase''' or '''S-adenosylmethionine synthase''' or '''S-adenosylmethionine transferase''' or '''methionine adenosyltransferase''' (MAT) catalyzes the conversion of methionine and ATP to S-adenosylmethionine (AdoMet), pyrophosphate (PPi) and orthophosphate (Pi). The catalytic entity of MAT is a dimer. MAT cofactors are Mg+2 (or Co+2) and K+ ions<ref>PMID:8611562</ref>. <br />
<br />
[[Image:Sam rxn 2.jpg|800px]]<br />
<br />
The nucleophilic sulfur atom of methionine attacks the slightly positive 5' carbon of the adenosine sugar unit. Following this, the bond from the 5' carbon to the oxygen breaks, separating the tripolyphosphate from the newly formed S-adenosylmethionine (SAM) <ref name="Murray et al.">Murray B, Antonyuk SV, Marina A, Lu SC, Mato JM, Hasnain SS, Rojas Al. Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes. PNAS. 2016 Feb 8;113 (8) 2104-2109. doi: https://doi.org/10.1073/pnas.1510959113</ref>. This is an example of an SN2 reaction, where the substrates move through a transition state to then form the products. The products are only released after the methionine binds and the C-O bond breaks.<br />
<br />
== Structure ==<br />
<StructureSection load='5a1i' size='400' side='right' caption='Caption for this structure' scene=''><br />
MAT consists of α and β subunits. The MATα1 and <scene name='90/907472/Mat2a/4'>MATα2</scene> subunits are catalytic subunits while MATβ is a regulatory subunit. Not much is currently known about the function of this regulatory subunit and how it regulates the function of the enzyme<ref>DOI:10.1107/S2052252514012585</ref>. The subunits are encoded on different genes in humans, so they are created separately and can then come together to form various complexes, such as MATαβ or MATα2 dimers <ref name="Murray et al." />.<br />
<br />
The biological assembly of rat S-adenosylmethionine synthetase is <scene name='49/493038/Cv/7'>homotetramer</scene>. The <scene name='49/493038/Cv/8'>active site of MAT is located between adjacent subunuts</scene><ref>PMID:12888348</ref>. The <scene name='90/907472/Substrates/1'>substrates</scene> used by the enzyme are methionine and ATP. Notably, ATP is not used as a source of energy in this reaction like it is for many other processes. Instead, it is used as a substrate in the synthesis reaction. Methionine and ATP enter the active site and are stabilized by residues present there, including lysine and histidine. Once the reaction begins to take place, methionine flips toward the 5' carbon of the adenosine sugar<ref>doi:10.1042/BJ20121580</ref>. Following nucleophilic attack of the sulfur on the carbon, the C-O bond between the phosphates and the carbon breaks, and the <scene name='90/907472/Product/2'>products</scene> are formed (tripolyphosphate not pictured). SAM is released from the active site first. MAT also catalyzes hydrolysis of the tripolyphosphate into pyrophosphate and orthophosphate, which are then released from the active site <ref>Niland CN, Ghosh A, Cahill SM, Schramm VL. Mechanism and Inhibition of Human Methionine Adenosyltransferase 2A. ACS Biochemistry. 2021 Mar 3;60 (10) 791-801. doi: https://doi.org/10.1021/acs.biochem.0c00998</ref>.<br />
<br />
== Gating Loop ==<br />
MAT has been shown to have a <scene name='49/493038/Loop/2'>gating loop</scene> next to the active site <ref name="Murray et al." />. <br />
<br />
<jmol><br />
<jmolRadioGroup><br />
<item><br />
<script>model 1</script><br />
<text>ordered with SAM</text><br />
<checked>true</checked><br />
</item><br />
<item><br />
<script>model 2</script><br />
<text>disordered apo</text><br />
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<br />
This structure is thought to allow access to the active site, becoming ordered or disordered. When the loop is ordered, the active site is closed, and it is opened again when the loop is disordered. Murray et al. <ref name="Murray et al." /> found that when SAM or adenosine is bound to the active site the gate is closed, and when PPNP (tripolyphosphate in the body) is bound to the active site the gate is open.<br />
</StructureSection><br />
<br />
==3D structures of S-adenosylmethionine synthetase==<br />
<br />
[[S-adenosylmethionine synthetase 3D structures]]<br />
<br />
{{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}<br />
{{#tree:id=OrganizedByTopic|openlevels=0|<br />
<br />
*S-adenosylmethionine synthetase<br />
<br />
**[[1fug]] – EcMAT – ''Escherichia coli''<br /><br />
**[[3iml]] – MAT – ''Burkholderia pseudomallei''<br /><br />
**[[2ydy]] – hMAT II subunit β – human<br /><br />
**[[4le5]] – MAT- ''Campylobacter jejuni''<br /><br />
**[[4hpv]] - SsMAT – ''Sulfolobus solfataricus''<br /><br />
**[[3tde]] – MAT- ''Mycobacterium tuberculosis''<br /><br />
**[[3s82]] – MAT- ''Mycobacterium avium''<br /><br />
**[[3rv2]] – MAT- ''Mycobacterium marinum''<br /><br />
<br />
<br />
*S-adenosylmethionine synthetase complexes<br />
<br />
**[[1xra]], [[1xrb]] – EcMAT + Pi + K + Mg <br /><br />
**[[1xrc]] - EcMAT + Pi + Co + K<br /><br />
**[[1mxa]] - EcMAT + Pi + PPi + Mg + K<br /><br />
**[[1mxb]] - EcMAT + Pi + ADP + Mg + K<br /><br />
**[[1mxc]] - EcMAT + Pi + Br-ADP + Mg + K<br /><br />
**[[1p7l]] – EcMAT + methionine + AdoMet + AMPPNP + Mg + K<br /><br />
**[[1rg9]] - EcMAT + AdoMet + AMPPNP + Mg + K<br /><br />
**[[1qm4]] - rMAT+ methionine analog + K + Mg – rat<br /><br />
**[[1o90]] - rMAT + Pi + Mg + K<br /><br />
**[[1o92]] – rMAT + methionine analog + ADP + Mg + K<br /><br />
**[[1o93]] – rMAT + methionine analog + ATP + Mg + K<br /><br />
**[[1o9t]] – rMAT + methionine + ADP + Mg + K<br /><br />
**[[2obv]] – hMAT I + AdoMet + Na <br /><br />
**[[2p02]] - hMAT II + AdoMet<br /><br />
**[[2ydx]] – MAT + resveratrol + NADP + Ca + ADP derivative<br /><br />
**[[4l2z]], [[4k0b]] - SsMAT + Pi + PPi + Mg + SAM derivative <br /><br />
}}<br />
== References ==<br />
<references/><br />
[[Category:Topic Page]][[Category:One-carbon metabolism]]</div>Anna Postnikovahttps://proteopedia.org/index.php?title=Methionine_synthase&diff=3550505Methionine synthase2022-04-22T15:21:56Z<p>Anna Postnikova: </p>
<hr />
<div>This page is being worked on during the Spring 2022 semester.<br />
<br />
Addlt ref 1<ref>DOI: 10.1128/JB.00208-06</ref><br />
<br />
<br />
Addlt ref 2<ref>DOI:10.1073/pnas.1133218100</ref><br />
<br />
'''Methionine synthase''' (MS; EC: 2.1.1.13) is an important enzyme in [[one-carbon metabolism]]. MS catalyzes the transfer of a methyl group from methyltetrahydrofolate (MTHF) to homocysteine, resulting in the formation of methionine. Methionine is an essential amino acid required by our bodies for healthy cell and tissue growth. It is essential as it is not naturally derived in our bodies, thus requiring the conversion of homocysteine to methionine as needed.<br />
<br />
==Function==<br />
<br />
[[Image:Overall.jpeg]]<br />
<br />
MS is a B12-dependent enzyme responsible for regenerating methionine from homocysteine and uses vitamin B12 Cobalamin as a cofactor. The change from homocysteine to methionine is an SN2 reaction, as seen above, where the methyl group on N-5 from methyltetrahydrofolate (MTHF), is donated. MTHF is a product of methylenetetrahydrofolate reductase [[MTHFR]] from the folate cycle. This is a complex reaction as tetrahydrofolate (THF), the product, is a poor leaving group and requires a "super nucleophile", vitamin B12 Cob(I)alamin, to carry out the reaction<ref>DOI:10.1146/annurev.biochem.72.121801.161828</ref><ref name="Kung et al">DOI: 10.1038/nature10916</ref>; the methyl carrier. <br />
<br />
=== Oxidation states ===<br />
== Oxidation States of Cobalamin == <br />
<br />
Cobalamin exists in three different oxidation states during the MS cycle.<br />
<br />
'''Cob(I)alamin''': Cobalt in the +1 oxidation state is nicknamed the "super nucleophile" as its high energy is required to carry out the complex SN2 reaction of breaking the bond between THF and the methyl group, in the catalytic cycle.<br />
<br />
'''Co(III)alamin''': Cobalt in +3 oxidation state occurs when His 759 replaces the dimethylbenzimidazole (DMB) ligand to allow for the methyl to be accepted by Cob(I)alamin, forming Me-Cob(III)alamin.<br />
<br />
'''Cob(II)alamin''': Cob(I)alamin is highlight reactive towards oxygen so occasionally under aerobic conditions, Cob(I)alamin will occasionally undergo oxidation leading to an inactive Cob(II)alamin enzyme in the +2 oxidation state. This is regulated by reductive methylation by using Flavodoxin as an electron donor to reactivate Cob(I)alamin, and subsequently regenerates Me-Cob(III)alamin with a methyl being donated from SAM.<br />
<br />
== Relevance ==<br />
<br />
MS is an important enzyme responsible for generating methionine, required by our bodies for healthy cell and tissue growth, and protein synthesis. Any MS and/or B12 deficiencies can result in diseases such as abnormal birth defects or anemia<ref name="Kung et al"/>.<br />
<br />
Uses in treating cancer.<br />
<br />
<br />
== Structural highlights ==<br />
<br />
=== 1. Domain organization ===<br />
<StructureSection load='1bmt' size='310' side='right' caption='Homodimer of B12 binding domain of MS. Cobalt in pink.' scene=''><br />
<br />
The full structure of MS has yet to be determined but studies have found it contains four domains, each with a unique function that bind to Cob(I)alamin as the methyl carrier, MTHF as the methyl donor in the catalytic cycle, homocysteine as the methyl acceptor, and S-adenosylmethionine or SAM, as the methyl donor in the reactivation cycle<ref name="Bandarian et al">DOI: 10.1038/nsb738</ref>. The orientation of the domains changes during the catalytic cycle.<br />
<br />
Shown here is the <scene name='90/907471/Superposition/7'>theoretical prediction</scene> of the structure by the alphafold algorithm, with experimental structures of the N-terminal 2 domains as well as of the C-terminal 2 domins superposed.<br />
<br />
<jmol><br />
<jmolRadioGroup><br />
<item><br />
<script>hide 1.1</script><br />
<text>experimental fragments</text><br />
<checked>false</checked><br />
</item><br />
<item><br />
<script>display 1.1</script><br />
<text>theoretical</text><br />
<checked>false</checked><br />
</item><br />
<item><br />
<script>display all</script><br />
<text>both</text><br />
<checked>true</checked><br />
</item><br />
</jmolRadioGroup><br />
</jmol><br />
<br />
As the graph below shows, the prediction has high confidence in the internal structure of individual domains but not the relative orientation.<br />
<br />
[[Image:Position error alphafold P13009.jpg|400px]]<br />
<br />
During each cycle, the domains must be positioned close enough to Cobalamin in order for methyl transfers to be successful. Conformations of MS allows substrates to be presented to Cobalamin for reactions to occur.<br />
<br />
=== 2. Cobalamin binding ===<br />
<br />
[[Image:cob_1_alamin.jpeg|500px]]<br />
<br />
The vitamin B12 Cobalamin binding domain has a special characteristic in that, it is most naturally found in a protective conformation to prevent unwanted chemistry from occurring (PDB: 1BMT). This is referred to as a 'capping' mechanism.<br />
<br />
<scene name='90/907471/Bindingdomain2/1'>scene 1</scene><br />
<br />
<scene name='90/907471/Bindingdomain3/2'>scene 2</scene><br />
<br />
<br />
=== 3. Cobalamin activation ===<br />
<scene name='90/907471/B12_activation_w_sah/1'>B12 activation</scene><br />
<br />
=== 4. Cap domain ===<br />
<br />
When B12 is not engaged with one of the other three substrate binding domains, it is protected by a <scene name='90/907471/Cap/1'>cap</scene>.<br />
<br />
In the Cob(I)alamin binding domain, the imidazole side chain containing His 759 replaces the dimethylbenzimidazole (DMB) ligand. His 759 bonds to Asp 757 and Ser 810 via hydrogen bonds to create a ligand trifecta that increases the efficiency of the methyl transfer during the catalytic cycle. With His on, the cap is off of Cobalamin to allow for it to hold onto the methyl from MTHF. With His off, the cap is on thus no reaction.<ref name="Bandarian et al"/>.<br />
<br />
<br />
</StructureSection><br />
<br />
== References ==<br />
<br />
<references/><br />
[[Category:One-carbon metabolism]]</div>Anna Postnikovahttps://proteopedia.org/index.php?title=Thymidylate_synthase&diff=3547501Thymidylate synthase2022-04-20T15:13:09Z<p>Anna Postnikova: </p>
<hr />
<div>Thymidylate Synthase (TS) is an important enzyme in [[one-carbon metabolism]]. TS catalyzes the transfer of a methyl group and a hydride from 5,10-methylenetetrahydrofolate to 2-deoxyuridine-5'-monophosphate, resulting in the formation of thymidine 5'-monophosphate and dihydrofolate. This is the only de novo source of dTMP (a precursor to Thymine) in humans. <ref>DOI 10.1021/acs.biochem.1c00063</ref><br />
<br />
2-deoxyuridine-5'-monophosphate(dUMP) + 5, 10-methylenetetrahydrofolate(CH<sub>2</sub>H<sub>4</sub>F) ⇌ thymidine 5'-monophosphate(dTMP) + Dihydrofolate(H<sub>2</sub>F)<br />
<br />
[[Image:TS Overview.jpg]]<br />
== Function ==<br />
'''Thymidylate synthase''' (TS) catalyzes the methylation of dUMP to dTMP using 5,10-methylenetetrahydrofolate as a cofactor. TS is essential for DNA replication and repair<ref>PMID:2243092</ref>. In protozoa, [[dihydrofolate reductase]] (DHFR) and TS are expressed as a bifunctional monomeric enzyme ('''DHFR-TS)''' with the DHFR entity at the N terminal. DHFR and TS catalyze consecutive reactions in the dTMP biosynthesis. There are two different types of TS – '''ThyA''' and '''ThyX'''. The types differ in their activity and structure. The TS ThyX are flavin-dependent enzymes.<br />
<br />
== Relevance ==<br />
One of the nucleobase of DNA, cytosine, spontaneously deaminates to form uracil, changing the encoded message. Different from RNA, DNA does not contain uracil but instead contains the methylated form thymine, avoiding missense mutations. The [https://proteopedia.org/wiki/index.php/Category:Dna-repair DNA repair protein] [[Uracil DNA glycosylase]] will recognize uracil as damaged DNA, removing it and re-establishing the original message<ref>DOI:10.1038/sj.onc.1205996</ref>. Because thymine contains an additional methyl group, it is distinguishable from uracil, and is not removed through DNA repair. Thymidylate synthase helps to turn the abundant uridine (containing the nucleobase uracil) into deoxythymidine (containing the nucleobase thymine) in preparation for DNA synthesis prior to cell division. Thus, thymidylate synthase plays a role in making DNA a more reliable long-term storage of genetic information compared to RNA.<br />
<br />
TS inhibition at its folate-binding site is used in anticancer therapeutic drugs. DHFR-TS inhibitors are potential drug targets against parasite-transferred diseases. TS exhibits oncogene-like activity.<ref>PMID:15093541</ref><br />
<br />
<StructureSection load='' size='350' side='right' caption='Thymidylate synthase complex with dUMP (PDB entry [[1tsv]])' scene='49/493689/Cv/1'><br />
==Structure and ligand binding==<br />
TS forms a homodimer consisting of two domains (reload <scene name='49/493689/Cv/1'>initial scene</scene>). Their <scene name='49/493689/Cv/4'>active sites can each bind the substrate dUMP</scene><ref>PMID:9053905</ref>. Maley et al. show that E.coli TS uses a half-the-sites mechanism when catalyzing its reaction<ref>DOI:10.1021/bi00005a001</ref>. One of the two active sites catalyzes the reaction while the other remains inactive. The way the two domains communicate with each other to coordinate this is still unknown.<br />
<br />
The active site Cysteine has two <scene name='49/493689/Ts_7jxf_percentb/4'>conformations</scene>. Conformation 1 shows the active site cysteine unbound to the intermediate 4.21 Angstroms away from the C6 carbon of the dNMP ring. Conformation 2 shows the active site cysteine bound to the intermediate 3.84 Angstroms away from the C6 carbon of the dNMP ring. <br />
<jmol><br />
<jmolRadioGroup><br />
<item><br />
<script>hide (VNM or 146:B) and altloc=A</script><br />
<text>Conformation 1</text><br />
<checked>true</checked><br />
</item><br />
<item><br />
<script>hide (VNM or 146:B) and altloc=B</script><br />
<text>Conformation 2</text><br />
<checked>false</checked><br />
</item><br />
<item><br />
<script>hide none</script><br />
<text>both conformations</text><br />
<checked>false</checked><br />
</item><br />
</jmolRadioGroup><br />
</jmol><br />
==Inhibition==<br />
Methotrexate, a competitive inhibitor competes with folate substrate to bind to the active site of TS. Inhibits the conversion of CH<sub>2</sub>H<sub>4</sub>F to H<sub>2</sub>F. This inhibition stops the conversion of products to reactants, stopping cellular reproduction. <scene name='49/493689/Inhibited/1'>inhibits</scene> TS.<br />
<br />
Due to its role in cell division, thymidylate synthase has become a popular target for anticancer drugs. Indirect inhibition of thymidylate synthase by the drug 5-fluorouracil (5-FU) is one of the most used inhibitors for study of TS function. This drug indirectly inhibits TS as it it eventually converted to FdUMP, which forms a covalent complex with both the active site cysteine and CH<sub>2</sub>H<sub>4</sub>F. Inhibition of TS halts the production of dTMP and, indirectly, 2'-deoxythymidine-5'-triphosphate (dTTP). Both dTMP and dTTP are essential building blocks for DNA synthesis and their absence halts the ability of cells to replicate their genetic information. This is especially effective in cancer cells that rapidly divide and require large amounts of dTMP and dTTP. <ref>DOI 10.2174/0929867054864868</ref><br />
<br />
[[Image:Methotrexate.png|400px]]<br />
</StructureSection><br />
<br />
==3D structures of thymidylate synthase==<br />
[[Thymidylate synthase 3D structures]]<br />
<br />
== References ==<br />
<references/><br />
[[Category:Topic Page]]<br />
[[Category:Dihydrofolate]]<br />
[[Category:One-carbon metabolism]]</div>Anna Postnikovahttps://proteopedia.org/index.php?title=Thymidylate_synthase&diff=3547497Thymidylate synthase2022-04-20T15:07:45Z<p>Anna Postnikova: </p>
<hr />
<div>Thymidylate Synthase (TS) is an important enzyme in [[one-carbon metabolism]]. TS catalyzes the transfer of a methyl group and a hydride from 5,10-methylenetetrahydrofolate to 2-deoxyuridine-5'-monophosphate, resulting in the formation of thymidine 5'-monophosphate and dihydrofolate. This is the only de novo source of dTMP (a precursor to Thymine) in humans. <ref>DOI 10.1021/acs.biochem.1c00063</ref><br />
<br />
2-deoxyuridine-5'-monophosphate(dUMP) + 5, 10-methylenetetrahydrofolate(CH<sub>2</sub>H<sub>4</sub>F) ⇌ thymidine 5'-monophosphate(dTMP) + Dihydrofolate(H<sub>2</sub>F)<br />
<br />
[[Image:TS Overview.jpg]]<br />
== Function ==<br />
'''Thymidylate synthase''' (TS) catalyzes the methylation of dUMP to dTMP using 5,10-methylenetetrahydrofolate as a cofactor. TS is essential for DNA replication and repair<ref>PMID:2243092</ref>. In protozoa, [[dihydrofolate reductase]] (DHFR) and TS are expressed as a bifunctional monomeric enzyme ('''DHFR-TS)''' with the DHFR entity at the N terminal. DHFR and TS catalyze consecutive reactions in the dTMP biosynthesis. There are two different types of TS – '''ThyA''' and '''ThyX'''. The types differ in their activity and structure. The TS ThyX are flavin-dependent enzymes.<br />
<br />
== Relevance ==<br />
One of the nucleobase of DNA, cytosine, spontaneously deaminates to form uracil, changing the encoded message. Different from RNA, DNA does not contain uracil but instead contains the methylated form thymine, avoiding missense mutations. The [https://proteopedia.org/wiki/index.php/Category:Dna-repair DNA repair protein] [[Uracil DNA glycosylase]] will recognize uracil as damaged DNA, removing it and re-establishing the original message<ref>DOI:10.1038/sj.onc.1205996</ref>. Because thymine contains an additional methyl group, it is distinguishable from uracil, and is not removed through DNA repair. Thymidylate synthase helps to turn the abundant uridine (containing the nucleobase uracil) into deoxythymidine (containing the nucleobase thymine) in preparation for DNA synthesis prior to cell division. Thus, thymidylate synthase plays a role in making DNA a more reliable long-term storage of genetic information compared to RNA.<br />
<br />
TS inhibition at its folate-binding site is used in anticancer therapeutic drugs. DHFR-TS inhibitors are potential drug targets against parasite-transferred diseases. TS exhibits oncogene-like activity.<ref>PMID:15093541</ref><br />
<br />
<StructureSection load='' size='350' side='right' caption='Thymidylate synthase complex with dUMP (PDB entry [[1tsv]])' scene='49/493689/Cv/1'><br />
==Structure and ligand binding==<br />
TS forms a homodimer consisting of two domains (reload <scene name='49/493689/Cv/1'>initial scene</scene>). Their <scene name='49/493689/Cv/4'>active sites can each bind the substrate dUMP</scene><ref>PMID:9053905</ref>. Maley et al. show that E.coli TS uses a half-the-sites mechanism when catalyzing its reaction. One of the two active sites catalyzes the reaction while the other remains inactive. The way the two domains communicate with each other to coordinate this is still unknown.<br />
<br />
The active site Cysteine has two <scene name='49/493689/Ts_7jxf_percentb/4'>conformations</scene>. Conformation 1 shows the active site cysteineunbound to the intermediate 4.21 Angstroms away from the C6 carbon of the dNMP ring. Conformation 2 shows the active site cysteine bound to the intermediate 3.84 Angstroms away from the C6 carbon of the dNMP ring. <br />
<jmol><br />
<jmolRadioGroup><br />
<item><br />
<script>hide (VNM or 146:B) and altloc=A</script><br />
<text>Conformation 1</text><br />
<checked>true</checked><br />
</item><br />
<item><br />
<script>hide (VNM or 146:B) and altloc=B</script><br />
<text>Conformation 2</text><br />
<checked>false</checked><br />
</item><br />
<item><br />
<script>hide none</script><br />
<text>both conformations</text><br />
<checked>false</checked><br />
</item><br />
</jmolRadioGroup><br />
</jmol><br />
==Inhibition==<br />
Methotrexate, a competitive inhibitor competes with folate substrate to bind to the active site of TS. Inhibits the conversion of CH<sub>2</sub>H<sub>4</sub>F to H<sub>2</sub>F. This inhibition stops the conversion of products to reactants, stopping cellular reproduction. <scene name='49/493689/Inhibited/1'>inhibits</scene> TS.<br />
<br />
Due to its role in cell division, thymidylate synthase has become a popular target for anticancer drugs. Indirect inhibition of thymidylate synthase by the drug 5-fluorouracil (5-FU) is one of the most used inhibitors for study of TS function. This drug indirectly inhibits TS as it it eventually converted to FdUMP, which forms a covalent complex with both the active site cysteine and CH<sub>2</sub>H<sub>4</sub>F. Inhibition of TS halts the production of dTMP and, indirectly, 2'-deoxythymidine-5'-triphosphate (dTTP). Both dTMP and dTTP are essential building blocks for DNA synthesis and their absence halts the ability of cells to replicate their genetic information. This is especially effective in cancer cells that rapidly divide and require large amounts of dTMP and dTTP. <ref>DOI 10.2174/0929867054864868</ref><br />
</StructureSection><br />
<br />
<br />
==3D structures of thymidylate synthase==<br />
[[Thymidylate synthase 3D structures]]<br />
<br />
== References ==<br />
<references/><br />
[[Category:Topic Page]]<br />
[[Category:Dihydrofolate]]<br />
[[Category:One-carbon metabolism]]</div>Anna Postnikovahttps://proteopedia.org/index.php?title=Thymidylate_synthase&diff=3547496Thymidylate synthase2022-04-20T15:06:56Z<p>Anna Postnikova: </p>
<hr />
<div>Thymidylate Synthase (TS) is an important enzyme in [[one-carbon metabolism]]. TS catalyzes the transfer of a methyl group and a hydride from 5,10-methylenetetrahydrofolate to 2-deoxyuridine-5'-monophosphate, resulting in the formation of thymidine 5'-monophosphate and dihydrofolate. This is the only de novo source of dTMP (a precursor to Thymine) in humans. <ref>DOI 10.1021/acs.biochem.1c00063</ref><br />
<br />
2-deoxyuridine-5'-monophosphate(dUMP) + 5, 10-methylenetetrahydrofolate(CH<sub>2</sub>H<sub>4</sub>F) ⇌ thymidine 5'-monophosphate(dTMP) + Dihydrofolate(H<sub>2</sub>F)<br />
<br />
[[Image:TS Overview.jpg]]<br />
== Function ==<br />
'''Thymidylate synthase''' (TS) catalyzes the methylation of dUMP to dTMP using 5,10-methylenetetrahydrofolate as a cofactor. TS is essential for DNA replication and repair<ref>PMID:2243092</ref>. In protozoa, [[dihydrofolate reductase]] (DHFR) and TS are expressed as a bifunctional monomeric enzyme ('''DHFR-TS)''' with the DHFR entity at the N terminal. DHFR and TS catalyze consecutive reactions in the dTMP biosynthesis. There are two different types of TS – '''ThyA''' and '''ThyX'''. The types differ in their activity and structure. The TS ThyX are flavin-dependent enzymes.<br />
<br />
== Relevance ==<br />
One of the nucleobase of DNA, cytosine, spontaneously deaminates to form uracil, changing the encoded message. Different from RNA, DNA does not contain uracil but instead contains the methylated form thymine, avoiding missense mutations. The [https://proteopedia.org/wiki/index.php/Category:Dna-repair DNA repair protein] [[Uracil DNA glycosylase]] will recognize uracil as damaged DNA, removing it and re-establishing the original message<ref>DOI:10.1038/sj.onc.1205996</ref>. Because thymine contains an additional methyl group, it is distinguishable from uracil, and is not removed through DNA repair. Thymidylate synthase helps to turn the abundant uridine (containing the nucleobase uracil) into deoxythymidine (containing the nucleobase thymine) in preparation for DNA synthesis prior to cell division. Thus, thymidylate synthase plays a role in making DNA a more reliable long-term storage of genetic information compared to RNA.<br />
<br />
TS inhibition at its folate-binding site is used in anticancer therapeutic drugs. DHFR-TS inhibitors are potential drug targets against parasite-transferred diseases. TS exhibits oncogene-like activity.<ref>PMID:15093541</ref><br />
<br />
<StructureSection load='' size='350' side='right' caption='Thymidylate synthase complex with dUMP (PDB entry [[1tsv]])' scene='49/493689/Cv/1'><br />
==Structure and ligand binding==<br />
TS forms a homodimer consisting of two domains (reload <scene name='49/493689/Cv/1'>initial scene</scene>). Their <scene name='49/493689/Cv/4'>active sites can each bind the substrate dUMP</scene><ref>PMID:9053905</ref>. Maley et al. show that E.coli TS uses a half-the-sites mechanism when catalyzing its reaction <ref>doi:10.1093/protein/9.1.69</ref>. One of the two active sites catalyzes the reaction while the other remains inactive. The way the two domains communicate with each other to coordinate this is still unknown.<br />
<br />
The active site Cysteine has two <scene name='49/493689/Ts_7jxf_percentb/4'>conformations</scene>. Conformation 1 shows the active site cysteineunbound to the intermediate 4.21 Angstroms away from the C6 carbon of the dNMP ring. Conformation 2 shows the active site cysteine bound to the intermediate 3.84 Angstroms away from the C6 carbon of the dNMP ring. <br />
<jmol><br />
<jmolRadioGroup><br />
<item><br />
<script>hide (VNM or 146:B) and altloc=A</script><br />
<text>Conformation 1</text><br />
<checked>true</checked><br />
</item><br />
<item><br />
<script>hide (VNM or 146:B) and altloc=B</script><br />
<text>Conformation 2</text><br />
<checked>false</checked><br />
</item><br />
<item><br />
<script>hide none</script><br />
<text>both conformations</text><br />
<checked>false</checked><br />
</item><br />
</jmolRadioGroup><br />
</jmol><br />
==Inhibition==<br />
Methotrexate, a competitive inhibitor competes with folate substrate to bind to the active site of TS. Inhibits the conversion of CH<sub>2</sub>H<sub>4</sub>F to H<sub>2</sub>F. This inhibition stops the conversion of products to reactants, stopping cellular reproduction. <scene name='49/493689/Inhibited/1'>inhibits</scene> TS.<br />
<br />
Due to its role in cell division, thymidylate synthase has become a popular target for anticancer drugs. Indirect inhibition of thymidylate synthase by the drug 5-fluorouracil (5-FU) is one of the most used inhibitors for study of TS function. This drug indirectly inhibits TS as it it eventually converted to FdUMP, which forms a covalent complex with both the active site cysteine and CH<sub>2</sub>H<sub>4</sub>F. Inhibition of TS halts the production of dTMP and, indirectly, 2'-deoxythymidine-5'-triphosphate (dTTP). Both dTMP and dTTP are essential building blocks for DNA synthesis and their absence halts the ability of cells to replicate their genetic information. This is especially effective in cancer cells that rapidly divide and require large amounts of dTMP and dTTP. <ref>DOI 10.2174/0929867054864868</ref><br />
</StructureSection><br />
<br />
<br />
==3D structures of thymidylate synthase==<br />
[[Thymidylate synthase 3D structures]]<br />
<br />
== References ==<br />
<references/><br />
[[Category:Topic Page]]<br />
[[Category:Dihydrofolate]]<br />
[[Category:One-carbon metabolism]]</div>Anna Postnikovahttps://proteopedia.org/index.php?title=Methylenetetrahydrofolate_reductase&diff=3546254Methylenetetrahydrofolate reductase2022-04-15T14:48:38Z<p>Anna Postnikova: </p>
<hr />
<div>[[Methylenetetrahydrofolate reductase]] (MTHFR) is an enzyme is a regulatory agent of folate [[one-carbon metabolism]]. The enzyme is present in both eukaryotes and prokaryotes however, the structure is unique in eukaryotes as it has a SAM binding domain. The enzyme has an essential role in S-Adenosyl Methionine (SAM) regulation in order to promote homeostasis within the folate cycle. This shows the importance of MTHFR within the human body, and identifies the issues that may arise if MTHFR dysfunction occurs.<br />
<br />
5,10-methylenetetrahydrofolate + NADPH + H+ <-> 5-methyltetrahydrofolate + NADP+<br />
<br />
[[Image:MTHFR Reaction.jpg|800px]]<br />
<br />
== Function ==<br />
Methylenetetrahydrofolate reductase (MTHFR) enzyme catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate to be recycled back into the folate cycle, and for aiding folate uptake in the body. This reduction reaction requires the cofactor molecule flavin adenine dinucleotide (FAD) and the second substrate nicotinamide adenine dinucleotide phosphate (NADPH) as the electron donor in the reaction. MTHFR has a unique folding structure. Its N-terminal is abundant in serine and acts as a phosphorylation site, its situated in close proximity to it's C-terminal S-adenosyl methionine (SAM) binding site. A linker joins the catalytic domain (N-terminal) to the regulatory domain (C-terminal) for interaction and increases the sensitivity to SAM binding and feedback properties. <br />
<br />
<br />
== Disease ==<br />
In addition to the folate cycle, MTHFR is also a major component of the homeostasis of homocysteine in the blood stream. When this homeostasis is disrupted, mutations are created that result in hyperhomocysteinemia with homocystinuria, or mild hyperhomocysteinemia. Hyperhomocysteinemia is an excess of the amino acid circulating in the body, and is a direct correlation of cardiovascular disease, Alzheimer's disease, depression, and neural tube defects within the fetus. Furthermore, homocystinuria is clinically described as the body's inability to adequately process homocysteine and the amino acid methionine. This dysfunction can be clinically presented with skeletal, vision, and blood clotting abnormalities coupled with learning disorders. <br />
<br />
== Relevance ==<br />
<br />
<br />
<StructureSection load='' size='340' side='right' scene='90/907473/Mthfr_protein/2'><br />
<br />
<br />
== Structural highlights ==<br />
{{Template:Button Toggle Animation2}}<br />
MTHFR catalyzes the reaction using a <scene name='90/907473/Superposition/5'>ping pong mechanism</scene>, where a substrate binds and forms an intermediate before releasing the product, followed by the binding of a second substrate and later release of a second product <ref>DOI:10.1021/bi9007325</ref>.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/><br />
[[Category:One-carbon metabolism]]</div>Anna Postnikovahttps://proteopedia.org/index.php?title=Methylenetetrahydrofolate_reductase&diff=3546253Methylenetetrahydrofolate reductase2022-04-15T14:45:30Z<p>Anna Postnikova: </p>
<hr />
<div>[[Methylenetetrahydrofolate reductase]] (MTHFR) is an enzyme is a regulatory agent of folate [[one-carbon metabolism]]. The enzyme is present in both eukaryotes and prokaryotes however, the structure is unique in eukaryotes as it has a SAM binding domain. The enzyme has an essential role in S-Adenosyl Methionine (SAM) regulation in order to promote homeostasis within the folate cycle. This shows the importance of MTHFR within the human body, and identifies the issues that may arise if MTHFR dysfunction occurs.<br />
<br />
5,10-methylenetetrahydrofolate + NADPH + H+ <-> 5-methyltetrahydrofolate + NADP+<br />
<br />
[[Image:MTHFR Reaction.jpg|800px]]<br />
<br />
== Function ==<br />
Methylenetetrahydrofolate reductase (MTHFR) enzyme catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate to be recycled back into the folate cycle, and for aiding folate uptake in the body. This reduction reaction requires the cofactor molecule flavin adenine dinucleotide (FAD) and the second substrate nicotinamide adenine dinucleotide phosphate (NADPH) as the electron donor in the reaction. MTHFR has a unique folding structure. Its N-terminal is abundant in serine and acts as a phosphorylation site, its situated in close proximity to it's C-terminal S-adenosyl methionine (SAM) binding site. A linker joins the catalytic domain (N-terminal) to the regulatory domain (C-terminal) for interaction and increases the sensitivity to SAM binding and feedback properties. <br />
<br />
<br />
== Disease ==<br />
In addition to the folate cycle, MTHFR is also a major component of the homeostasis of homocysteine in the blood stream. When this homeostasis is disrupted, mutations are created that result in hyperhomocysteinemia with homocystinuria, or mild hyperhomocysteinemia. Hyperhomocysteinemia is an excess of the amino acid circulating in the body, and is a direct correlation of cardiovascular disease, Alzheimer's disease, depression, and neural tube defects within the fetus. Furthermore, homocystinuria is clinically described as the body's inability to adequately process homocysteine and the amino acid methionine. This dysfunction can be clinically presented with skeletal, vision, and blood clotting abnormalities coupled with learning disorders. <br />
<br />
== Relevance ==<br />
<br />
<br />
<StructureSection load='' size='340' side='right' scene='90/907473/Mthfr_protein/2'><br />
<br />
<br />
== Structural highlights ==<br />
{{Template:Button Toggle Animation2}}<br />
MTHFR catalyzes the reaction using a <scene name='90/907473/Superposition/5'>ping pong mechanism</scene>, where a substrate binds and forms an intermediate before releasing the product, followed by the binding of a second substrate and later release of a second product (cite).<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/><br />
[[Category:One-carbon metabolism]]</div>Anna Postnikovahttps://proteopedia.org/index.php?title=Methionine_adenosyltransferase&diff=3546063Methionine adenosyltransferase2022-04-14T14:03:38Z<p>Anna Postnikova: </p>
<hr />
<div>[[Methionine adenosyltransferase]] (MAT) or S-adenosylmethionine synthetase (SAM synthetase) synthesizes S-adenosylmethionine (SAM or AdoMet) from the substrates adenosine triphosphate (ATP) and methionine. ATP isn’t used as a source of energy like it is in other reactions but gets a methionine added onto the 5th carbon while the three phosphate groups are broken down and released from the active site. This enzyme is conserved and found in many organisms, so it is essential for life. Problems with this enzyme have been shown to cause diseases such as various cancers.<br />
<br />
== Relevance ==<br />
The product of this enzymatic reaction, SAM, is the universal methyl donor of metabolism. SAM is involved in N-methylation, O-methylation and C-methylation, yielding S-adenosyl homocysteine as a product that gets recycled by the [[one-carbon metabolism]]. Radical SAM enzymes break down SAM into an adenosyl radical and methionine, enabling a host of otherwise difficult to achieve reactions, e.g. in molybdenum cofactors biosynthesis<ref>DOI:10.1073/pnas.0404624101</ref>. Accumulation of S-adenosyl homocysteine (or homocysteine itself) indicates an imbalance in supply and demand for SAM in the organism. Methionine metabolism impairment in liver diseases is related in alteration in MAT<ref>PMID:7741002</ref>.<br />
<br />
<br />
== Function and reaction mechanism ==<br />
'''S-adenosylmethionine synthetase''' or '''S-adenosylmethionine synthase''' or '''S-adenosylmethionine transferase''' or '''methionine adenosyltransferase''' (MAT) catalyzes the conversion of methionine and ATP to S-adenosylmethionine (AdoMet), pyrophosphate (PPi) and orthophosphate (Pi). The catalytic entity of MAT is a dimer. MAT cofactors are Mg+2 (or Co+2) and K+ ions<ref>PMID:8611562</ref>. <br />
<br />
[[Image:Sam rxn 2.jpg|800px]]<br />
<br />
The nucleophilic sulfur atom of methionine attacks the slightly positive 5' carbon of the adenosine sugar unit. Following this, the bond from the 5' carbon to the oxygen breaks, separating the tripolyphosphate from the newly formed S-adenosylmethionine (SAM) <ref name="Murray et al.">Murray B, Antonyuk SV, Marina A, Lu SC, Mato JM, Hasnain SS, Rojas Al. Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes. PNAS. 2016 Feb 8;113 (8) 2104-2109. doi: https://doi.org/10.1073/pnas.1510959113</ref>. This is an example of an SN2 reaction, where the substrates move through a transition state to then form the products. The products are only released after the methionine binds and the C-O bond breaks.<br />
<br />
== Structure ==<br />
<br />
<StructureSection load='5a1i' size='400' side='right' caption='Caption for this structure' scene=''><br />
<br />
MAT consists of α and β subunits. The MATα1 and <scene name='90/907472/Mat2a/4'>MATα2</scene> subunits are catalytic subunits while MATβ is a regulatory subunit. Not much is currently known about the function of this regulatory subunit and how it regulates the function of the enzyme. The subunits are encoded on different genes in humans, so they are created separately and can then come together to form various complexes, such as MATαβ or MATα2 dimers <ref name="Murray et al." />.<br />
<br />
The <scene name='90/907472/Substrates/1'>substrates</scene> used by the enzyme are methionine and ATP. Notably, ATP is not used as a source of energy in this reaction like it is for many other processes. Instead, it is used as a substrate in the synthesis reaction. Methionine and ATP enter the active site and are stabilized by residues present there, including lysine and histidine. Once the reaction begins to take place, methionine flips toward the 5' carbon of the adenosine sugar. Following nucleophilic attack of the sulfur on the carbon, the C-O bond between the phosphates and the carbon breaks, and the <scene name='90/907472/Product/2'>products</scene> are formed (tripolyphosphate not pictured). SAM is released from the active site first. MAT also catalyzes hydrolysis of the tripolyphosphate into pyrophosphate and orthophosphate, which are then released from the active site <ref>Niland CN, Ghosh A, Cahill SM, Schramm VL. Mechanism and Inhibition of Human Methionine Adenosyltransferase 2A. ACS Biochemistry. 2021 Mar 3;60 (10) 791-801. doi: https://doi.org/10.1021/acs.biochem.0c00998</ref>.<br />
<br />
== Gating Loop ==<br />
MAT has been shown to have a gating loop next to the active site <ref name="Murray et al." />. This structure is thought to allow access to the active site, becoming ordered or disordered. When the loop is ordered, the active site is closed, and it is opened again when the loop is disordered. Murray et al. <ref name="Murray et al." /> found that when SAM or adenosine is bound to the active site the gate is closed, and when PPNP (tripolyphosphate in the body) is bound to the active site the gate is open.<br />
<br />
<br />
<br />
<br />
== Structural highlights == <br />
The biological assembly of rat S-adenosylmethionine synthetase is <scene name='49/493038/Cv/7'>homotetramer</scene>. The <scene name='49/493038/Cv/8'>active site of MAT is located between adjacent subunuts</scene><ref>PMID:12888348</ref>.<br />
</StructureSection><br />
<br />
<br />
==3D structures of S-adenosylmethionine synthetase==<br />
<br />
[[S-adenosylmethionine synthetase 3D structures]]<br />
<br />
{{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}<br />
{{#tree:id=OrganizedByTopic|openlevels=0|<br />
<br />
*S-adenosylmethionine synthetase<br />
<br />
**[[1fug]] – EcMAT – ''Escherichia coli''<br /><br />
**[[3iml]] – MAT – ''Burkholderia pseudomallei''<br /><br />
**[[2ydy]] – hMAT II subunit β – human<br /><br />
**[[4le5]] – MAT- ''Campylobacter jejuni''<br /><br />
**[[4hpv]] - SsMAT – ''Sulfolobus solfataricus''<br /><br />
**[[3tde]] – MAT- ''Mycobacterium tuberculosis''<br /><br />
**[[3s82]] – MAT- ''Mycobacterium avium''<br /><br />
**[[3rv2]] – MAT- ''Mycobacterium marinum''<br /><br />
<br />
<br />
*S-adenosylmethionine synthetase complexes<br />
<br />
**[[1xra]], [[1xrb]] – EcMAT + Pi + K + Mg <br /><br />
**[[1xrc]] - EcMAT + Pi + Co + K<br /><br />
**[[1mxa]] - EcMAT + Pi + PPi + Mg + K<br /><br />
**[[1mxb]] - EcMAT + Pi + ADP + Mg + K<br /><br />
**[[1mxc]] - EcMAT + Pi + Br-ADP + Mg + K<br /><br />
**[[1p7l]] – EcMAT + methionine + AdoMet + AMPPNP + Mg + K<br /><br />
**[[1rg9]] - EcMAT + AdoMet + AMPPNP + Mg + K<br /><br />
**[[1qm4]] - rMAT+ methionine analog + K + Mg – rat<br /><br />
**[[1o90]] - rMAT + Pi + Mg + K<br /><br />
**[[1o92]] – rMAT + methionine analog + ADP + Mg + K<br /><br />
**[[1o93]] – rMAT + methionine analog + ATP + Mg + K<br /><br />
**[[1o9t]] – rMAT + methionine + ADP + Mg + K<br /><br />
**[[2obv]] – hMAT I + AdoMet + Na <br /><br />
**[[2p02]] - hMAT II + AdoMet<br /><br />
**[[2ydx]] – MAT + resveratrol + NADP + Ca + ADP derivative<br /><br />
**[[4l2z]], [[4k0b]] - SsMAT + Pi + PPi + Mg + SAM derivative <br /><br />
}}<br />
== References ==<br />
<references/><br />
[[Category:Topic Page]]</div>Anna Postnikovahttps://proteopedia.org/index.php?title=Methionine_adenosyltransferase&diff=3545951Methionine adenosyltransferase2022-04-13T15:20:16Z<p>Anna Postnikova: </p>
<hr />
<div>[[Methionine adenosyltransferase]] (MAT) or S-adenosylmethionine synthetase (SAM synthetase) synthesizes S-adenosylmethionine from the substrates adenosine triphosphate (ATP) and methionine. ATP isn’t used as a source of energy like it is in other reactions but gets a methionine added onto the 5th carbon while the three phosphate groups are broken down and released from the active site. This enzyme is conserved and found in many organisms, so it is essential for life. Problems with this enzyme have been shown to cause diseases such as various cancers.<br />
<br />
== Relevance ==<br />
<br />
== Active Site Mechanism ==<br />
[[Image:Sam rxn 2.jpg|800px]]<br />
<br />
The nucleophilic sulfur atom of methionine attacks the slightly positive 5' carbon of the adenosine sugar unit. Following this, the bond from the 5' carbon to the oxygen breaks, separating the tripolyphosphate from the newly formed S-adenosylmethionine (SAM) <ref name="Murray et al.">Murray B, Antonyuk SV, Marina A, Lu SC, Mato JM, Hasnain SS, Rojas Al. Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes. PNAS. 2016 Feb 8;113 (8) 2104-2109. doi: https://doi.org/10.1073/pnas.1510959113</ref>. This is an example of an SN2 reaction, where an intermediate briefly forms as the substrates are transitioning to their product forms. The product is only released after the methionine binds and the C-O bond breaks.<br />
<br />
== Structure ==<br />
<br />
<StructureSection load='5a1i' size='400' side='right' caption='Caption for this structure' scene=''><br />
<br />
MAT consists of α and β subunits. The MATα1 and <scene name='90/907472/Mat2a/4'>MATα2</scene> subunits are catalytic subunits while MATβ is a regulatory subunit. Not much is currently known about the function of this regulatory subunit and how it regulates the function of the enzyme. The subunits are encoded on different genes in humans, so they are created separately and can then come together to form various complexes, such as MATαβ or MATα2 dimers <ref name="Murray et al." />.<br />
<br />
The <scene name='90/907472/Substrates/1'>substrates</scene> used by the enzyme are methionine and ATP. Notably, ATP is not used as a source of energy in this reaction like it is for many other processes. Instead, it is used as a substrate in the synthesis reaction. Methionine and ATP enter the active site and are stabilized by residues present there, including lysine and histidine. Once the reaction begins to take place, methionine flips toward the 5' carbon of the adenosine sugar. Following nucleophilic attack of the sulfur on the carbon, the C-O bond between the phosphates and the carbon breaks, and the <scene name='90/907472/Product/2'>products</scene> are formed (tripolyphosphate not pictured). SAM is released from the active site first. MAT also catalyzes hydrolysis of the tripolyphosphate into pyrophosphate and orthophosphate, which are then released from the active site <ref>Niland CN, Ghosh A, Cahill SM, Schramm VL. Mechanism and Inhibition of Human Methionine Adenosyltransferase 2A. ACS Biochemistry. 2021 Mar 3;60 (10) 791-801. doi: https://doi.org/10.1021/acs.biochem.0c00998</ref>.<br />
<br />
== Gating Loop ==<br />
MAT has been shown to have a gating loop next to the active site <ref name="Murray et al." />. This structure is thought to allow access to the active site, becoming ordered or disordered. When the loop is ordered, the active site is closed, and it is opened again when the loop is disordered. Murray et al. <ref name="Murray et al." /> found that when SAM or adenosine is bound to the active site the gate is closed, and when PPNP (tripolyphosphate in the body) is bound to the active site the gate is open.<br />
<br />
== Other Substrates ==<br />
<br />
== Function ==<br />
'''S-adenosylmethionine synthetase''' or '''S-adenosylmethionine synthase''' or '''S-adenosylmethionine transferase''' or '''methionine adenosyltransferase''' (MAT) catalyzes the conversion of methionine and ATP to S-adenosylmethionine (AdoMet), pyrophosphate (PPi) and orthophosphate (Pi). AdoMet is a methyl donor. The catalytic entity of MAT is a dimer. MAT cofactors are Mg+2 (or Co+2) and K+ ions<ref>PMID:8611562</ref>. <br />
<br />
== Relevance ==<br />
Methionine metabolism impairment in liver diseases is related in alteration in MAT<ref>PMID:7741002</ref>.<br />
<br />
== Structural highlights == <br />
The biological assembly of rat S-adenosylmethionine synthetase is <scene name='49/493038/Cv/7'>homotetramer</scene>. The <scene name='49/493038/Cv/8'>active site of MAT is located between adjacent subunuts</scene><ref>PMID:12888348</ref>.<br />
</StructureSection><br />
<br />
<br />
== References ==<br />
<references/><br />
<br />
<br />
<br />
<br />
<br />
<br />
==3D structures of S-adenosylmethionine synthetase==<br />
<br />
[[S-adenosylmethionine synthetase 3D structures]]<br />
<br />
{{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}<br />
{{#tree:id=OrganizedByTopic|openlevels=0|<br />
<br />
*S-adenosylmethionine synthetase<br />
<br />
**[[1fug]] – EcMAT – ''Escherichia coli''<br /><br />
**[[3iml]] – MAT – ''Burkholderia pseudomallei''<br /><br />
**[[2ydy]] – hMAT II subunit β – human<br /><br />
**[[4le5]] – MAT- ''Campylobacter jejuni''<br /><br />
**[[4hpv]] - SsMAT – ''Sulfolobus solfataricus''<br /><br />
**[[3tde]] – MAT- ''Mycobacterium tuberculosis''<br /><br />
**[[3s82]] – MAT- ''Mycobacterium avium''<br /><br />
**[[3rv2]] – MAT- ''Mycobacterium marinum''<br /><br />
<br />
<br />
*S-adenosylmethionine synthetase complexes<br />
<br />
**[[1xra]], [[1xrb]] – EcMAT + Pi + K + Mg <br /><br />
**[[1xrc]] - EcMAT + Pi + Co + K<br /><br />
**[[1mxa]] - EcMAT + Pi + PPi + Mg + K<br /><br />
**[[1mxb]] - EcMAT + Pi + ADP + Mg + K<br /><br />
**[[1mxc]] - EcMAT + Pi + Br-ADP + Mg + K<br /><br />
**[[1p7l]] – EcMAT + methionine + AdoMet + AMPPNP + Mg + K<br /><br />
**[[1rg9]] - EcMAT + AdoMet + AMPPNP + Mg + K<br /><br />
**[[1qm4]] - rMAT+ methionine analog + K + Mg – rat<br /><br />
**[[1o90]] - rMAT + Pi + Mg + K<br /><br />
**[[1o92]] – rMAT + methionine analog + ADP + Mg + K<br /><br />
**[[1o93]] – rMAT + methionine analog + ATP + Mg + K<br /><br />
**[[1o9t]] – rMAT + methionine + ADP + Mg + K<br /><br />
**[[2obv]] – hMAT I + AdoMet + Na <br /><br />
**[[2p02]] - hMAT II + AdoMet<br /><br />
**[[2ydx]] – MAT + resveratrol + NADP + Ca + ADP derivative<br /><br />
**[[4l2z]], [[4k0b]] - SsMAT + Pi + PPi + Mg + SAM derivative <br /><br />
}}<br />
== References ==<br />
<references/><br />
[[Category:Topic Page]]</div>Anna Postnikovahttps://proteopedia.org/index.php?title=Methionine_adenosyltransferase&diff=3545949Methionine adenosyltransferase2022-04-13T15:17:41Z<p>Anna Postnikova: </p>
<hr />
<div>[[Methionine adenosyltransferase]] (MAT) or S-adenosylmethionine synthetase (SAM synthetase) synthesizes S-adenosylmethionine from the substrates adenosine triphosphate (ATP) and methionine. ATP isn’t used as a source of energy like it is in other reactions but gets a methionine added onto the 5th carbon while the three phosphate groups are broken down and released from the active site. This enzyme is conserved and found in many organisms, so it is essential for life. Problems with this enzyme have been shown to cause diseases such as various cancers.<br />
<br />
== Relevance ==<br />
<br />
== Active Site Mechanism ==<br />
[[Image:Sam rxn 2.jpg|800px]]<br />
<br />
The nucleophilic sulfur atom of methionine attacks the slightly positive 5' carbon of the adenosine sugar unit. Following this, the bond from the 5' carbon to the oxygen breaks, separating the tripolyphosphate from the newly formed S-adenosylmethionine (SAM) <ref name="Murray et al.">Murray B, Antonyuk SV, Marina A, Lu SC, Mato JM, Hasnain SS, Rojas Al. Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes. PNAS. 2016 Feb 8;113 (8) 2104-2109. doi: https://doi.org/10.1073/pnas.1510959113</ref>. This is an example of an SN2 reaction, where an intermediate briefly forms as the substrates are transitioning to their product forms. The product is only released after the methionine binds and the C-O bond breaks.<br />
<br />
== Structure ==<br />
<br />
<StructureSection load='5a1i' size='400' side='right' caption='Caption for this structure' scene=''><br />
<br />
MAT consists of α and β subunits. The MATα1 and <scene name='90/907472/Mat2a/4'>MATα2</scene> subunits are catalytic subunits while MATβ is a regulatory subunit. Not much is currently known about the function of this regulatory subunit and how it regulates the function of the enzyme. The subunits are encoded on different genes in humans, so they are created separately and can then come together to form various complexes, such as MATαβ or MATα2 dimers <ref name="Murray et al." />.<br />
<br />
The <scene name='90/907472/Substrates/1'>substrates</scene> used by the enzyme are methionine and ATP. Notably, ATP is not used as a source of energy in this reaction like it is for many other processes. Instead, it is used as a substrate in the synthesis reaction. Methionine and ATP enter the active site and are stabilized by residues present there, including lysine and histidine. Once the reaction begins to take place, methionine flips toward the 5' carbon of the adenosine sugar. Following nucleophilic attack of the sulfur on the carbon, the C-O bond between the phosphates and the carbon breaks, and the <scene name='90/907472/Product/2'>products</scene> are formed (tripolyphosphate not pictured). SAM is released from the active site first. MAT also catalyzes hydrolysis of the tripolyphosphate into pyrophosphate and orthophosphate, which are then released from the active site <ref>Niland CN, Ghosh A, Cahill SM, Schramm VL. Mechanism and Inhibition of Human Methionine Adenosyltransferase 2A. ACS Biochemistry. 2021 Mar 3 </ref>.<br />
<br />
== Gating Loop ==<br />
MAT has been shown to have a gating loop next to the active site <ref name="Murray et al." />. This structure is thought to allow access to the active site, becoming ordered or disordered. When the loop is ordered, the active site is closed, and it is opened again when the loop is disordered. Murray et al. <ref name="Murray et al." /> found that when SAM or adenosine is bound to the active site the gate is closed, and when PPNP (tripolyphosphate in the body) is bound to the active site the gate is open.<br />
<br />
== Other Substrates ==<br />
<br />
== Function ==<br />
'''S-adenosylmethionine synthetase''' or '''S-adenosylmethionine synthase''' or '''S-adenosylmethionine transferase''' or '''methionine adenosyltransferase''' (MAT) catalyzes the conversion of methionine and ATP to S-adenosylmethionine (AdoMet), pyrophosphate (PPi) and orthophosphate (Pi). AdoMet is a methyl donor. The catalytic entity of MAT is a dimer. MAT cofactors are Mg+2 (or Co+2) and K+ ions<ref>PMID:8611562</ref>. <br />
<br />
== Relevance ==<br />
Methionine metabolism impairment in liver diseases is related in alteration in MAT<ref>PMID:7741002</ref>.<br />
<br />
== Structural highlights == <br />
The biological assembly of rat S-adenosylmethionine synthetase is <scene name='49/493038/Cv/7'>homotetramer</scene>. The <scene name='49/493038/Cv/8'>active site of MAT is located between adjacent subunuts</scene><ref>PMID:12888348</ref>.<br />
</StructureSection><br />
<br />
<br />
== References ==<br />
<references/><br />
<br />
<br />
<br />
<br />
<br />
<br />
==3D structures of S-adenosylmethionine synthetase==<br />
<br />
[[S-adenosylmethionine synthetase 3D structures]]<br />
<br />
{{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}<br />
{{#tree:id=OrganizedByTopic|openlevels=0|<br />
<br />
*S-adenosylmethionine synthetase<br />
<br />
**[[1fug]] – EcMAT – ''Escherichia coli''<br /><br />
**[[3iml]] – MAT – ''Burkholderia pseudomallei''<br /><br />
**[[2ydy]] – hMAT II subunit β – human<br /><br />
**[[4le5]] – MAT- ''Campylobacter jejuni''<br /><br />
**[[4hpv]] - SsMAT – ''Sulfolobus solfataricus''<br /><br />
**[[3tde]] – MAT- ''Mycobacterium tuberculosis''<br /><br />
**[[3s82]] – MAT- ''Mycobacterium avium''<br /><br />
**[[3rv2]] – MAT- ''Mycobacterium marinum''<br /><br />
<br />
<br />
*S-adenosylmethionine synthetase complexes<br />
<br />
**[[1xra]], [[1xrb]] – EcMAT + Pi + K + Mg <br /><br />
**[[1xrc]] - EcMAT + Pi + Co + K<br /><br />
**[[1mxa]] - EcMAT + Pi + PPi + Mg + K<br /><br />
**[[1mxb]] - EcMAT + Pi + ADP + Mg + K<br /><br />
**[[1mxc]] - EcMAT + Pi + Br-ADP + Mg + K<br /><br />
**[[1p7l]] – EcMAT + methionine + AdoMet + AMPPNP + Mg + K<br /><br />
**[[1rg9]] - EcMAT + AdoMet + AMPPNP + Mg + K<br /><br />
**[[1qm4]] - rMAT+ methionine analog + K + Mg – rat<br /><br />
**[[1o90]] - rMAT + Pi + Mg + K<br /><br />
**[[1o92]] – rMAT + methionine analog + ADP + Mg + K<br /><br />
**[[1o93]] – rMAT + methionine analog + ATP + Mg + K<br /><br />
**[[1o9t]] – rMAT + methionine + ADP + Mg + K<br /><br />
**[[2obv]] – hMAT I + AdoMet + Na <br /><br />
**[[2p02]] - hMAT II + AdoMet<br /><br />
**[[2ydx]] – MAT + resveratrol + NADP + Ca + ADP derivative<br /><br />
**[[4l2z]], [[4k0b]] - SsMAT + Pi + PPi + Mg + SAM derivative <br /><br />
}}<br />
== References ==<br />
<references/><br />
[[Category:Topic Page]]</div>Anna Postnikovahttps://proteopedia.org/index.php?title=Methionine_adenosyltransferase&diff=3542789Methionine adenosyltransferase2022-04-11T15:15:26Z<p>Anna Postnikova: </p>
<hr />
<div>[[Methionine adenosyltransferase]] (MAT) or S-adenosylmethionine synthetase (SAM synthetase) synthesizes S-adenosylmethionine from the substrates adenosine triphosphate (ATP) and methionine. ATP isn’t used as a source of energy like it is in other reactions but gets a methionine added onto the 5th carbon while the three phosphate groups are broken down and released from the active site. This enzyme is conserved and found in many organisms, so it is essential for life. Problems with this enzyme have been shown to cause diseases such as various cancers.<br />
<br />
== Relevance ==<br />
<br />
== Active Site Mechanism ==<br />
[[Image:Sam rxn 2.jpg|800px]]<br />
<br />
The nucleophilic sulfur atom of methionine attacks the slightly positive 5' carbon of the adenosine sugar unit. Following this, the bond from the 5' carbon to the oxygen breaks, separating the tripolyphosphate from the newly formed S-adenosylmethionine (SAM) <ref name="Murray et al.">Murray B, Antonyuk SV, Marina A, Lu SC, Mato JM, Hasnain SS, Rojas Al. Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes. PNAS. 2016 Feb 8;113 (8) 2104-2109. doi: https://doi.org/10.1073/pnas.1510959113</ref>. This is an example of an SN2 reaction, where an intermediate briefly forms as the substrates are transitioning to their product forms. The product is only released after the methionine binds and the C-O bond breaks.<br />
<br />
== Structure ==<br />
<br />
<StructureSection load='5a1i' size='400' side='right' caption='Caption for this structure' scene=''><br />
<br />
MAT consists of α and β subunits. The MATα1 and <scene name='90/907472/Mat2a/4'>MATα2</scene> subunits are catalytic subunits while MATβ is a regulatory subunit. Not much is currently known about the function of this regulatory subunit and how it regulates the function of the enzyme. The subunits are encoded on different genes in humans, so they are created separately and can then come together to form various complexes, such as MATαβ or MATα2 dimers <ref name="Murray et al." />.<br />
<br />
The <scene name='90/907472/Substrates/1'>substrates</scene> used by the enzyme are methionine and ATP. Notably, ATP is not used as a source of energy in this reaction like it is for many other processes. Instead, it is used as a substrate in the synthesis reaction. Methionine and ATP enter the active site and are stabilized by residues present there, including lysine and histidine. Once the reaction begins to take place, methionine flips toward the 5' carbon of the adenosine sugar. Following nucleophilic attack of the sulfur on the carbon, the C-O bond between the phosphates and the carbon breaks, and the <scene name='90/907472/Product/2'>products</scene> are formed (tripolyphosphate not pictured). SAM is released from the active site first. MAT also catalyzes hydrolysis of the tripolyphosphate into pyrophosphate and orthophosphate, which are then released from the active site <ref>Niland CN, Ghosh A, Cahill SM, Schramm VL. Mechanism and Inhibition of Human Methionine Adenosyltransferase 2A. ACS Biochemistry. 2021 Mar 3 </ref>.<br />
<br />
== Gating Loop ==<br />
<br />
== Other Substrates ==<br />
<br />
== Function ==<br />
'''S-adenosylmethionine synthetase''' or '''S-adenosylmethionine synthase''' or '''S-adenosylmethionine transferase''' or '''methionine adenosyltransferase''' (MAT) catalyzes the conversion of methionine and ATP to S-adenosylmethionine (AdoMet), pyrophosphate (PPi) and orthophosphate (Pi). AdoMet is a methyl donor. The catalytic entity of MAT is a dimer. MAT cofactors are Mg+2 (or Co+2) and K+ ions<ref>PMID:8611562</ref>. <br />
<br />
== Relevance ==<br />
Methionine metabolism impairment in liver diseases is related in alteration in MAT<ref>PMID:7741002</ref>.<br />
<br />
== Structural highlights == <br />
The biological assembly of rat S-adenosylmethionine synthetase is <scene name='49/493038/Cv/7'>homotetramer</scene>. The <scene name='49/493038/Cv/8'>active site of MAT is located between adjacent subunuts</scene><ref>PMID:12888348</ref>.<br />
</StructureSection><br />
<br />
<br />
== References ==<br />
<references/><br />
<br />
<br />
<br />
<br />
<br />
<br />
==3D structures of S-adenosylmethionine synthetase==<br />
<br />
[[S-adenosylmethionine synthetase 3D structures]]<br />
<br />
{{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}<br />
{{#tree:id=OrganizedByTopic|openlevels=0|<br />
<br />
*S-adenosylmethionine synthetase<br />
<br />
**[[1fug]] – EcMAT – ''Escherichia coli''<br /><br />
**[[3iml]] – MAT – ''Burkholderia pseudomallei''<br /><br />
**[[2ydy]] – hMAT II subunit β – human<br /><br />
**[[4le5]] – MAT- ''Campylobacter jejuni''<br /><br />
**[[4hpv]] - SsMAT – ''Sulfolobus solfataricus''<br /><br />
**[[3tde]] – MAT- ''Mycobacterium tuberculosis''<br /><br />
**[[3s82]] – MAT- ''Mycobacterium avium''<br /><br />
**[[3rv2]] – MAT- ''Mycobacterium marinum''<br /><br />
<br />
<br />
*S-adenosylmethionine synthetase complexes<br />
<br />
**[[1xra]], [[1xrb]] – EcMAT + Pi + K + Mg <br /><br />
**[[1xrc]] - EcMAT + Pi + Co + K<br /><br />
**[[1mxa]] - EcMAT + Pi + PPi + Mg + K<br /><br />
**[[1mxb]] - EcMAT + Pi + ADP + Mg + K<br /><br />
**[[1mxc]] - EcMAT + Pi + Br-ADP + Mg + K<br /><br />
**[[1p7l]] – EcMAT + methionine + AdoMet + AMPPNP + Mg + K<br /><br />
**[[1rg9]] - EcMAT + AdoMet + AMPPNP + Mg + K<br /><br />
**[[1qm4]] - rMAT+ methionine analog + K + Mg – rat<br /><br />
**[[1o90]] - rMAT + Pi + Mg + K<br /><br />
**[[1o92]] – rMAT + methionine analog + ADP + Mg + K<br /><br />
**[[1o93]] – rMAT + methionine analog + ATP + Mg + K<br /><br />
**[[1o9t]] – rMAT + methionine + ADP + Mg + K<br /><br />
**[[2obv]] – hMAT I + AdoMet + Na <br /><br />
**[[2p02]] - hMAT II + AdoMet<br /><br />
**[[2ydx]] – MAT + resveratrol + NADP + Ca + ADP derivative<br /><br />
**[[4l2z]], [[4k0b]] - SsMAT + Pi + PPi + Mg + SAM derivative <br /><br />
}}<br />
== References ==<br />
<references/><br />
[[Category:Topic Page]]</div>Anna Postnikovahttps://proteopedia.org/index.php?title=Methionine_adenosyltransferase&diff=3542788Methionine adenosyltransferase2022-04-11T15:14:03Z<p>Anna Postnikova: </p>
<hr />
<div>[[Methionine adenosyltransferase]] (MAT) synthesizes S-adenosylmethionine from the substrates adenosine triphosphate (ATP) and methionine. ATP isn’t used as a source of energy like it is in other reactions but gets a methionine added onto the 5th carbon while the three phosphate groups are broken down and released from the active site. This enzyme is conserved and found in many organisms, so it is essential for life. Problems with this enzyme have been shown to cause diseases such as various cancers.<br />
<br />
== Relevance ==<br />
<br />
== Active Site Mechanism ==<br />
[[Image:Sam rxn 2.jpg|800px]]<br />
<br />
The nucleophilic sulfur atom of methionine attacks the slightly positive 5' carbon of the adenosine sugar unit. Following this, the bond from the 5' carbon to the oxygen breaks, separating the tripolyphosphate from the newly formed S-adenosylmethionine (SAM) <ref name="Murray et al.">Murray B, Antonyuk SV, Marina A, Lu SC, Mato JM, Hasnain SS, Rojas Al. Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes. PNAS. 2016 Feb 8;113 (8) 2104-2109. doi: https://doi.org/10.1073/pnas.1510959113</ref>. This is an example of an SN2 reaction, where an intermediate briefly forms as the substrates are transitioning to their product forms. The product is only released after the methionine binds and the C-O bond breaks.<br />
<br />
== Structure ==<br />
<br />
<StructureSection load='5a1i' size='400' side='right' caption='Caption for this structure' scene=''><br />
<br />
MAT consists of α and β subunits. The MATα1 and <scene name='90/907472/Mat2a/4'>MATα2</scene> subunits are catalytic subunits while MATβ is a regulatory subunit. Not much is currently known about the function of this regulatory subunit and how it regulates the function of the enzyme. The subunits are encoded on different genes in humans, so they are created separately and can then come together to form various complexes, such as MATαβ or MATα2 dimers <ref name="Murray et al." />.<br />
<br />
The <scene name='90/907472/Substrates/1'>substrates</scene> used by the enzyme are methionine and ATP. Notably, ATP is not used as a source of energy in this reaction like it is for many other processes. Instead, it is used as a substrate in the synthesis reaction. Methionine and ATP enter the active site and are stabilized by residues present there, including lysine and histidine. Once the reaction begins to take place, methionine flips toward the 5' carbon of the adenosine sugar. Following nucleophilic attack of the sulfur on the carbon, the C-O bond between the phosphates and the carbon breaks, and the <scene name='90/907472/Product/2'>products</scene> are formed (tripolyphosphate not pictured). SAM is released from the active site first. MAT also catalyzes hydrolysis of the tripolyphosphate into pyrophosphate and orthophosphate, which are then released from the active site <ref>Niland CN, Ghosh A, Cahill SM, Schramm VL. Mechanism and Inhibition of Human Methionine Adenosyltransferase 2A. ACS Biochemistry. 2021 Mar 3 </ref>.<br />
<br />
== Gating Loop ==<br />
<br />
== Other Substrates ==<br />
<br />
== Function ==<br />
'''S-adenosylmethionine synthetase''' or '''S-adenosylmethionine synthase''' or '''S-adenosylmethionine transferase''' or '''methionine adenosyltransferase''' (MAT) catalyzes the conversion of methionine and ATP to S-adenosylmethionine (AdoMet), pyrophosphate (PPi) and orthophosphate (Pi). AdoMet is a methyl donor. The catalytic entity of MAT is a dimer. MAT cofactors are Mg+2 (or Co+2) and K+ ions<ref>PMID:8611562</ref>. <br />
<br />
== Relevance ==<br />
Methionine metabolism impairment in liver diseases is related in alteration in MAT<ref>PMID:7741002</ref>.<br />
<br />
== Structural highlights == <br />
The biological assembly of rat S-adenosylmethionine synthetase is <scene name='49/493038/Cv/7'>homotetramer</scene>. The <scene name='49/493038/Cv/8'>active site of MAT is located between adjacent subunuts</scene><ref>PMID:12888348</ref>.<br />
</StructureSection><br />
<br />
<br />
== References ==<br />
<references/><br />
<br />
<br />
<br />
<br />
<br />
<br />
==3D structures of S-adenosylmethionine synthetase==<br />
<br />
[[S-adenosylmethionine synthetase 3D structures]]<br />
<br />
{{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}<br />
{{#tree:id=OrganizedByTopic|openlevels=0|<br />
<br />
*S-adenosylmethionine synthetase<br />
<br />
**[[1fug]] – EcMAT – ''Escherichia coli''<br /><br />
**[[3iml]] – MAT – ''Burkholderia pseudomallei''<br /><br />
**[[2ydy]] – hMAT II subunit β – human<br /><br />
**[[4le5]] – MAT- ''Campylobacter jejuni''<br /><br />
**[[4hpv]] - SsMAT – ''Sulfolobus solfataricus''<br /><br />
**[[3tde]] – MAT- ''Mycobacterium tuberculosis''<br /><br />
**[[3s82]] – MAT- ''Mycobacterium avium''<br /><br />
**[[3rv2]] – MAT- ''Mycobacterium marinum''<br /><br />
<br />
<br />
*S-adenosylmethionine synthetase complexes<br />
<br />
**[[1xra]], [[1xrb]] – EcMAT + Pi + K + Mg <br /><br />
**[[1xrc]] - EcMAT + Pi + Co + K<br /><br />
**[[1mxa]] - EcMAT + Pi + PPi + Mg + K<br /><br />
**[[1mxb]] - EcMAT + Pi + ADP + Mg + K<br /><br />
**[[1mxc]] - EcMAT + Pi + Br-ADP + Mg + K<br /><br />
**[[1p7l]] – EcMAT + methionine + AdoMet + AMPPNP + Mg + K<br /><br />
**[[1rg9]] - EcMAT + AdoMet + AMPPNP + Mg + K<br /><br />
**[[1qm4]] - rMAT+ methionine analog + K + Mg – rat<br /><br />
**[[1o90]] - rMAT + Pi + Mg + K<br /><br />
**[[1o92]] – rMAT + methionine analog + ADP + Mg + K<br /><br />
**[[1o93]] – rMAT + methionine analog + ATP + Mg + K<br /><br />
**[[1o9t]] – rMAT + methionine + ADP + Mg + K<br /><br />
**[[2obv]] – hMAT I + AdoMet + Na <br /><br />
**[[2p02]] - hMAT II + AdoMet<br /><br />
**[[2ydx]] – MAT + resveratrol + NADP + Ca + ADP derivative<br /><br />
**[[4l2z]], [[4k0b]] - SsMAT + Pi + PPi + Mg + SAM derivative <br /><br />
}}<br />
== References ==<br />
<references/><br />
[[Category:Topic Page]]</div>Anna Postnikovahttps://proteopedia.org/index.php?title=Methionine_adenosyltransferase&diff=3542777Methionine adenosyltransferase2022-04-11T15:05:16Z<p>Anna Postnikova: </p>
<hr />
<div>[[Methionine adenosyltransferase]] (MAT) synthesizes S-adenosylmethionine from the substrates adenosine triphosphate (ATP) and methionine. ATP isn’t used as a source of energy like it is in other reactions but gets a methionine added onto the 5th carbon while the three phosphate groups are broken down and released from the active site. This enzyme is conserved and found in many organisms, so it is essential for life. Problems with this enzyme have been shown to cause diseases such as various cancers.<br />
<br />
== Relevance ==<br />
<br />
== Active Site Mechanism ==<br />
[[Image:Sam rxn 2.jpg|800px]]<br />
<br />
The slightly negative sulfur atom of methionine undergoes a nucleophilic attack on the slightly positive 5th carbon of the adenosine sugar unit. Following this, the bond from the 5th carbon to the oxygen breaks, separating the tripolyphosphate from the newly formed S-adenosylmethionine (SAM) <ref name="Murray et al.">Murray B, Antonyuk SV, Marina A, Lu SC, Mato JM, Hasnain SS, Rojas Al. Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes. PNAS. 2016 Feb 8;113 (8) 2104-2109. doi: https://doi.org/10.1073/pnas.1510959113</ref>. This is an example of an SN2 reaction, where an intermediate forms as the substrates are transitioning to their product forms. The product is only released after the methionine binds and the C-O bond breaks.<br />
<br />
== Structure ==<br />
<br />
<StructureSection load='5a1i' size='400' side='right' caption='Caption for this structure' scene=''><br />
<br />
MAT consists of α and β subunits. The MATα1 and <scene name='90/907472/Mat2a/4'>MATα2</scene> subunits are catalytic subunits while MATβ is a regulatory subunit. Not much is currently known about the function of this regulatory subunit and how it regulates the function of the enzyme. The subunits are encoded on different genes in humans, so they are created separately and can then come together to form various complexes, such as MATαβ or MATα2 dimers <ref name="Murray et al." />.<br />
<br />
The <scene name='90/907472/Substrates/1'>substrates</scene> used by the enzyme are methionine and ATP. Notably, ATP is not used as a source of energy in this reaction like it is for many other processes. Instead, it is used as a substrate in the synthesis reaction. Methionine and ATP enter the active site and are stabilized by residues present there, including lysine and histidine. Once the reaction begins to take place, methionine flips toward the 5th carbon of the adenosine sugar. Following nucleophilic attack of the sulfur on the carbon, the C-O bond between the phosphates and the carbon breaks, and the <scene name='90/907472/Product/2'>products</scene> are formed (tripolyphosphate not pictured). SAM is released from the active site first. MAT also catalyzes hydrolysis of the tripolyphosphate into pyrophosphate and orthophosphate, which are then released from the active site <ref>Niland CN, Ghosh A, Cahill SM, Schramm VL. Mechanism and Inhibition of Human Methionine Adenosyltransferase 2A. ACS Biochemistry. 2021 Mar 3 </ref>.<br />
<br />
== Gating Loop ==<br />
<br />
== Other Substrates ==<br />
<br />
== Function ==<br />
'''S-adenosylmethionine synthetase''' or '''S-adenosylmethionine synthase''' or '''S-adenosylmethionine transferase''' or '''methionine adenosyltransferase''' (MAT) catalyzes the conversion of methionine and ATP to S-adenosylmethionine (AdoMet), pyrophosphate (PPi) and orthophosphate (Pi). AdoMet is a methyl donor. The catalytic entity of MAT is a dimer. MAT cofactors are Mg+2 (or Co+2) and K+ ions<ref>PMID:8611562</ref>. <br />
<br />
== Relevance ==<br />
Methionine metabolism impairment in liver diseases is related in alteration in MAT<ref>PMID:7741002</ref>.<br />
<br />
== Structural highlights == <br />
The biological assembly of rat S-adenosylmethionine synthetase is <scene name='49/493038/Cv/7'>homotetramer</scene>. The <scene name='49/493038/Cv/8'>active site of MAT is located between adjacent subunuts</scene><ref>PMID:12888348</ref>.<br />
</StructureSection><br />
<br />
<br />
== References ==<br />
<references/><br />
<br />
<br />
<br />
<br />
<br />
<br />
==3D structures of S-adenosylmethionine synthetase==<br />
<br />
[[S-adenosylmethionine synthetase 3D structures]]<br />
<br />
{{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}<br />
{{#tree:id=OrganizedByTopic|openlevels=0|<br />
<br />
*S-adenosylmethionine synthetase<br />
<br />
**[[1fug]] – EcMAT – ''Escherichia coli''<br /><br />
**[[3iml]] – MAT – ''Burkholderia pseudomallei''<br /><br />
**[[2ydy]] – hMAT II subunit β – human<br /><br />
**[[4le5]] – MAT- ''Campylobacter jejuni''<br /><br />
**[[4hpv]] - SsMAT – ''Sulfolobus solfataricus''<br /><br />
**[[3tde]] – MAT- ''Mycobacterium tuberculosis''<br /><br />
**[[3s82]] – MAT- ''Mycobacterium avium''<br /><br />
**[[3rv2]] – MAT- ''Mycobacterium marinum''<br /><br />
<br />
<br />
*S-adenosylmethionine synthetase complexes<br />
<br />
**[[1xra]], [[1xrb]] – EcMAT + Pi + K + Mg <br /><br />
**[[1xrc]] - EcMAT + Pi + Co + K<br /><br />
**[[1mxa]] - EcMAT + Pi + PPi + Mg + K<br /><br />
**[[1mxb]] - EcMAT + Pi + ADP + Mg + K<br /><br />
**[[1mxc]] - EcMAT + Pi + Br-ADP + Mg + K<br /><br />
**[[1p7l]] – EcMAT + methionine + AdoMet + AMPPNP + Mg + K<br /><br />
**[[1rg9]] - EcMAT + AdoMet + AMPPNP + Mg + K<br /><br />
**[[1qm4]] - rMAT+ methionine analog + K + Mg – rat<br /><br />
**[[1o90]] - rMAT + Pi + Mg + K<br /><br />
**[[1o92]] – rMAT + methionine analog + ADP + Mg + K<br /><br />
**[[1o93]] – rMAT + methionine analog + ATP + Mg + K<br /><br />
**[[1o9t]] – rMAT + methionine + ADP + Mg + K<br /><br />
**[[2obv]] – hMAT I + AdoMet + Na <br /><br />
**[[2p02]] - hMAT II + AdoMet<br /><br />
**[[2ydx]] – MAT + resveratrol + NADP + Ca + ADP derivative<br /><br />
**[[4l2z]], [[4k0b]] - SsMAT + Pi + PPi + Mg + SAM derivative <br /><br />
}}<br />
== References ==<br />
<references/><br />
[[Category:Topic Page]]</div>Anna Postnikovahttps://proteopedia.org/index.php?title=User:Anna_Postnikova/MAT&diff=3542776User:Anna Postnikova/MAT2022-04-11T14:59:30Z<p>Anna Postnikova: </p>
<hr />
<div>=Methionine adenosyltransferase=<br />
Methionine adenosyltransferase (MAT) synthesizes S-adenosylmethionine from the substrates adenosine triphosphate (ATP) and methionine. ATP isn’t used as a source of energy like it is in other reactions but gets a methionine added onto the 5th carbon while the three phosphate groups are broken down and released from the active site. This enzyme is conserved and found in many organisms, so it is essential for life. Problems with this enzyme have been shown to cause diseases such as various cancers.<br />
<br />
== Relevance ==<br />
<br />
== Active Site Mechanism ==<br />
[[Image:Sam rxn 2.jpg|800px]]<br />
<br />
The slightly negative sulfur atom of methionine undergoes a nucleophilic attack on the slightly positive 5th carbon of the adenosine sugar unit. Following this, the bond from the 5th carbon to the oxygen breaks, separating the tripolyphosphate from the newly formed S-adenosylmethionine (SAM) <ref name="Murray et al.">Murray B, Antonyuk SV, Marina A, Lu SC, Mato JM, Hasnain SS, Rojas Al. Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes. PNAS. 2016 Feb 8;113 (8) 2104-2109. doi: https://doi.org/10.1073/pnas.1510959113</ref>. This is an example of an SN2 reaction, where an intermediate forms as the substrates are transitioning to their product forms. The product is only released after the methionine binds and the C-O bond breaks.<br />
<br />
== Structure ==<br />
<br />
<StructureSection load='5a1i' size='400' side='right' caption='Caption for this structure' scene=''><br />
<br />
MAT consists of α and β subunits. The MATα1 and <scene name='90/907472/Mat2a/4'>MATα2</scene> subunits are catalytic subunits while MATβ is a regulatory subunit. Not much is currently known about the function of this regulatory subunit and how it regulates the function of the enzyme. The subunits are encoded on different genes in humans, so they are created separately and can then come together to form various complexes, such as MATαβ or MATα2 dimers <ref name="Murray et al." />.<br />
<br />
The <scene name='90/907472/Substrates/1'>substrates</scene> used by the enzyme are methionine and ATP. Notably, ATP is not used as a source of energy in this reaction like it is for many other processes. Instead, it is used as a substrate in the synthesis reaction. Methionine and ATP enter the active site and are stabilized by residues present there, including lysine and histidine. Once the reaction begins to take place, methionine flips toward the 5th carbon of the adenosine sugar. Following nucleophilic attack of the sulfur on the carbon, the C-O bond between the phosphates and the carbon breaks, and the <scene name='90/907472/Product/2'>products</scene> are formed (tripolyphosphate not pictured). SAM is released from the active site first. MAT also catalyzes hydrolysis of the tripolyphosphate into pyrophosphate and orthophosphate, which are then released from the active site <ref>Niland CN, Ghosh A, Cahill SM, Schramm VL. Mechanism and Inhibition of Human Methionine Adenosyltransferase 2A. ACS Biochemistry. 2021 Mar 3 </ref>.<br />
<br />
== Gating Loop ==<br />
<br />
== Other Substrates ==<br />
</StructureSection><br />
<br />
<br />
== References ==<br />
<references/></div>Anna Postnikovahttps://proteopedia.org/index.php?title=User:Anna_Postnikova/MAT&diff=3542775User:Anna Postnikova/MAT2022-04-11T14:58:36Z<p>Anna Postnikova: </p>
<hr />
<div>=Methionine adenosyltransferase=<br />
Methionine adenosyltransferase (MAT) synthesizes S-adenosylmethionine from the substrates adenosine triphosphate (ATP) and methionine. ATP isn’t used as a source of energy like it is in other reactions but gets a methionine added onto the 5th carbon while the three phosphate groups are broken down and released from the active site. This enzyme is conserved and found in many organisms, so it is essential for life. Problems with this enzyme have been shown to cause diseases such as various cancers.<br />
<br />
== Relevance ==<br />
<br />
== Active Site Mechanism ==<br />
[[Image:Sam rxn 2.jpg|1000px]]<br />
<br />
For higher resolution, see [Image:Sam rxn 2.png|1000pix]. The slightly negative sulfur atom of methionine undergoes a nucleophilic attack on the slightly positive 5th carbon of the adenosine sugar unit. Following this, the bond from the 5th carbon to the oxygen breaks, separating the tripolyphosphate from the newly formed S-adenosylmethionine (SAM) <ref name="Murray et al.">Murray B, Antonyuk SV, Marina A, Lu SC, Mato JM, Hasnain SS, Rojas Al. Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes. PNAS. 2016 Feb 8;113 (8) 2104-2109. doi: https://doi.org/10.1073/pnas.1510959113</ref>. This is an example of an SN2 reaction, where an intermediate forms as the substrates are transitioning to their product forms. The product is only released after the methionine binds and the C-O bond breaks.<br />
<br />
== Structure ==<br />
<br />
<StructureSection load='5a1i' size='400' side='right' caption='Caption for this structure' scene=''><br />
<br />
MAT consists of α and β subunits. The MATα1 and <scene name='90/907472/Mat2a/4'>MATα2</scene> subunits are catalytic subunits while MATβ is a regulatory subunit. Not much is currently known about the function of this regulatory subunit and how it regulates the function of the enzyme. The subunits are encoded on different genes in humans, so they are created separately and can then come together to form various complexes, such as MATαβ or MATα2 dimers <ref name="Murray et al." />.<br />
<br />
The <scene name='90/907472/Substrates/1'>substrates</scene> used by the enzyme are methionine and ATP. Notably, ATP is not used as a source of energy in this reaction like it is for many other processes. Instead, it is used as a substrate in the synthesis reaction. Methionine and ATP enter the active site and are stabilized by residues present there, including lysine and histidine. Once the reaction begins to take place, methionine flips toward the 5th carbon of the adenosine sugar. Following nucleophilic attack of the sulfur on the carbon, the C-O bond between the phosphates and the carbon breaks, and the <scene name='90/907472/Product/2'>products</scene> are formed (tripolyphosphate not pictured). SAM is released from the active site first. MAT also catalyzes hydrolysis of the tripolyphosphate into pyrophosphate and orthophosphate, which are then released from the active site <ref>Niland CN, Ghosh A, Cahill SM, Schramm VL. Mechanism and Inhibition of Human Methionine Adenosyltransferase 2A. </ref>.<br />
<br />
== Gating Loop ==<br />
<br />
== Other Substrates ==<br />
</StructureSection><br />
<br />
<br />
== References ==<br />
<references/></div>Anna Postnikovahttps://proteopedia.org/index.php?title=User:Anna_Postnikova/MAT&diff=3542774User:Anna Postnikova/MAT2022-04-11T14:55:58Z<p>Anna Postnikova: </p>
<hr />
<div>=Methionine adenosyltransferase=<br />
Methionine adenosyltransferase (MAT) synthesizes S-adenosylmethionine from the substrates adenosine triphosphate (ATP) and methionine. ATP isn’t used as a source of energy like it is in other reactions but gets a methionine added onto the 5th carbon while the three phosphate groups are broken down and released from the active site. This enzyme is conserved and found in many organisms, so it is essential for life. Problems with this enzyme have been shown to cause diseases such as various cancers.<br />
<br />
== Relevance ==<br />
<br />
== Active Site Mechanism ==<br />
[[Image:Sam rxn 2.jpg|1000pix]]<br />
<br />
For higher resolution, see [Image:Sam rxn 2.png|1000pix]. The slightly negative sulfur atom of methionine undergoes a nucleophilic attack on the slightly positive 5th carbon of the adenosine sugar unit. Following this, the bond from the 5th carbon to the oxygen breaks, separating the tripolyphosphate from the newly formed S-adenosylmethionine (SAM) <ref name="Murray et al.">Murray B, Antonyuk SV, Marina A, Lu SC, Mato JM, Hasnain SS, Rojas Al. Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes. PNAS. 2016 Feb 8;113 (8) 2104-2109. doi: https://doi.org/10.1073/pnas.1510959113</ref>. This is an example of an SN2 reaction, where an intermediate forms as the substrates are transitioning to their product forms. The product is only released after the methionine binds and the C-O bond breaks.<br />
<br />
== Structure ==<br />
<br />
<StructureSection load='5a1i' size='400' side='right' caption='Caption for this structure' scene=''><br />
<br />
MAT consists of α and β subunits. The MATα1 and <scene name='90/907472/Mat2a/4'>MATα2</scene> subunits are catalytic subunits while MATβ is a regulatory subunit. Not much is currently known about the function of this regulatory subunit and how it regulates the function of the enzyme. The subunits are encoded on different genes in humans, so they are created separately and can then come together to form various complexes, such as MATαβ or MATα2 dimers <ref name="Murray et al." />.<br />
<br />
The <scene name='90/907472/Substrates/1'>substrates</scene> used by the enzyme are methionine and ATP. Notably, ATP is not used as a source of energy in this reaction like it is for many other processes. Instead, it is used as a substrate in the synthesis reaction. Methionine and ATP enter the active site and are stabilized by residues present there, including lysine and histidine. Once the reaction begins to take place, methionine flips toward the 5th carbon of the adenosine sugar. Following nucleophilic attack of the sulfur on the carbon, the C-O bond between the phosphates and the carbon breaks, and the <scene name='90/907472/Product/2'>products</scene> are formed (tripolyphosphate not pictured). SAM is released from the active site first. MAT also catalyzes hydrolysis of the tripolyphosphate into pyrophosphate and orthophosphate, which are then released from the active site <ref>Niland CN, Ghosh A, Cahill SM, Schramm VL. Mechanism and Inhibition of Human Methionine Adenosyltransferase 2A. </ref>.<br />
<br />
== Gating Loop ==<br />
<br />
== Other Substrates ==<br />
</StructureSection><br />
<br />
<br />
== References ==<br />
<references/></div>Anna Postnikovahttps://proteopedia.org/index.php?title=User:Anna_Postnikova/MAT&diff=3542772User:Anna Postnikova/MAT2022-04-11T14:54:27Z<p>Anna Postnikova: </p>
<hr />
<div>=Methionine adenosyltransferase=<br />
Methionine adenosyltransferase (MAT) synthesizes S-adenosylmethionine from the substrates adenosine triphosphate (ATP) and methionine. ATP isn’t used as a source of energy like it is in other reactions but gets a methionine added onto the 5th carbon while the three phosphate groups are broken down and released from the active site. This enzyme is conserved and found in many organisms, so it is essential for life. Problems with this enzyme have been shown to cause diseases such as various cancers.<br />
<br />
== Relevance ==<br />
<br />
== Active Site Mechanism ==<br />
[[Image:Sam rxn 21.png|1000pix]]<br />
<br />
For higher resolution, see #REDIRECT[[Image:Sam rxn 2.png|1000pix]]. The slightly negative sulfur atom of methionine undergoes a nucleophilic attack on the slightly positive 5th carbon of the adenosine sugar unit. Following this, the bond from the 5th carbon to the oxygen breaks, separating the tripolyphosphate from the newly formed S-adenosylmethionine (SAM) <ref name="Murray et al.">Murray B, Antonyuk SV, Marina A, Lu SC, Mato JM, Hasnain SS, Rojas Al. Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes. PNAS. 2016 Feb 8;113 (8) 2104-2109. doi: https://doi.org/10.1073/pnas.1510959113</ref>. This is an example of an SN2 reaction, where an intermediate forms as the substrates are transitioning to their product forms. The product is only released after the methionine binds and the C-O bond breaks.<br />
<br />
== Structure ==<br />
<br />
<StructureSection load='5a1i' size='400' side='right' caption='Caption for this structure' scene=''><br />
<br />
MAT consists of α and β subunits. The MATα1 and <scene name='90/907472/Mat2a/4'>MATα2</scene> subunits are catalytic subunits while MATβ is a regulatory subunit. Not much is currently known about the function of this regulatory subunit and how it regulates the function of the enzyme. The subunits are encoded on different genes in humans, so they are created separately and can then come together to form various complexes, such as MATαβ or MATα2 dimers <ref name="Murray et al." />.<br />
<br />
The <scene name='90/907472/Substrates/1'>substrates</scene> used by the enzyme are methionine and ATP. Notably, ATP is not used as a source of energy in this reaction like it is for many other processes. Instead, it is used as a substrate in the synthesis reaction. Methionine and ATP enter the active site and are stabilized by residues present there, including lysine and histidine. Once the reaction begins to take place, methionine flips toward the 5th carbon of the adenosine sugar. Following nucleophilic attack of the sulfur on the carbon, the C-O bond between the phosphates and the carbon breaks, and the <scene name='90/907472/Product/2'>products</scene> are formed (tripolyphosphate not pictured). SAM is released from the active site first. MAT also catalyzes hydrolysis of the tripolyphosphate into pyrophosphate and orthophosphate, which are then released from the active site <ref>Niland CN, Ghosh A, Cahill SM, Schramm VL. Mechanism and Inhibition of Human Methionine Adenosyltransferase 2A. </ref>.<br />
<br />
== Gating Loop ==<br />
<br />
== Other Substrates ==<br />
</StructureSection><br />
<br />
<br />
== References ==<br />
<references/></div>Anna Postnikovahttps://proteopedia.org/index.php?title=User:Anna_Postnikova/MAT&diff=3542770User:Anna Postnikova/MAT2022-04-11T14:53:12Z<p>Anna Postnikova: </p>
<hr />
<div>=Methionine adenosyltransferase=<br />
Methionine adenosyltransferase (MAT) synthesizes S-adenosylmethionine from the substrates adenosine triphosphate (ATP) and methionine. ATP isn’t used as a source of energy like it is in other reactions but gets a methionine added onto the 5th carbon while the three phosphate groups are broken down and released from the active site. This enzyme is conserved and found in many organisms, so it is essential for life. Problems with this enzyme have been shown to cause diseases such as various cancers.<br />
<br />
== Relevance ==<br />
<br />
== Active Site Mechanism ==<br />
[[Image:Sam rxn 21.png|1000pix]]<br />
<br />
For higher resolution, see [Image:Sam rxn 2.png|1000pix]. The slightly negative sulfur atom of methionine undergoes a nucleophilic attack on the slightly positive 5th carbon of the adenosine sugar unit. Following this, the bond from the 5th carbon to the oxygen breaks, separating the tripolyphosphate from the newly formed S-adenosylmethionine (SAM) <ref name="Murray et al.">Murray B, Antonyuk SV, Marina A, Lu SC, Mato JM, Hasnain SS, Rojas Al. Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes. PNAS. 2016 Feb 8;113 (8) 2104-2109. doi: https://doi.org/10.1073/pnas.1510959113</ref>. This is an example of an SN2 reaction, where an intermediate forms as the substrates are transitioning to their product forms. The product is only released after the methionine binds and the C-O bond breaks.<br />
<br />
== Structure ==<br />
<br />
<StructureSection load='5a1i' size='400' side='right' caption='Caption for this structure' scene=''><br />
<br />
MAT consists of α and β subunits. The MATα1 and <scene name='90/907472/Mat2a/4'>MATα2</scene> subunits are catalytic subunits while MATβ is a regulatory subunit. Not much is currently known about the function of this regulatory subunit and how it regulates the function of the enzyme. The subunits are encoded on different genes in humans, so they are created separately and can then come together to form various complexes, such as MATαβ or MATα2 dimers <ref name="Murray et al." />.<br />
<br />
The <scene name='90/907472/Substrates/1'>substrates</scene> used by the enzyme are methionine and ATP. Notably, ATP is not used as a source of energy in this reaction like it is for many other processes. Instead, it is used as a substrate in the synthesis reaction. Methionine and ATP enter the active site and are stabilized by residues present there, including lysine and histidine. Once the reaction begins to take place, methionine flips toward the 5th carbon of the adenosine sugar. Following nucleophilic attack of the sulfur on the carbon, the C-O bond between the phosphates and the carbon breaks, and the <scene name='90/907472/Product/2'>products</scene> are formed (tripolyphosphate not pictured). SAM is released from the active site first. MAT also catalyzes hydrolysis of the tripolyphosphate into pyrophosphate and orthophosphate, which are then released from the active site <ref>Niland CN, Ghosh A, Cahill SM, Schramm VL. Mechanism and Inhibition of Human Methionine Adenosyltransferase 2A. </ref>.<br />
<br />
== Gating Loop ==<br />
<br />
== Other Substrates ==<br />
</StructureSection><br />
<br />
<br />
== References ==<br />
<references/></div>Anna Postnikovahttps://proteopedia.org/index.php?title=User:Anna_Postnikova/MAT&diff=3542769User:Anna Postnikova/MAT2022-04-11T14:52:55Z<p>Anna Postnikova: </p>
<hr />
<div>=Methionine adenosyltransferase=<br />
Methionine adenosyltransferase (MAT) synthesizes S-adenosylmethionine from the substrates adenosine triphosphate (ATP) and methionine. ATP isn’t used as a source of energy like it is in other reactions but gets a methionine added onto the 5th carbon while the three phosphate groups are broken down and released from the active site. This enzyme is conserved and found in many organisms, so it is essential for life. Problems with this enzyme have been shown to cause diseases such as various cancers.<br />
<br />
== Relevance ==<br />
<br />
== Active Site Mechanism ==<br />
[[Image:Sam rxn 21.png|1000pix]]<br />
<br />
For higher resolution, see [[Image:Sam rxn 2.png|1000pix]]. The slightly negative sulfur atom of methionine undergoes a nucleophilic attack on the slightly positive 5th carbon of the adenosine sugar unit. Following this, the bond from the 5th carbon to the oxygen breaks, separating the tripolyphosphate from the newly formed S-adenosylmethionine (SAM) <ref name="Murray et al.">Murray B, Antonyuk SV, Marina A, Lu SC, Mato JM, Hasnain SS, Rojas Al. Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes. PNAS. 2016 Feb 8;113 (8) 2104-2109. doi: https://doi.org/10.1073/pnas.1510959113</ref>. This is an example of an SN2 reaction, where an intermediate forms as the substrates are transitioning to their product forms. The product is only released after the methionine binds and the C-O bond breaks.<br />
<br />
== Structure ==<br />
<br />
<StructureSection load='5a1i' size='400' side='right' caption='Caption for this structure' scene=''><br />
<br />
MAT consists of α and β subunits. The MATα1 and <scene name='90/907472/Mat2a/4'>MATα2</scene> subunits are catalytic subunits while MATβ is a regulatory subunit. Not much is currently known about the function of this regulatory subunit and how it regulates the function of the enzyme. The subunits are encoded on different genes in humans, so they are created separately and can then come together to form various complexes, such as MATαβ or MATα2 dimers <ref name="Murray et al." />.<br />
<br />
The <scene name='90/907472/Substrates/1'>substrates</scene> used by the enzyme are methionine and ATP. Notably, ATP is not used as a source of energy in this reaction like it is for many other processes. Instead, it is used as a substrate in the synthesis reaction. Methionine and ATP enter the active site and are stabilized by residues present there, including lysine and histidine. Once the reaction begins to take place, methionine flips toward the 5th carbon of the adenosine sugar. Following nucleophilic attack of the sulfur on the carbon, the C-O bond between the phosphates and the carbon breaks, and the <scene name='90/907472/Product/2'>products</scene> are formed (tripolyphosphate not pictured). SAM is released from the active site first. MAT also catalyzes hydrolysis of the tripolyphosphate into pyrophosphate and orthophosphate, which are then released from the active site <ref>Niland CN, Ghosh A, Cahill SM, Schramm VL. Mechanism and Inhibition of Human Methionine Adenosyltransferase 2A. </ref>.<br />
<br />
== Gating Loop ==<br />
<br />
== Other Substrates ==<br />
</StructureSection><br />
<br />
<br />
== References ==<br />
<references/></div>Anna Postnikovahttps://proteopedia.org/index.php?title=User:Anna_Postnikova/MAT&diff=3542768User:Anna Postnikova/MAT2022-04-11T14:45:02Z<p>Anna Postnikova: </p>
<hr />
<div>=Methionine adenosyltransferase=<br />
Methionine adenosyltransferase (MAT) synthesizes S-adenosylmethionine from the substrates adenosine triphosphate (ATP) and methionine. ATP isn’t used as a source of energy like it is in other reactions but gets a methionine added onto the 5th carbon while the three phosphate groups are broken down and released from the active site. This enzyme is conserved and found in many organisms, so it is essential for life. Problems with this enzyme have been shown to cause diseases such as various cancers.<br />
<br />
== Relevance ==<br />
<br />
== Active Site Mechanism ==<br />
[[Image:Sam rxn 21.png|1000pix]]<br />
<br />
The slightly negative sulfur atom of methionine undergoes a nucleophilic attack on the slightly positive 5th carbon of the adenosine sugar unit. Following this, the bond from the 5th carbon to the oxygen breaks, separating the tripolyphosphate from the newly formed S-adenosylmethionine (SAM) <ref name="Murray et al.">Murray B, Antonyuk SV, Marina A, Lu SC, Mato JM, Hasnain SS, Rojas Al. Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes. PNAS. 2016 Feb 8;113 (8) 2104-2109. doi: https://doi.org/10.1073/pnas.1510959113</ref>. This is an example of an SN2 reaction, where an intermediate forms as the substrates are transitioning to their product forms. The product is only released after the methionine binds and the C-O bond breaks.<br />
<br />
== Structure ==<br />
<br />
<StructureSection load='5a1i' size='400' side='right' caption='Caption for this structure' scene=''><br />
<br />
MAT consists of α and β subunits. The MATα1 and <scene name='90/907472/Mat2a/4'>MATα2</scene> subunits are catalytic subunits while MATβ is a regulatory subunit. Not much is currently known about the function of this regulatory subunit and how it regulates the function of the enzyme. The subunits are encoded on different genes in humans, so they are created separately and can then come together to form various complexes, such as MATαβ or MATα2 dimers <ref name="Murray et al." />.<br />
<br />
The <scene name='90/907472/Substrates/1'>substrates</scene> used by the enzyme are methionine and ATP. Notably, ATP is not used as a source of energy in this reaction like it is for many other processes. Instead, it is used as a substrate in the synthesis reaction. Methionine and ATP enter the active site and are stabilized by residues present there, including lysine and histidine. Once the reaction begins to take place, methionine flips toward the 5th carbon of the adenosine sugar. Following nucleophilic attack of the sulfur on the carbon, the C-O bond between the phosphates and the carbon breaks, and the <scene name='90/907472/Product/2'>products</scene> are formed (tripolyphosphate not pictured). SAM is released from the active site first. MAT also catalyzes hydrolysis of the tripolyphosphate into pyrophosphate and orthophosphate, which are then released from the active site <ref>Niland CN, Ghosh A, Cahill SM, Schramm VL. Mechanism and Inhibition of Human Methionine Adenosyltransferase 2A. </ref>.<br />
<br />
== Gating Loop ==<br />
<br />
== Other Substrates ==<br />
</StructureSection><br />
<br />
<br />
== References ==<br />
<references/></div>Anna Postnikovahttps://proteopedia.org/index.php?title=User:Anna_Postnikova/MAT&diff=3542765User:Anna Postnikova/MAT2022-04-11T14:40:44Z<p>Anna Postnikova: </p>
<hr />
<div>=Methionine adenosyltransferase=<br />
Methionine adenosyltransferase (MAT) synthesizes S-adenosylmethionine from the substrates adenosine triphosphate (ATP) and methionine. ATP isn’t used as a source of energy like it is in other reactions but gets a methionine added onto the 5th carbon while the three phosphate groups are broken down and released from the active site. This enzyme is conserved and found in many organisms, so it is essential for life. Problems with this enzyme have been shown to cause diseases such as various cancers.<br />
<br />
== Relevance ==<br />
<br />
== Active Site Mechanism ==<br />
[[Image:Sam rxn 21.png|700pix]]<br />
<br />
The slightly negative sulfur atom of methionine undergoes a nucleophilic attack on the slightly positive 5th carbon of the adenosine sugar unit. Following this, the bond from the 5th carbon to the oxygen breaks, separating the tripolyphosphate from the newly formed S-adenosylmethionine (SAM) <ref name="Murray et al.">Murray B, Antonyuk SV, Marina A, Lu SC, Mato JM, Hasnain SS, Rojas Al. Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes. PNAS. 2016 Feb 8;113 (8) 2104-2109. doi: https://doi.org/10.1073/pnas.1510959113</ref>. This is an example of an SN2 reaction, where an intermediate forms as the substrates are transitioning to their product forms. The product is only released after the methionine binds and the C-O bond breaks.<br />
<br />
== Structure ==<br />
<br />
<StructureSection load='5a1i' size='400' side='right' caption='Caption for this structure' scene=''><br />
<br />
MAT consists of α and β subunits. The MATα1 and <scene name='90/907472/Mat2a/4'>MATα2</scene> subunits are catalytic subunits while MATβ is a regulatory subunit. Not much is currently known about the function of this regulatory subunit and how it regulates the function of the enzyme. The subunits are encoded on different genes in humans, so they are created separately and can then come together to form various complexes, such as MATαβ or MATα2 dimers <ref name="Murray et al." />.<br />
<br />
The <scene name='90/907472/Substrates/1'>substrates</scene> used by the enzyme are methionine and ATP. Notably, ATP is not used as a source of energy in this reaction like it is for many other processes. Instead, it is used as a substrate in the synthesis reaction. Methionine and ATP enter the active site and are stabilized by residues present there, including lysine and histidine. Once the reaction begins to take place, methionine flips toward the 5th carbon of the adenosine sugar. Following nucleophilic attack of the sulfur on the carbon, the C-O bond between the phosphates and the carbon breaks, and the <scene name='90/907472/Product/2'>products</scene> are formed (tripolyphosphate not pictured). SAM is released from the active site first. MAT also catalyzes hydrolysis of the tripolyphosphate into pyrophosphate and orthophosphate, which are then released from the active site <ref>Niland CN, Ghosh A, Cahill SM, Schramm VL. Mechanism and Inhibition of Human Methionine Adenosyltransferase 2A. </ref>.<br />
<br />
== Gating Loop ==<br />
<br />
== Other Substrates ==<br />
</StructureSection><br />
<br />
<br />
== References ==<br />
<references/></div>Anna Postnikovahttps://proteopedia.org/index.php?title=User:Anna_Postnikova/MAT&diff=3542763User:Anna Postnikova/MAT2022-04-11T14:40:20Z<p>Anna Postnikova: </p>
<hr />
<div>=Methionine adenosyltransferase=<br />
Methionine adenosyltransferase (MAT) synthesizes S-adenosylmethionine from the substrates adenosine triphosphate (ATP) and methionine. ATP isn’t used as a source of energy like it is in other reactions but gets a methionine added onto the 5th carbon while the three phosphate groups are broken down and released from the active site. This enzyme is conserved and found in many organisms, so it is essential for life. Problems with this enzyme have been shown to cause diseases such as various cancers.<br />
<br />
== Relevance ==<br />
<br />
== Active Site Mechanism ==<br />
[[Image:Sam rxn 21.png|600pix]]<br />
<br />
The slightly negative sulfur atom of methionine undergoes a nucleophilic attack on the slightly positive 5th carbon of the adenosine sugar unit. Following this, the bond from the 5th carbon to the oxygen breaks, separating the tripolyphosphate from the newly formed S-adenosylmethionine (SAM) <ref name="Murray et al.">Murray B, Antonyuk SV, Marina A, Lu SC, Mato JM, Hasnain SS, Rojas Al. Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes. PNAS. 2016 Feb 8;113 (8) 2104-2109. doi: https://doi.org/10.1073/pnas.1510959113</ref>. This is an example of an SN2 reaction, where an intermediate forms as the substrates are transitioning to their product forms. The product is only released after the methionine binds and the C-O bond breaks.<br />
<br />
== Structure ==<br />
<br />
<StructureSection load='5a1i' size='400' side='right' caption='Caption for this structure' scene=''><br />
<br />
MAT consists of α and β subunits. The MATα1 and <scene name='90/907472/Mat2a/4'>MATα2</scene> subunits are catalytic subunits while MATβ is a regulatory subunit. Not much is currently known about the function of this regulatory subunit and how it regulates the function of the enzyme. The subunits are encoded on different genes in humans, so they are created separately and can then come together to form various complexes, such as MATαβ or MATα2 dimers <ref name="Murray et al." />.<br />
<br />
The <scene name='90/907472/Substrates/1'>substrates</scene> used by the enzyme are methionine and ATP. Notably, ATP is not used as a source of energy in this reaction like it is for many other processes. Instead, it is used as a substrate in the synthesis reaction. Methionine and ATP enter the active site and are stabilized by residues present there, including lysine and histidine. Once the reaction begins to take place, methionine flips toward the 5th carbon of the adenosine sugar. Following nucleophilic attack of the sulfur on the carbon, the C-O bond between the phosphates and the carbon breaks, and the <scene name='90/907472/Product/2'>products</scene> are formed (tripolyphosphate not pictured). SAM is released from the active site first. MAT also catalyzes hydrolysis of the tripolyphosphate into pyrophosphate and orthophosphate, which are then released from the active site <ref>Niland CN, Ghosh A, Cahill SM, Schramm VL. Mechanism and Inhibition of Human Methionine Adenosyltransferase 2A. </ref>.<br />
<br />
== Gating Loop ==<br />
<br />
== Other Substrates ==<br />
</StructureSection><br />
<br />
<br />
== References ==<br />
<references/></div>Anna Postnikovahttps://proteopedia.org/index.php?title=File:Sam_rxn_21.png&diff=3542761File:Sam rxn 21.png2022-04-11T14:39:38Z<p>Anna Postnikova: </p>
<hr />
<div></div>Anna Postnikovahttps://proteopedia.org/index.php?title=User:Anna_Postnikova/MAT&diff=3542758User:Anna Postnikova/MAT2022-04-11T14:35:14Z<p>Anna Postnikova: </p>
<hr />
<div>=Methionine adenosyltransferase=<br />
Methionine adenosyltransferase (MAT) synthesizes S-adenosylmethionine from the substrates adenosine triphosphate (ATP) and methionine. ATP isn’t used as a source of energy like it is in other reactions but gets a methionine added onto the 5th carbon while the three phosphate groups are broken down and released from the active site. This enzyme is conserved and found in many organisms, so it is essential for life. Problems with this enzyme have been shown to cause diseases such as various cancers.<br />
<br />
== Relevance ==<br />
<br />
== Active Site Mechanism ==<br />
[[Image:Sam rxn 2.png|600pix]]<br />
<br />
The slightly negative sulfur atom of methionine undergoes a nucleophilic attack on the slightly positive 5th carbon of the adenosine sugar unit. Following this, the bond from the 5th carbon to the oxygen breaks, separating the tripolyphosphate from the newly formed S-adenosylmethionine (SAM) <ref name="Murray et al.">Murray B, Antonyuk SV, Marina A, Lu SC, Mato JM, Hasnain SS, Rojas Al. Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes. PNAS. 2016 Feb 8;113 (8) 2104-2109. doi: https://doi.org/10.1073/pnas.1510959113</ref>. This is an example of an SN2 reaction, where an intermediate forms as the substrates are transitioning to their product forms. The product is only released after the methionine binds and the C-O bond breaks.<br />
<br />
== Structure ==<br />
<br />
<StructureSection load='5a1i' size='400' side='right' caption='Caption for this structure' scene=''><br />
<br />
MAT consists of α and β subunits. The MATα1 and <scene name='90/907472/Mat2a/4'>MATα2</scene> subunits are catalytic subunits while MATβ is a regulatory subunit. Not much is currently known about the function of this regulatory subunit and how it regulates the function of the enzyme. The subunits are encoded on different genes in humans, so they are created separately and can then come together to form various complexes, such as MATαβ or MATα2 dimers <ref name="Murray et al." />.<br />
<br />
The <scene name='90/907472/Substrates/1'>substrates</scene> used by the enzyme are methionine and ATP. Notably, ATP is not used as a source of energy in this reaction like it is for many other processes. Instead, it is used as a substrate in the synthesis reaction. Methionine and ATP enter the active site and are stabilized by residues present there, including lysine and histidine. Once the reaction begins to take place, methionine flips toward the 5th carbon of the adenosine sugar. Following nucleophilic attack of the sulfur on the carbon, the C-O bond between the phosphates and the carbon breaks, and the <scene name='90/907472/Product/2'>products</scene> are formed (tripolyphosphate not pictured). SAM is released from the active site first. MAT also catalyzes hydrolysis of the tripolyphosphate into pyrophosphate and orthophosphate, which are then released from the active site <ref>Niland CN, Ghosh A, Cahill SM, Schramm VL. Mechanism and Inhibition of Human Methionine Adenosyltransferase 2A. </ref>.<br />
<br />
== Gating Loop ==<br />
<br />
== Other Substrates ==<br />
</StructureSection><br />
<br />
<br />
== References ==<br />
<references/></div>Anna Postnikovahttps://proteopedia.org/index.php?title=User:Anna_Postnikova/MAT&diff=3542756User:Anna Postnikova/MAT2022-04-11T14:33:13Z<p>Anna Postnikova: </p>
<hr />
<div>=Methionine adenosyltransferase=<br />
Methionine adenosyltransferase (MAT) synthesizes S-adenosylmethionine from the substrates adenosine triphosphate (ATP) and methionine. ATP isn’t used as a source of energy like it is in other reactions but gets a methionine added onto the 5th carbon while the three phosphate groups are broken down and released from the active site. This enzyme is conserved and found in many organisms, so it is essential for life. Problems with this enzyme have been shown to cause diseases such as various cancers.<br />
<br />
== Relevance ==<br />
<br />
== Active Site Mechanism ==<br />
[[Image:Sam rxn 2.png]]<br />
<br />
The slightly negative sulfur atom of methionine undergoes a nucleophilic attack on the slightly positive 5th carbon of the adenosine sugar unit. Following this, the bond from the 5th carbon to the oxygen breaks, separating the tripolyphosphate from the newly formed S-adenosylmethionine (SAM) <ref name="Murray et al.">Murray B, Antonyuk SV, Marina A, Lu SC, Mato JM, Hasnain SS, Rojas Al. Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes. PNAS. 2016 Feb 8;113 (8) 2104-2109. doi: https://doi.org/10.1073/pnas.1510959113</ref>. This is an example of an SN2 reaction, where an intermediate forms as the substrates are transitioning to their product forms. The product is only released after the methionine binds and the C-O bond breaks.<br />
<br />
== Structure ==<br />
<br />
<StructureSection load='5a1i' size='400' side='right' caption='Caption for this structure' scene=''><br />
<br />
MAT consists of α and β subunits. The MATα1 and <scene name='90/907472/Mat2a/4'>MATα2</scene> subunits are catalytic subunits while MATβ is a regulatory subunit. Not much is currently known about the function of this regulatory subunit and how it regulates the function of the enzyme. The subunits are encoded on different genes in humans, so they are created separately and can then come together to form various complexes, such as MATαβ or MATα2 dimers <ref name="Murray et al." />.<br />
<br />
The <scene name='90/907472/Substrates/1'>substrates</scene> used by the enzyme are methionine and ATP. Notably, ATP is not used as a source of energy in this reaction like it is for many other processes. Instead, it is used as a substrate in the synthesis reaction. Methionine and ATP enter the active site and are stabilized by residues present there, including lysine and histidine. Once the reaction begins to take place, methionine flips toward the 5th carbon of the adenosine sugar. Following nucleophilic attack of the sulfur on the carbon, the C-O bond between the phosphates and the carbon breaks, and the <scene name='90/907472/Product/2'>products</scene> are formed (tripolyphosphate not pictured). SAM is released from the active site first. MAT also catalyzes hydrolysis of the tripolyphosphate into pyrophosphate and orthophosphate, which are then released from the active site <ref>Niland CN, Ghosh A, Cahill SM, Schramm VL. Mechanism and Inhibition of Human Methionine Adenosyltransferase 2A. </ref>.<br />
<br />
== Gating Loop ==<br />
<br />
== Other Substrates ==<br />
</StructureSection><br />
<br />
<br />
== References ==<br />
<references/></div>Anna Postnikovahttps://proteopedia.org/index.php?title=File:Sam_rxn_2.png&diff=3542755File:Sam rxn 2.png2022-04-11T14:29:57Z<p>Anna Postnikova: </p>
<hr />
<div></div>Anna Postnikovahttps://proteopedia.org/index.php?title=User:Anna_Postnikova/MAT&diff=3542558User:Anna Postnikova/MAT2022-04-06T20:01:57Z<p>Anna Postnikova: </p>
<hr />
<div>=Methionine adenosyltransferase=<br />
Methionine adenosyltransferase (MAT) synthesizes S-adenosylmethionine from the substrates adenosine triphosphate (ATP) and methionine. ATP isn’t used as a source of energy like it is in other reactions but gets a methionine added onto the 5th carbon while the three phosphate groups are broken down and released from the active site. This enzyme is conserved and found in many organisms, so it is essential for life. Problems with this enzyme have been shown to cause diseases such as various cancers.<br />
<br />
== Relevance ==<br />
<br />
== Active Site Mechanism ==<br />
[[Image:SAM production rxn.png]]<br />
<br />
The slightly negative sulfur atom of methionine undergoes a nucleophilic attack on the slightly positive 5th carbon of the adenosine sugar unit. Following this, the bond from the 5th carbon to the oxygen breaks, separating the tripolyphosphate from the newly formed S-adenosylmethionine (SAM) <ref name="Murray et al.">Murray B, Antonyuk SV, Marina A, Lu SC, Mato JM, Hasnain SS, Rojas Al. Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes. PNAS. 2016 Feb 8;113 (8) 2104-2109. doi: https://doi.org/10.1073/pnas.1510959113</ref>. This is an example of an SN2 reaction, where an intermediate forms as the substrates are transitioning to their product forms. The product is only released after the methionine binds and the C-O bond breaks.<br />
<br />
== Structure ==<br />
<br />
<StructureSection load='5a1i' size='400' side='right' caption='Caption for this structure' scene=''><br />
<br />
MAT consists of α and β subunits. The MATα1 and <scene name='90/907472/Mat2a/4'>MATα2</scene> subunits are catalytic subunits while MATβ is a regulatory subunit. Not much is currently known about the function of this regulatory subunit and how it regulates the function of the enzyme. The subunits are encoded on different genes in humans, so they are created separately and can then come together to form various complexes, such as MATαβ or MATα2 dimers <ref name="Murray et al." />.<br />
<br />
The <scene name='90/907472/Substrates/1'>substrates</scene> used by the enzyme are methionine and ATP. Notably, ATP is not used as a source of energy in this reaction like it is for many other processes. Instead, it is used as a substrate in the synthesis reaction. Methionine and ATP enter the active site and are stabilized by residues present there, including lysine and histidine. Once the reaction begins to take place, methionine flips toward the 5th carbon of the adenosine sugar. Following nucleophilic attack of the sulfur on the carbon, the C-O bond between the phosphates and the carbon breaks, and the <scene name='90/907472/Product/2'>products</scene> are formed (tripolyphosphate not pictured). SAM is released from the active site first. MAT also catalyzes hydrolysis of the tripolyphosphate into pyrophosphate and orthophosphate, which are then released from the active site <ref>Niland CN, Ghosh A, Cahill SM, Schramm VL. Mechanism and Inhibition of Human Methionine Adenosyltransferase 2A. </ref>.<br />
<br />
== Gating Loop ==<br />
<br />
== Other Substrates ==<br />
</StructureSection><br />
<br />
<br />
== References ==<br />
<references/></div>Anna Postnikovahttps://proteopedia.org/index.php?title=User:Anna_Postnikova/MAT&diff=3542544User:Anna Postnikova/MAT2022-04-06T15:16:16Z<p>Anna Postnikova: </p>
<hr />
<div>=Methionine adenosyltransferase=<br />
Methionine adenosyltransferase (MAT) synthesizes S-adenosylmethionine from the substrates adenosine triphosphate (ATP) and methionine. ATP isn’t used as a source of energy like it is in other reactions but gets a methionine added onto the 5th carbon while the three phosphate groups are broken down and released from the active site. This enzyme is conserved and found in many organisms, so it is essential for life. Problems with this enzyme have been shown to cause diseases such as various cancers.<br />
<br />
== Relevance ==<br />
<br />
== Active Site Mechanism ==<br />
[[Image:SAM production rxn.png]]<br />
<br />
The slightly negative sulfur atom of methionine undergoes a nucleophilic attack on the slightly positive 5th carbon of the adenosine sugar unit. Following this, the bond from the 5th carbon to the oxygen breaks, separating the tripolyphosphate from the newly formed S-adenosylmethionine (SAM) <ref name="Murray et al.">Murray B, Antonyuk SV, Marina A, Lu SC, Mato JM, Hasnain SS, Rojas Al. Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes. PNAS. 2016 Feb 8;113 (8) 2104-2109. doi: https://doi.org/10.1073/pnas.1510959113</ref>. This is an example of an SN2 reaction, where an intermediate forms as the substrates are transitioning to their product forms. The product is only released after the methionine binds and the C-O bond breaks.<br />
<br />
== Structure ==<br />
<br />
<StructureSection load='5a1i' size='400' side='right' caption='Caption for this structure' scene=''><br />
<br />
MAT consists of α and β subunits. The MATα1 and <scene name='90/907472/Mat2a/4'>MATα2</scene> subunits are catalytic subunits while MATβ is a regulatory subunit. Not much is currently known about the function of this regulatory subunit and how it regulates the function of the enzyme. The subunits are encoded on different genes in humans, so they are created separately and can then come together to form various complexes, such as MATαβ or MATα2 dimers <ref name="Murray et al." />.<br />
<br />
The <scene name='90/907472/Substrates/1'>substrates</scene> used by the enzyme are methionine and ATP. Notably, ATP is not used as a source of energy in this reaction like it is for many other processes. Instead, it is used as a substrate in the synthesis reaction. Methionine and ATP enter the active site and are stabilized by residues present there, including lysine and histidine. Once the reaction begins to take place, methionine flips toward the 5th carbon of the adenosine sugar. Following nucleophilic attack of the sulfur on the carbon, the C-O bond between the phosphates and the carbon breaks, and the <scene name='90/907472/Product/2'>products</scene> are formed (tripolyphosphate not pictured). SAM is released from the active site first. MAT also catalyzes hydrolysis of the tripolyphosphate into pyrophosphate and orthophosphate, which are then released from the active site <ref>Niland et al.</ref>.<br />
<br />
== Gating Loop ==<br />
<br />
== Other Substrates ==<br />
</StructureSection><br />
<br />
<br />
== References ==<br />
<references/></div>Anna Postnikovahttps://proteopedia.org/index.php?title=User:Anna_Postnikova/MAT&diff=3542543User:Anna Postnikova/MAT2022-04-06T15:15:41Z<p>Anna Postnikova: </p>
<hr />
<div>=Methionine adenosyltransferase=<br />
Methionine adenosyltransferase (MAT) synthesizes S-adenosylmethionine from the substrates adenosine triphosphate (ATP) and methionine. ATP isn’t used as a source of energy like it is in other reactions but gets a methionine added onto the 5th carbon while the three phosphate groups are broken down and released from the active site. This enzyme is conserved and found in many organisms, so it is essential for life. Problems with this enzyme have been shown to cause diseases such as various cancers.<br />
<br />
== Relevance ==<br />
<br />
== Active Site Mechanism ==<br />
[[Image:SAM production rxn.png]]<br />
<br />
The slightly negative sulfur atom of methionine undergoes a nucleophilic attack on the slightly positive 5th carbon of the adenosine sugar unit. Following this, the bond from the 5th carbon to the oxygen breaks, separating the tripolyphosphate from the newly formed S-adenosylmethionine (SAM) <ref name="Murray et al.">Murray B, Antonyuk SV, Marina A, Lu SC, Mato JM, Hasnain SS, Rojas Al. Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes. PNAS. 2016 Feb 8;113 (8) 2104-2109. doi: https://doi.org/10.1073/pnas.1510959113</ref>. This is an example of an SN2 reaction, where an intermediate forms as the substrates are transitioning to their product forms. The product is only released after the methionine binds and the C-O bond breaks.<br />
<br />
== Structure ==<br />
<br />
<StructureSection load='5a1i' size='400' side='right' caption='Caption for this structure' scene=''><br />
<br />
MAT consists of α and β subunits. The MATα1 and <scene name='90/907472/Mat2a/4'>MATα2</scene> subunits are catalytic subunits while MATβ is a regulatory subunit. Not much is currently known about the function of this regulatory subunit and how it regulates the function of the enzyme. The subunits are encoded on different genes in humans, so they are created separately and can then come together to form various complexes, such as MATαβ or MATα2 dimers <ref name="Murray et al." />.<br />
<br />
The <scene name='90/907472/Substrates/1'>substrates</scene> used by the enzyme are methionine and ATP. Notably, ATP is not used as a source of energy in this reaction like it is for many other processes. Instead, it is used as a substrate in the synthesis reaction. Methionine and ATP enter the active site and are stabilized by residues present there, including lysine and histidine. Once the reaction begins to take place, methionine flips toward the 5th carbon of the adenosine sugar. Following nucleophilic attack of the sulfur on the carbon, the C-O bond between the phosphates and the carbon breaks, and the <scene name='90/907472/Product/2'>products</scene> are formed (tripolyphosphate not pictured). SAM is released from the active site first. Then, MAT also catalyzes hydrolysis of the tripolyphosphate into pyrophosphate and orthophosphate, which are then released from the active site <ref>Niland et al.</ref>.<br />
<br />
== Gating Loop ==<br />
<br />
== Other Substrates ==<br />
</StructureSection><br />
<br />
<br />
== References ==<br />
<references/></div>Anna Postnikovahttps://proteopedia.org/index.php?title=User:Anna_Postnikova/MAT&diff=3542539User:Anna Postnikova/MAT2022-04-06T15:06:11Z<p>Anna Postnikova: </p>
<hr />
<div>=Methionine adenosyltransferase=<br />
Methionine adenosyltransferase (MAT) synthesizes S-adenosylmethionine from the substrates adenosine triphosphate (ATP) and methionine. ATP isn’t used as a source of energy like it is in other reactions but gets a methionine added onto the 5th carbon while the three phosphate groups are broken down and released from the active site. This enzyme is conserved and found in many organisms, so it is essential for life. Problems with this enzyme have been shown to cause diseases such as various cancers.<br />
<br />
== Relevance ==<br />
<br />
== Active Site Mechanism ==<br />
[[Image:SAM production rxn.png]]<br />
<br />
The slightly negative sulfur atom of methionine undergoes a nucleophilic attack on the slightly positive 5th carbon of the adenosine sugar unit. Following this, the bond from the 5th carbon to the oxygen breaks, separating the tripolyphosphate from the newly formed S-adenosylmethionine (SAM) <ref name="Murray et al.">Murray B, Antonyuk SV, Marina A, Lu SC, Mato JM, Hasnain SS, Rojas Al. Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes. PNAS. 2016 Feb 8;113 (8) 2104-2109. doi: https://doi.org/10.1073/pnas.1510959113</ref>. This is an example of an SN2 reaction, where an intermediate forms as the substrates are transitioning to their product forms. The product is only released after the methionine binds and the C-O bond breaks.<br />
<br />
== Structure ==<br />
<br />
<StructureSection load='5a1i' size='400' side='right' caption='Caption for this structure' scene=''><br />
<br />
MAT consists of α and β subunits. The MATα1 and <scene name='90/907472/Mat2a/4'>MATα2</scene> subunits are catalytic subunits while MATβ is a regulatory subunit. Not much is currently known about the function of this regulatory subunit and how it regulates the function of the enzyme. The subunits are encoded on different genes in humans, so they are created separately and can then come together to form various complexes, such as MATαβ or MATα2 dimers <ref name="Murray et al." />.<br />
<br />
The <scene name='90/907472/Substrates/1'>substrates</scene> used by the enzyme are methionine and ATP. Notably, ATP is not used as a source of energy in this reaction like it is for many other processes. Instead, it is used as a substrate in the synthesis reaction. Methionine and ATP enter the active site and are stabilized by residues present there, including lysine and histidine. Once the reaction begins to take place, methionine flips toward the 5th carbon of the adenosine sugar. Following nucleophilic attack of the sulfur on the carbon, the C-O bond between the phosphates and the carbon breaks, and the <scene name='90/907472/Product/2'>products</scene> are formed (tripolyphosphate not pictured). SAM is released from the active site first. The tripolyphosphate is hydrolyzed into pyrophosphate and orthophosphate and released from the active site (cite; is this catalyzed by the enzyme?)<br />
<br />
== Gating Loop ==<br />
<br />
== Other Substrates ==<br />
</StructureSection><br />
<br />
<br />
== References ==<br />
<references/></div>Anna Postnikovahttps://proteopedia.org/index.php?title=User:Anna_Postnikova/MAT&diff=3542537User:Anna Postnikova/MAT2022-04-06T15:05:19Z<p>Anna Postnikova: </p>
<hr />
<div>=Methionine adenosyltransferase=<br />
Methionine adenosyltransferase (MAT) synthesizes S-adenosylmethionine from the substrates adenosine triphosphate (ATP) and methionine. ATP isn’t used as a source of energy like it is in other reactions but gets a methionine added onto the 5th carbon while the three phosphate groups are broken down and released from the active site. This enzyme is conserved and found in many organisms, so it is essential for life. Problems with this enzyme have been shown to cause diseases such as various cancers.<br />
<br />
== Relevance ==<br />
<br />
== Active Site Mechanism ==<br />
[[Image:SAM production rxn.png]]<br />
<br />
The slightly negative sulfur atom of methionine undergoes a nucleophilic attack on the slightly positive 5th carbon of the adenosine sugar unit. Following this, the bond from the 5th carbon to the oxygen breaks, separating the tripolyphosphate from the newly formed S-adenosylmethionine (SAM) <ref name="Murray et al.">Murray B, Antonyuk SV, Marina A, Lu SC, Mato JM, Hasnain SS, Rojas Al. Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes. PNAS. 2016 Feb 8;113 (8) 2104-2109. doi: https://doi.org/10.1073/pnas.1510959113</ref>. This is an example of an SN2 reaction, where an intermediate forms as the substrates are transitioning to their product forms. The product is only released after the methionine binds and the C-O bond breaks.<br />
<br />
== Structure ==<br />
<br />
<StructureSection load='5a1i' size='400' side='right' caption='Caption for this structure' scene=''><br />
<br />
MAT consists of α and β subunits. MATα1 and <scene name='90/907472/Mat2a/4'>MATα2 Subunit</scene> are catalytic subunits while MATβ is a regulatory subunit. Not much is currently known about the function of this regulatory subunit and how it regulates the function of the enzyme. The subunits are encoded on different genes in humans, so they are created separately and can then come together to form various complexes, such as MATαβ or MATα2 dimers <ref name="Murray et al." />.<br />
<br />
The <scene name='90/907472/Substrates/1'>substrates</scene> used by the enzyme are methionine and ATP. Notably, ATP is not used as a source of energy in this reaction like it is for many other processes. Instead, it is used as a substrate in the synthesis reaction. Methionine and ATP enter the active site and are stabilized by residues present there, including lysine and histidine. Once the reaction begins to take place, methionine flips toward the 5th carbon of the adenosine sugar. Following nucleophilic attack of the sulfur on the carbon, the C-O bond between the phosphates and the carbon breaks, and the <scene name='90/907472/Product/2'>products</scene> are formed (tripolyphosphate not pictured). SAM is released from the active site first. The tripolyphosphate is hydrolyzed into pyrophosphate and orthophosphate and released from the active site (cite; is this catalyzed by the enzyme?)<br />
<br />
== Gating Loop ==<br />
<br />
== Other Substrates ==<br />
</StructureSection><br />
<br />
<br />
== References ==<br />
<references/></div>Anna Postnikovahttps://proteopedia.org/index.php?title=User:Anna_Postnikova/MAT&diff=3542535User:Anna Postnikova/MAT2022-04-06T15:04:21Z<p>Anna Postnikova: </p>
<hr />
<div>=Methionine adenosyltransferase=<br />
Methionine adenosyltransferase (MAT) synthesizes S-adenosylmethionine from the substrates adenosine triphosphate (ATP) and methionine. ATP isn’t used as a source of energy like it is in other reactions but gets a methionine added onto the 5th carbon while the three phosphate groups are broken down and released from the active site. This enzyme is conserved and found in many organisms, so it is essential for life. Problems with this enzyme have been shown to cause diseases such as various cancers.<br />
<br />
== Relevance ==<br />
<br />
== Active Site Mechanism ==<br />
[[Image:SAM production rxn.png]]<br />
<br />
The slightly negative sulfur atom of methionine undergoes a nucleophilic attack on the slightly positive 5th carbon of the adenosine sugar unit. Following this, the bond from the 5th carbon to the oxygen breaks, separating the tripolyphosphate from the newly formed S-adenosylmethionine (SAM) <ref name="Murray et al.">Murray B, Antonyuk SV, Marina A, Lu SC, Mato JM, Hasnain SS, Rojas Al. Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes. PNAS. 2016 Feb 8;113 (8) 2104-2109. doi: https://doi.org/10.1073/pnas.1510959113</ref>. This is an example of an SN2 reaction, where an intermediate forms as the substrates are transitioning to their product forms. The product is only released after the methionine binds and the C-O bond breaks.<br />
<br />
== Structure ==<br />
<br />
<StructureSection load='5a1i' size='400' side='right' caption='Caption for this structure' scene=''><br />
<scene name='90/907472/Mat2a/4'>MATa2 Subunit</scene><br />
MAT consists of α and β subunits. MATα1 and MATα2 are catalytic subunits while MATβ is a regulatory subunit. Not much is currently known about the function of this regulatory subunit and how it regulates the function of the enzyme. The subunits are encoded on different genes in humans, so they are created separately and can then come together to form various complexes, such as MATαβ or MATα2 dimers <ref name="Murray et al." />.<br />
<br />
The <scene name='90/907472/Substrates/1'>substrates</scene> used by the enzyme are methionine and ATP. Notably, ATP is not used as a source of energy in this reaction like it is for many other processes. Instead, it is used as a substrate in the synthesis reaction. Methionine and ATP enter the active site and are stabilized by residues present there, including lysine and histidine. Once the reaction begins to take place, methionine flips toward the 5th carbon of the adenosine sugar. Following nucleophilic attack of the sulfur on the carbon, the C-O bond between the phosphates and the carbon breaks, and the <scene name='90/907472/Product/2'>products</scene> are formed (tripolyphosphate not pictured). SAM is released from the active site first. The tripolyphosphate is hydrolyzed into pyrophosphate and orthophosphate and released from the active site (cite; is this catalyzed by the enzyme?)<br />
<br />
== Gating Loop ==<br />
<br />
== Other Substrates ==<br />
</StructureSection><br />
<br />
<br />
== References ==<br />
<references/></div>Anna Postnikovahttps://proteopedia.org/index.php?title=User:Anna_Postnikova/MAT&diff=3542534User:Anna Postnikova/MAT2022-04-06T15:03:52Z<p>Anna Postnikova: </p>
<hr />
<div>=Methionine adenosyltransferase=<br />
Methionine adenosyltransferase (MAT) synthesizes S-adenosylmethionine from the substrates adenosine triphosphate (ATP) and methionine. ATP isn’t used as a source of energy like it is in other reactions but gets a methionine added onto the 5th carbon while the three phosphate groups are broken down and released from the active site. This enzyme is conserved and found in many organisms, so it is essential for life. Problems with this enzyme have been shown to cause diseases such as various cancers.<br />
<br />
== Relevance ==<br />
<br />
== Active Site Mechanism ==<br />
[[Image:SAM production rxn.png]]<br />
<br />
The slightly negative sulfur atom of methionine undergoes a nucleophilic attack on the slightly positive 5th carbon of the adenosine sugar unit. Following this, the bond from the 5th carbon to the oxygen breaks, separating the tripolyphosphate from the newly formed S-adenosylmethionine (SAM) <ref name="Murray et al.">Murray B, Antonyuk SV, Marina A, Lu SC, Mato JM, Hasnain SS, Rojas Al. Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes. PNAS. 2016 Feb 8;113 (8) 2104-2109. doi: https://doi.org/10.1073/pnas.1510959113</ref>. This is an example of an SN2 reaction, where an intermediate forms as the substrates are transitioning to their product forms. The product is only released after the methionine binds and the C-O bond breaks.<br />
<br />
== Structure ==<br />
<br />
<StructureSection load='5a1i' size='400' side='right' caption='Caption for this structure' scene=''><br />
<scene name='90/907472/Mat2a/4'>MATa2 Subunit</scene><br />
MAT consists of α and β subunits. MATα1 and MATα2 are catalytic subunits while MATβ is a regulatory subunit. Not much is currently known about the function of this regulatory subunit and how it regulates the function of the enzyme. The subunits are encoded on different genes in humans, so they are created separately and can then come together to form various complexes, such as MATαβ or MATα2 dimers <ref name="Murray et al." />.<br />
<br />
The <scene name='90/907472/Substrates/1'>substrates</scene> used by the enzyme are methionine and ATP. Notably, ATP is not used as a source of energy in this reaction like it is for many other processes. Instead, it is used as a substrate in the synthesis reaction. Methionine and ATP enter the active site and are stabilized by residues present there, including lysine and histidine. Once the reaction begins to take place, methionine flips toward the 5th carbon of the adenosine sugar. Following nucleophilic attack of the sulfur on the carbon, the C-O bond between the phosphates and the carbon breaks, and the <scene name='90/907472/Product/2'>products</scene> are formed (tripolyphosphate not pictured). SAM is released from the active site first. The tripolyphosphate is hydrolyzed into pyrophosphate and orthophosphate and released from the active site (cite; is this catalyzed by the enzyme?)<br />
<br />
<br />
== Other Substrates ==<br />
</StructureSection><br />
<br />
<br />
== References ==<br />
<references/></div>Anna Postnikovahttps://proteopedia.org/index.php?title=User:Anna_Postnikova/MAT&diff=3542533User:Anna Postnikova/MAT2022-04-06T15:03:22Z<p>Anna Postnikova: </p>
<hr />
<div>=Methionine adenosyltransferase=<br />
Methionine adenosyltransferase (MAT) synthesizes S-adenosylmethionine from the substrates adenosine triphosphate (ATP) and methionine. ATP isn’t used as a source of energy like it is in other reactions but gets a methionine added onto the 5th carbon while the three phosphate groups are broken down and released from the active site. This enzyme is conserved and found in many organisms, so it is essential for life. Problems with this enzyme have been shown to cause diseases such as various cancers.<br />
<br />
== Relevance ==<br />
<br />
<br />
== Structure ==<br />
== Active Site Mechanism ==<br />
</StructureSection><br />
[[Image:SAM production rxn.png]]<br />
<br />
The slightly negative sulfur atom of methionine undergoes a nucleophilic attack on the slightly positive 5th carbon of the adenosine sugar unit. Following this, the bond from the 5th carbon to the oxygen breaks, separating the tripolyphosphate from the newly formed S-adenosylmethionine (SAM) <ref name="Murray et al.">Murray B, Antonyuk SV, Marina A, Lu SC, Mato JM, Hasnain SS, Rojas Al. Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes. PNAS. 2016 Feb 8;113 (8) 2104-2109. doi: https://doi.org/10.1073/pnas.1510959113</ref>. This is an example of an SN2 reaction, where an intermediate forms as the substrates are transitioning to their product forms. The product is only released after the methionine binds and the C-O bond breaks.<br />
<br />
<StructureSection load='5a1i' size='400' side='right' caption='Caption for this structure' scene=''><br />
<scene name='90/907472/Mat2a/4'>MATa2 Subunit</scene><br />
MAT consists of α and β subunits. MATα1 and MATα2 are catalytic subunits while MATβ is a regulatory subunit. Not much is currently known about the function of this regulatory subunit and how it regulates the function of the enzyme. The subunits are encoded on different genes in humans, so they are created separately and can then come together to form various complexes, such as MATαβ or MATα2 dimers <ref name="Murray et al." />.<br />
<br />
The <scene name='90/907472/Substrates/1'>substrates</scene> used by the enzyme are methionine and ATP. Notably, ATP is not used as a source of energy in this reaction like it is for many other processes. Instead, it is used as a substrate in the synthesis reaction. Methionine and ATP enter the active site and are stabilized by residues present there, including lysine and histidine. Once the reaction begins to take place, methionine flips toward the 5th carbon of the adenosine sugar. Following nucleophilic attack of the sulfur on the carbon, the C-O bond between the phosphates and the carbon breaks, and the <scene name='90/907472/Product/2'>products</scene> are formed (tripolyphosphate not pictured). SAM is released from the active site first. The tripolyphosphate is hydrolyzed into pyrophosphate and orthophosphate and released from the active site (cite; is this catalyzed by the enzyme?)<br />
<br />
<br />
== Other Substrates ==<br />
</StructureSection><br />
<br />
<br />
== References ==<br />
<references/></div>Anna Postnikovahttps://proteopedia.org/index.php?title=User:Anna_Postnikova/MAT&diff=3542532User:Anna Postnikova/MAT2022-04-06T15:02:21Z<p>Anna Postnikova: </p>
<hr />
<div>=Methionine adenosyltransferase=<br />
Methionine adenosyltransferase (MAT) synthesizes S-adenosylmethionine from the substrates adenosine triphosphate (ATP) and methionine. ATP isn’t used as a source of energy like it is in other reactions but gets a methionine added onto the 5th carbon while the three phosphate groups are broken down and released from the active site. This enzyme is conserved and found in many organisms, so it is essential for life. Problems with this enzyme have been shown to cause diseases such as various cancers.<br />
<br />
== Relevance ==<br />
<br />
<br />
== Structure ==<br />
== Active Site Mechanism ==<br />
[[Image:SAM production rxn.png]]<br />
<br />
The slightly negative sulfur atom of methionine undergoes a nucleophilic attack on the slightly positive 5th carbon of the adenosine sugar unit. Following this, the bond from the 5th carbon to the oxygen breaks, separating the tripolyphosphate from the newly formed S-adenosylmethionine (SAM) <ref name="Murray et al.">Murray B, Antonyuk SV, Marina A, Lu SC, Mato JM, Hasnain SS, Rojas Al. Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes. PNAS. 2016 Feb 8;113 (8) 2104-2109. doi: https://doi.org/10.1073/pnas.1510959113</ref>. This is an example of an SN2 reaction, where an intermediate forms as the substrates are transitioning to their product forms. The product is only released after the methionine binds and the C-O bond breaks.<br />
<br />
<StructureSection load='5a1i' size='400' side='right' caption='Caption for this structure' scene=''><br />
<scene name='90/907472/Mat2a/4'>MATa2 Subunit</scene><br />
MAT consists of α and β subunits. MATα1 and MATα2 are catalytic subunits while MATβ is a regulatory subunit. Not much is currently known about the function of this regulatory subunit and how it regulates the function of the enzyme. The subunits are encoded on different genes in humans, so they are created separately and can then come together to form various complexes, such as MATαβ or MATα2 dimers <ref name="Murray et al." />.<br />
<br />
The <scene name='90/907472/Substrates/1'>substrates</scene> used by the enzyme are methionine and ATP. Notably, ATP is not used as a source of energy in this reaction like it is for many other processes. Instead, it is used as a substrate in the synthesis reaction. Methionine and ATP enter the active site and are stabilized by residues present there, including lysine and histidine. Once the reaction begins to take place, methionine flips toward the 5th carbon of the adenosine sugar. Following nucleophilic attack of the sulfur on the carbon, the C-O bond between the phosphates and the carbon breaks, and the <scene name='90/907472/Product/2'>products</scene> are formed (tripolyphosphate not pictured). SAM is released from the active site first. The tripolyphosphate is hydrolyzed into pyrophosphate and orthophosphate and released from the active site (cite; is this catalyzed by the enzyme?)<br />
<br />
<br />
== Other Substrates ==<br />
</StructureSection><br />
<br />
<br />
== References ==<br />
<references/></div>Anna Postnikovahttps://proteopedia.org/index.php?title=User:Anna_Postnikova/MAT&diff=3542531User:Anna Postnikova/MAT2022-04-06T15:00:31Z<p>Anna Postnikova: </p>
<hr />
<div>=Methionine adenosyltransferase=<br />
Methionine adenosyltransferase (MAT) synthesizes S-adenosylmethionine from the substrates adenosine triphosphate (ATP) and methionine. ATP isn’t used as a source of energy like it is in other reactions but gets a methionine added onto the 5th carbon while the three phosphate groups are broken down and released from the active site. This enzyme is conserved and found in many organisms, so it is essential for life. Problems with this enzyme have been shown to cause diseases such as various cancers.<br />
<br />
== Relevance ==<br />
<br />
== Active Site Mechanism ==<br />
[[Image:SAM production rxn.png]]<br />
<br />
The slightly negative sulfur atom of methionine undergoes a nucleophilic attack on the slightly positive 5th carbon of the adenosine sugar unit. Following this, the bond from the 5th carbon to the oxygen breaks, separating the tripolyphosphate from the newly formed S-adenosylmethionine (SAM) <ref name="Murray et al.">Murray B, Antonyuk SV, Marina A, Lu SC, Mato JM, Hasnain SS, Rojas Al. Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes. PNAS. 2016 Feb 8;113 (8) 2104-2109. doi: https://doi.org/10.1073/pnas.1510959113</ref>. This is an example of an SN2 reaction, where an intermediate forms as the substrates are transitioning to their product forms. The product is only released after the methionine binds and the C-O bond breaks.<br />
<br />
== Structure ==<br />
<StructureSection load='5a1i' size='400' side='right' caption='Caption for this structure' scene=''><br />
<scene name='90/907472/Mat2a/4'>MATa2 Subunit</scene><br />
MAT consists of α and β subunits. MATα1 and MATα2 are catalytic subunits while MATβ is a regulatory subunit. Not much is currently known about the function of this regulatory subunit and how it regulates the function of the enzyme. The subunits are encoded on different genes in humans, so they are created separately and can then come together to form various complexes, such as MATαβ or MATα2 dimers <ref name="Murray et al." />.<br />
<br />
The <scene name='90/907472/Substrates/1'>substrates</scene> used by the enzyme are methionine and ATP. Notably, ATP is not used as a source of energy in this reaction like it is for many other processes. Instead, it is used as a substrate in the synthesis reaction. Methionine and ATP enter the active site and are stabilized by residues present there, including lysine and histidine. Once the reaction begins to take place, methionine flips toward the 5th carbon of the adenosine sugar. Following nucleophilic attack of the sulfur on the carbon, the C-O bond between the phosphates and the carbon breaks, and the <scene name='90/907472/Product/2'>products</scene> are formed (tripolyphosphate not pictured). SAM is released from the active site first. The tripolyphosphate is hydrolyzed into pyrophosphate and orthophosphate and released from the active site (cite; is this catalyzed by the enzyme?)<br />
<br />
<br />
== Other Substrates ==<br />
</StructureSection><br />
<br />
<br />
== References ==<br />
<references/></div>Anna Postnikovahttps://proteopedia.org/index.php?title=User:Anna_Postnikova/MAT&diff=3542530User:Anna Postnikova/MAT2022-04-06T14:59:20Z<p>Anna Postnikova: </p>
<hr />
<div>=Methionine adenosyltransferase=<br />
Methionine adenosyltransferase (MAT) synthesizes S-adenosylmethionine from the substrates adenosine triphosphate (ATP) and methionine. ATP isn’t used as a source of energy like it is in other reactions but gets a methionine added onto the 5th carbon while the three phosphate groups are broken down and released from the active site. This enzyme is conserved and found in many organisms, so it is essential for life. Problems with this enzyme have been shown to cause diseases such as various cancers.<br />
<br />
== Active Site Mechanism ==<br />
[[Image:SAM production rxn.png]]<br />
<br />
The slightly negative sulfur atom of methionine undergoes a nucleophilic attack on the slightly positive 5th carbon of the adenosine sugar unit. Following this, the bond from the 5th carbon to the oxygen breaks, separating the tripolyphosphate from the newly formed S-adenosylmethionine (SAM) <ref name="Murray et al.">Murray B, Antonyuk SV, Marina A, Lu SC, Mato JM, Hasnain SS, Rojas Al. Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes. PNAS. 2016 Feb 8;113 (8) 2104-2109. doi: https://doi.org/10.1073/pnas.1510959113</ref>. This is an example of an SN2 reaction, where an intermediate forms as the substrates are transitioning to their product forms. The product is only released after the methionine binds and the C-O bond breaks.<br />
<br />
== Structure ==<br />
<StructureSection load='5a1i' size='400' side='right' caption='Caption for this structure' scene=''><br />
<scene name='90/907472/Mat2a/4'>MATa2 Subunit</scene><br />
MAT consists of α and β subunits. MATα1 and MATα2 are catalytic subunits while MATβ is a regulatory subunit. Not much is currently known about the function of this regulatory subunit and how it regulates the function of the enzyme. The subunits are encoded on different genes in humans, so they are created separately and can then come together to form various complexes, such as MATαβ or MATα2 dimers <ref name="Murray et al." />.<br />
<br />
The <scene name='90/907472/Substrates/1'>substrates</scene> used by the enzyme are methionine and ATP. Notably, ATP is not used as a source of energy in this reaction like it is for many other processes. Instead, it is used as a substrate in the synthesis reaction. Methionine and ATP enter the active site and are stabilized by residues present there, including lysine and histidine. Once the reaction begins to take place, methionine flips toward the 5th carbon of the adenosine sugar. Following nucleophilic attack of the sulfur on the carbon, the C-O bond between the phosphates and the carbon breaks, and the <scene name='90/907472/Product/2'>products</scene> are formed. SAM is released from the active site first. The tripolyphosphate is hydrolyzed into pyrophosphate and orthophosphate and released from the active site (cite; is this catalyzed by the enzyme?)<br />
<br />
<br />
== Other Substrates ==<br />
<br />
== Relevance ==<br />
</StructureSection><br />
<br />
== References ==<br />
<references/></div>Anna Postnikovahttps://proteopedia.org/index.php?title=User:Anna_Postnikova/MAT&diff=3542525User:Anna Postnikova/MAT2022-04-06T14:46:12Z<p>Anna Postnikova: </p>
<hr />
<div>=Methionine adenosyltransferase=<br />
Methionine adenosyltransferase (MAT) synthesizes S-adenosylmethionine from the substrates adenosine triphosphate (ATP) and methionine. ATP isn’t used as a source of energy like it is in other reactions but gets a methionine added onto the 5th carbon while the three phosphate groups are broken down and released from the active site. This enzyme is conserved and found in many organisms, so it is essential for life. Problems with this enzyme have been shown to cause diseases such as various cancers.<br />
<br />
== Active Site Mechanism ==<br />
[[Image:SAM production rxn.png]]<br />
<br />
ATP and methionine are stabilized in the active site by the residues present there, including lysine and histidine. The slightly negative sulfur atom of methionine undergoes a nucleophilic attack on the slightly positive 5th carbon of the adenosine sugar unit. Following this, the bond from the 5th carbon to the oxygen breaks, separating the three phosphates from the newly formed S-adenosylmethionine (SAM) <ref name="Murray et al.">Murray B, Antonyuk SV, Marina A, Lu SC, Mato JM, Hasnain SS, Rojas Al. Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes. PNAS. 2016 Feb 8;113 (8) 2104-2109. doi: https://doi.org/10.1073/pnas.1510959113</ref>. This is an example of an SN2 reaction, where an intermediate forms as the substrates are transitioning to their product forms. The product is only released after the methionine binds and the C-O bond breaks.<br />
<br />
== Structure ==<br />
<StructureSection load='5a1i' size='400' side='right' caption='Caption for this structure' scene=''><br />
<scene name='90/907472/Mat2a/4'>MATa2 Subunit</scene><br />
MAT consists of α and β subunits. MATα1 and MATα2 are catalytic subunits while MATβ is a regulatory subunit. The subunits are encoded on different genes in humans, so they are created separately and can then come together to form various complexes, such as MATαβ or MATα2 dimers <ref name="Murray et al." />.<br />
<br />
The <scene name='90/907472/Substrates/1'>substrates</scene> used by the enzyme are methionine and <br />
and <scene name='90/907472/Product/2'>product</scene><br />
<br />
<br />
== Other Substrates ==<br />
<br />
== Relevance ==<br />
</StructureSection><br />
<br />
== References ==<br />
<references/></div>Anna Postnikovahttps://proteopedia.org/index.php?title=User:Anna_Postnikova/MAT&diff=3542518User:Anna Postnikova/MAT2022-04-06T14:38:44Z<p>Anna Postnikova: </p>
<hr />
<div>=Methionine adenosyltransferase=<br />
Methionine adenosyltransferase (MAT) synthesizes S-adenosylmethionine from the substrates adenosine triphosphate (ATP) and methionine. ATP isn’t used as a source of energy like it is in other reactions but gets a methionine added onto the 5th carbon while the three phosphate groups are broken down and released from the active site. This enzyme is conserved and found in many organisms, so it is essential for life. Problems with this enzyme have been shown to cause diseases such as various cancers.<br />
<br />
== SAM Formation Mechanism ==<br />
[[Image:SAM production rxn.png]]<br />
<br />
== Active Site Mechanism ==<br />
ATP and methionine are stabilized in the active site by the residues present there, including lysine and histidine. The slightly negative sulfur atom of methionine undergoes a nucleophilic attack on the slightly positive 5th carbon of the adenosine sugar unit. Following this, the bond from the 5th carbon to the oxygen breaks, separating the three phosphates from the newly formed S-adenosylmethionine (SAM) <ref name="Murray et al.">Murray B, Antonyuk SV, Marina A, Lu SC, Mato JM, Hasnain SS, Rojas Al. Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes. PNAS. 2016 Feb 8;113 (8) 2104-2109. doi: https://doi.org/10.1073/pnas.1510959113</ref>. This is an example of an SN2 reaction, where an intermediate forms as the substrates are transitioning to their product forms. The product is only released after the methionine binds and the C-O bond breaks.<br />
<br />
== Structure ==<br />
<StructureSection load='5a1i' size='400' side='right' caption='Caption for this structure' scene=''><br />
<scene name='90/907472/Mat2a/4'>MATa2 Subunit</scene><br />
MAT consists of α and β subunits. MATα1 and MATα2 are catalytic subunits while MATβ is a regulatory subunit. The subunits are encoded on different genes in humans, so they are created separately and can then come together to form various complexes, such as MATαβ or MATα2 dimers <ref name="Murray et al." />.<br />
<br />
The <scene name='90/907472/Substrates/1'>substrates</scene> used by the enzyme are methionine and <br />
and <scene name='90/907472/Product/2'>product</scene><br />
<br />
<br />
== Other Substrates ==<br />
<br />
== Relevance ==<br />
</StructureSection><br />
<br />
== References ==<br />
<references/></div>Anna Postnikovahttps://proteopedia.org/index.php?title=User:Anna_Postnikova/MAT&diff=3539857User:Anna Postnikova/MAT2022-04-05T18:50:22Z<p>Anna Postnikova: </p>
<hr />
<div>=Methionine adenosyltransferase=<br />
Methionine adenosyltransferase (MAT) synthesizes S-adenosylmethionine from the substrates adenosine triphosphate (ATP) and methionine. ATP isn’t used as a source of energy like it is in other reactions but gets a methionine added onto the 5th carbon while the three phosphate groups are broken down and released from the active site. This enzyme is conserved and found in many organisms, so it is essential for life. Problems with this enzyme have been shown to cause diseases such as various cancers.<br />
<br />
== SAM Formation Mechanism ==<br />
[[Image:SAM production rxn.png]]<br />
<br />
== Active Site Mechanism ==<br />
ATP and methionine are stabilized in the active site by the residues present there, including lysine and histidine. The methionine flips toward the 5th carbon of the ATP sugar, which forms the bond to the triphosphate group. The slightly negative sulfur atom of methionine undergoes a nucleophilic attack on the slightly positive 5th carbon. Following this, the bond from the 5th carbon to the oxygen breaks, separating the three phosphates from the newly formed S-adenosylmethionine (SAM) <ref name="Murray et al.">Murray B, Antonyuk SV, Marina A, Lu SC, Mato JM, Hasnain SS, Rojas Al. Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes. PNAS. 2016 Feb 8;113 (8) 2104-2109. doi: https://doi.org/10.1073/pnas.1510959113</ref>.<br />
<br />
== Structure ==<br />
<StructureSection load='5a1i' size='400' side='right' caption='Caption for this structure' scene=''><br />
<scene name='90/907472/Mat2a/4'>MATa2 Subunit</scene><br />
MAT consists of α and β subunits. MATα1 and MATα2 are catalytic subunits while MATβ is a regulatory subunit. The subunits are encoded on different genes in humans, so they are created separately and can then come together to form various complexes, such as MATαβ or MATα2 dimers <ref name="Murray et al." />.<br />
<br />
The <scene name='90/907472/Substrates/1'>substrates</scene> used by the enzyme are methionine and <br />
and <scene name='90/907472/Product/2'>product</scene><br />
<br />
<br />
== Other Substrates ==<br />
<br />
== Relevance ==<br />
</StructureSection><br />
<br />
== References ==<br />
<references/></div>Anna Postnikovahttps://proteopedia.org/index.php?title=User:Anna_Postnikova/MAT&diff=3539841User:Anna Postnikova/MAT2022-04-05T18:31:43Z<p>Anna Postnikova: </p>
<hr />
<div>=Methionine adenosyltransferase=<br />
Methionine adenosyltransferase (MAT) synthesizes S-adenosylmethionine from the substrates adenosine triphosphate (ATP) and methionine. ATP isn’t used as a source of energy like it is in other reactions but gets a methionine added onto the 5th carbon while the three phosphate groups are broken down and released from the active site. This enzyme is conserved and found in many organisms, so it is essential for life. Problems with this enzyme have been shown to cause diseases such as various cancers.<br />
<br />
== SAM Formation Mechanism ==<br />
[[Image:SAM production rxn.png]]<br />
<br />
== Active Site Mechanism ==<br />
ATP and methionine are stabilized in the active site by the residues present there, including lysine and histidine. The methionine flips toward the 5th carbon of the ATP sugar, which forms the bond to the triphosphate group. The slightly negative sulfur atom of methionine undergoes a nucleophilic attack on the slightly positive 5th carbon. Following this, the bond from the 5th carbon to the oxygen breaks, separating the three phosphates from the newly formed S-adenosylmethionine (SAM) <ref name="Murray et al.">Murray B, Antonyuk SV, Marina A, Lu SC, Mato JM, Hasnain SS, Rojas Al. Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes. PNAS. 2016 Feb 8;113 (8) 2104-2109. doi: https://doi.org/10.1073/pnas.1510959113</ref>.<br />
<br />
== Structure ==<br />
<StructureSection load='5a1i' size='400' side='right' caption='Caption for this structure' scene=''><br />
<scene name='90/907472/Mat2a/4'>MATa2 Subunit</scene><br />
<br />
<scene name='90/907472/Substrates/1'>Substrate</scene> and <scene name='90/907472/Product/2'>product</scene><br />
<br />
MAT consists of α and β subunits. MATα1 and MATα2 are catalytic subunits while MATβ is a regulatory subunit. The subunits are encoded on different genes in humans, so they are created separately and can then come together to form various complexes, such as MATαβ or MATα2 dimers <ref name="Murray et al." />.<br />
<br />
== Other Substrates ==<br />
<br />
== Relevance ==<br />
</StructureSection><br />
<br />
== References ==<br />
<references/></div>Anna Postnikovahttps://proteopedia.org/index.php?title=User:Anna_Postnikova/MAT&diff=3539839User:Anna Postnikova/MAT2022-04-05T18:31:01Z<p>Anna Postnikova: </p>
<hr />
<div>=Methionine adenosyltransferase=<br />
Methionine adenosyltransferase (MAT) synthesizes S-adenosylmethionine from the substrates adenosine triphosphate (ATP) and methionine. ATP isn’t used as a source of energy like it is in other reactions but gets a methionine added onto the 5th carbon while the three phosphate groups are broken down and released from the active site. This enzyme is conserved and found in many organisms, so it is essential for life. Problems with this enzyme have been shown to cause diseases such as various cancers.<br />
<br />
== SAM Formation Mechanism ==<br />
[[Image:SAM production rxn.png]]<br />
<br />
== Active Site Mechanism ==<br />
ATP and methionine are stabilized in the active site by the residues present there, including lysine and histidine. The methionine flips toward the 5th carbon of the ATP sugar, which forms the bond to the triphosphate group. The slightly negative sulfur atom of methionine undergoes a nucleophilic attack on the slightly positive 5th carbon. Following this, the bond from the 5th carbon to the oxygen breaks, separating the three phosphates from the newly formed S-adenosylmethionine (SAM) <ref name="Murray et al.">Murray B, Antonyuk SV, Marina A, Lu SC, Mato JM, Hasnain SS, Rojas Al. Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes. PNAS. 2016 Feb 8;113 (8) 2104-2109. doi: doi.org/10.1073/pnas.1510959113</ref>.<br />
<br />
== Structure ==<br />
<StructureSection load='5a1i' size='400' side='right' caption='Caption for this structure' scene=''><br />
<scene name='90/907472/Mat2a/4'>MATa2 Subunit</scene><br />
<br />
<scene name='90/907472/Substrates/1'>Substrate</scene> and <scene name='90/907472/Product/2'>product</scene><br />
<br />
MAT consists of α and β subunits. MATα1 and MATα2 are catalytic subunits while MATβ is a regulatory subunit. The subunits are encoded on different genes in humans, so they are created separately and can then come together to form various complexes, such as MATαβ or MATα2 dimers <ref name="Murray et al." />.<br />
<br />
== Other Substrates ==<br />
<br />
== Relevance ==<br />
</StructureSection><br />
<br />
== References ==<br />
<references/></div>Anna Postnikovahttps://proteopedia.org/index.php?title=User:Anna_Postnikova/MAT&diff=3539828User:Anna Postnikova/MAT2022-04-05T18:18:52Z<p>Anna Postnikova: </p>
<hr />
<div>=Methionine adenosyltransferase=<br />
Methionine adenosyltransferase (MAT) synthesizes S-adenosylmethionine from the substrates adenosine triphosphate (ATP) and methionine. ATP isn’t used as a source of energy like it is in other reactions but gets a methionine added onto the 5th carbon while the three phosphate groups are broken down and released from the active site. This enzyme is conserved and found in many organisms, so it is essential for life. Problems with this enzyme have been shown to cause diseases such as various cancers.<br />
<br />
== SAM Formation Mechanism ==<br />
[[Image:SAM production rxn.png]]<br />
<br />
== Active Site Mechanism ==<br />
ATP and methionine are stabilized in the active site by the residues present there, including lysine and histidine. The methionine flips toward the 5th carbon of the ATP sugar, which forms the bond to the triphosphate group. The slightly negative sulfur atom of methionine undergoes a nucleophilic attack on the slightly positive 5th carbon. Following this, the bond from the 5th carbon to the oxygen breaks, separating the three phosphates from the newly formed S-adenosylmethionine (SAM) <ref name="Murray et al.">...</ref>.<br />
<br />
== Structure ==<br />
<StructureSection load='5a1i' size='400' side='right' caption='Caption for this structure' scene=''><br />
<scene name='90/907472/Mat2a/4'>MATa2 Subunit</scene><br />
<br />
<scene name='90/907472/Substrates/1'>Substrate</scene> and <scene name='90/907472/Product/2'>product</scene><br />
<br />
MAT consists of α and β subunits. MATα1 and MATα2 are catalytic subunits while MATβ is a regulatory subunit. The subunits are encoded on different genes in humans, so they are created separately and can then come together to form various complexes, such as MATαβ or MATα2 dimers <ref name="Murray et al." />.<br />
<br />
== Other Substrates ==<br />
<br />
== Relevance ==<br />
</StructureSection><br />
<br />
== References ==<br />
<references/></div>Anna Postnikova