Methionine adenosyltransferase
From Proteopedia
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[[Image:Sam rxn 2.jpg|800px]] | [[Image:Sam rxn 2.jpg|800px]] | ||
| - | The | + | 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. |
== Structure == | == Structure == | ||
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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." />. | 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." />. | ||
| - | 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 | + | 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>. |
== Gating Loop == | == Gating Loop == | ||
Revision as of 15:14, 11 April 2022
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.
Contents |
Relevance
Active Site Mechanism
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) [1]. 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.
Structure
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References
- ↑ 1.0 1.1 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
- ↑ Niland CN, Ghosh A, Cahill SM, Schramm VL. Mechanism and Inhibition of Human Methionine Adenosyltransferase 2A. ACS Biochemistry. 2021 Mar 3
- ↑ Takusagawa F, Kamitori S, Markham GD. Structure and function of S-adenosylmethionine synthetase: crystal structures of S-adenosylmethionine synthetase with ADP, BrADP, and PPi at 28 angstroms resolution. Biochemistry. 1996 Feb 27;35(8):2586-96. PMID:8611562 doi:http://dx.doi.org/10.1021/bi952604z
- ↑ Mato JM, Alvarez L, Ortiz P, Mingorance J, Duran C, Pajares MA. S-adenosyl-L-methionine synthetase and methionine metabolism deficiencies in cirrhosis. Adv Exp Med Biol. 1994;368:113-7. PMID:7741002
- ↑ Gonzalez B, Pajares MA, Hermoso JA, Guillerm D, Guillerm G, Sanz-Aparicio J. Crystal structures of methionine adenosyltransferase complexed with substrates and products reveal the methionine-ATP recognition and give insights into the catalytic mechanism. J Mol Biol. 2003 Aug 8;331(2):407-16. PMID:12888348
3D structures of S-adenosylmethionine synthetase
S-adenosylmethionine synthetase 3D structures
11-April-2022
References
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