Methionine adenosyltransferase
From Proteopedia
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| - | [[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. | + | [[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. |
== Relevance == | == Relevance == | ||
| - | 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. | + | 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>. |
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| + | == Function and reaction mechanism == | ||
| + | '''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>. | ||
| - | == Reaction mechanism == | ||
[[Image:Sam rxn 2.jpg|800px]] | [[Image:Sam rxn 2.jpg|800px]] | ||
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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. | 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. | ||
| - | == Other Substrates == | ||
| - | == Function == | ||
| - | '''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>. | ||
| - | == Relevance == | ||
| - | Methionine metabolism impairment in liver diseases is related in alteration in MAT<ref>PMID:7741002</ref>. | ||
== Structural highlights == | == Structural highlights == | ||
Revision as of 13:38, 14 April 2022
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.
Contents |
Relevance
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[1]. 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[2].
Function and reaction mechanism
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[3].
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) [4]. 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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3D structures of S-adenosylmethionine synthetase
S-adenosylmethionine synthetase 3D structures
14-April-2022
References
- ↑ Hanzelmann P, Schindelin H. Crystal structure of the S-adenosylmethionine-dependent enzyme MoaA and its implications for molybdenum cofactor deficiency in humans. Proc Natl Acad Sci U S A. 2004 Aug 31;101(35):12870-5. Epub 2004 Aug 18. PMID:15317939 doi:10.1073/pnas.0404624101
- ↑ 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
- ↑ 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
- ↑ 4.0 4.1 4.2 4.3 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;60 (10) 791-801. doi: https://doi.org/10.1021/acs.biochem.0c00998
- ↑ 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
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