Methionine adenosyltransferase

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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 1 Relevance 2 Function and reaction mechanism 3 Structure 4 3D structures of S-adenosylmethionine synthetase 5 References

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

spinqualitylabelsall models Caption for this structure Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image MAT consists of α and β subunits. The MATα1 and 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 [4]. The 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 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 [5]. Gating Loop MAT has been shown to have a gating loop next to the active site [4]. 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. [4] 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. Structural highlights The biological assembly of rat S-adenosylmethionine synthetase is . The [6].

3D structures of S-adenosylmethionine synthetase

S-adenosylmethionine synthetase 3D structures

14-April-2022

References

1. ↑ 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
2. ↑ 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
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
4. ↑ ^{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
5. ↑ 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
6. ↑ 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