126.96.36.199 - Methionine adenosyltransferase
- AdoMet synthetase.
- S-adenosylmethionine synthetase.
ATP + H2O + L-methionine = diphosphate + phosphate + S-adenosyl-L-methionine
There are no Cofactors for this Enzyme
The catalytic site of this enzyme, found in a cleft between two subunits, conducts an unusual reaction pathway where a triphosphate chain is cleaved from ATP as AdoMet is formed and the triphosphate is hydrolysed to diphosphate and phosphate before the product is released. There are three similar domains arranged around a pseudo-threefold symmetry axis.
Mechanistic studies have shown the AdoMet forming reaction to follow an SN2 mechanism, with the S atom of methionine attacking the C5 atom of ATP directly. His29 acts as a general acid, activated by the surrounding basic backbone amide groups, towards the O5' as the C5'-O5' bond cleaves. Simultaneously, the methionine sulphur attacks the developing cation. This reaction is followed by the hydrolysis of triphosphate to phosphate and pyrophosphate, providing energy for the removal of the reaction product from the active site.
The reaction requires divalent metal cations for activity, two binding sites have been identified both by structural information and EPR studies.
|AA||Uniprot||Uniprot Resid||PDB||PDB Resid|
intermediate formation, intermediate terminated, native state of enzyme regenerated, dephosphorylation, overall reactant used, hydrolysis, bimolecular nucleophilic substitution, rate-determining step, intermediate collapse, proton transfer, overall product formed
The C5'-O5' bond of ATP dissociates, the phosphate of the leaving group deprotonates His29, the anionic histidine is stabilised by the main chain amides of Lys32 and Asp31. A simultaneous change in the ribose ring conformation from C4'-exo to C3'-endo occurs, and the SD of methionine makes a nucleophilic attack on the C5' to form S-adenosylmethionine. His29 deprotonates the leaving group in an overall nucleophilic substitution reaction.
Organism KM Value [mM] Substrate Comment Homo sapiens 0.076 S-(-)-methioninol pH 8.0, 37°C, wild-type enzyme Saccharolobus solfataricus 0.43 ATP pH 8.0, 37°C, cosubstrate: L-ethionine Plasmodium falciparum 1.5 ATP pH 8.4, 37°C, mutant enzyme Pyrococcus furiosus 65.2 ATP pH 8.0, 80°C
Organism Temperature Range Comment Streptomyces avermitilis 20 - 50 Lactiplantibacillus paraplantarum 20 - 50 more than 50% activity between 20 and 50°C. The activity is low below 20°C and above 55°C with less than 20% relative activity Escherichia coli 20 - 60 about 20% activity at 20°C, about 30% activity at 30°C, about 80% activity at 35°C, about 90% activity at 40°C, 100% at 45°C, about 850% activity at 50°C, about 45% activity at 60°C, and no activity at 70°C Bacillus subtilis 25 - 55 Thermus thermophilus 30 - 90 the enzyme shows activity at a broad temperature range, from 30 to 90°C. The reaction rate increases significantly with temperature, and reaches maximum at 80°C
Organism pH Range Comment Streptomyces avermitilis 5 - 10 Corynebacterium glutamicum 6 - 11 the activity is significantly reduced at pH values below 6.0 or above 11.0 Bacillus subtilis 6 - 10 Pyrococcus furiosus 7 - 9 half of the maximal activity at pH 7 and 9 Saccharomyces cerevisiae 7 - 10 more than 60% of maximum activity within
- Engineering of Methionine Adenosyltransferase Reveals Key Roles of Electrostatic Interactions in Enhanced Catalytic Activity.
- Discovery of novel methionine adenosyltransferase 2A (MAT2A) allosteric inhibitors by structure-based virtual screening.
- Dexmedetomidine alleviates the hypoxic-ischemic brain damage via miR-20a-5p/methionine adenosyltransferase 2B axis in rat pups: Erratum.
- High-Throughput Screening and Directed Evolution of Methionine Adenosyltransferase from Escherichia coli.
- Design and Structural Optimization of Methionine Adenosyltransferase 2A (MAT2A) Inhibitors with High In Vivo Potency and Oral Bioavailability.
- Long-term prognosis of 35 patients with methionine adenosyltransferase deficiency based on newborn screening in China.
- Methionine Adenosyltransferase I/III Deficiency Detected by Newborn Screening.
- Overview of Methionine Adenosyltransferase 2A (MAT2A) as an Anticancer Target: Structure, Function, and Inhibitors.
- Implications of divergence of methionine adenosyltransferase in archaea.
- mTORC1-independent translation control in mammalian cells by methionine adenosyltransferase 2A and S-adenosylmethionine.
- Polar Interactions at the Dimer-Dimer Interface of Methionine Adenosyltransferase MAT I Control Tetramerization.