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An Investigation of the Catalytic Mechanism of S-adenosylmethionine Synthetase by QM/MM Calculations

Markham, George D.
Takusagawa, Fusao
DiJuliio, Anthony M.
Bock, Charles W.
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Abstract
Catalysis by S-adenosylmethionine synthetase has been investigated by quantum mechanical/molecular mechanical calculations, exploiting structures of the active crystalline enzyme. The transition state energy of +19.1 kcal/mol computed for a nucleophilic attack of the methionyl sulfur on carbon-5′ of the nucleotide was indistinguishable from the experimental (solution) value when the QM residues were an uncharged histidine that hydrogen bonds to the leaving oxygen-5′ and an aspartate that chelates a Mg2+ ion, and was similar (+18.8 kcal/mol) when the QM region also included the active site arginine and lysines. The computed energy difference between reactant and product was also consistent with their equimolar abundance in co-crystals. The calculated geometrical changes support catalysis of a SN2 reaction through hydrogen bonding of the liberated oxygen-5′ to the histidine, charge neutralization by the 2 Mg2+ ions, and stabilization of the product sulfonium cation through a close, non-bonded, contact between the sulfur and the ribose 4′-oxygen.
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Date
2010-12-01
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Publisher
Elsevier
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Keywords
S-adenosylmethionine, Methionine adenosyltransferase, Enzyme mechanism, Substrate-assisted-catalysis, QM/MM
Citation
Markham, George D., Fusao Takusagawa, Anthony M. Dijulio, and Charles W. Bock. "An Investigation of the Catalytic Mechanism of S-adenosylmethionine Synthetase by QM/MM Calculations." Archives of Biochemistry and Biophysics 492.1-2 (2009): 82-92.
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