An investigation of the catalytic mechanism of S-adenosylmethionine synthetase by QM/MM calculations.
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 S(N)2 reaction through hydrogen bonding of the liberated oxygen-5' to the histidine, charge neutralization by the two Mg2+ ions, and stabilization of the product sulfonium cation through a close, non-bonded, contact between the sulfur and the ribose oxygen-4'.
Markham
George D
GD
Institute for Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA. gd_markham@fccc.edu
Takusagawa
Fusao
F
Dijulio
Anthony M
AM
Bock
Charles W
CW
D000266:Adenylyl Imidodiphosphate / Q000737:chemistry / Q000235:genetics; D002384:Catalysis; D020134:Catalytic Domain / Q000235:genetics; D003460:Crystallization; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000201:enzymology / Q000235:genetics; D029968:Escherichia coli Proteins / Q000737:chemistry* / Q000235:genetics; D008716:Methionine Adenosyltransferase / Q000737:chemistry* / Q000235:genetics; D016297:Mutagenesis, Site-Directed; D011789:Quantum Theory; D012436:S-Adenosylmethionine / Q000096:biosynthesis
D029968:Escherichia coli Proteins; D000266:Adenylyl Imidodiphosphate; D012436:S-Adenosylmethionine; D008716:Methionine Adenosyltransferase
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