title: An investigation of the catalytic mechanism of S-adenosylmethionine synthetase by QM/MM calculations.
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 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'.
authors.affiliation: Institute for Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA. gd_markham@fccc.edu
authors.forename: George D
authors.initials: GD
authors.lastname: Markham
authors.forename: Fusao
authors.initials: F
authors.lastname: Takusagawa
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Dijulio
authors.forename: Charles W
authors.initials: CW
authors.lastname: Bock
mesh_terms: 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
chemical_list: D029968:Escherichia coli Proteins; D000266:Adenylyl Imidodiphosphate; D012436:S-Adenosylmethionine; D008716:Methionine Adenosyltransferase
references.citation: J Biol Chem. 1981 Feb 25;256(4):1903-9
references.pmid: 6257692
references.citation: J Phys Chem B. 2007 Nov 29;111(47):13455-64
references.pmid: 17983217
references.citation: Biochemistry. 2000 Apr 18;39(15):4443-54
references.pmid: 10757994
references.citation: Biochemistry. 1999 Feb 23;38(8):2542-50
references.pmid: 10029549
references.citation: Annu Rev Plant Biol. 2004;55:41-68
references.pmid: 15725056
references.citation: Phys Rev B Condens Matter. 1988 Jan 15;37(2):785-789
references.pmid: 9944570
references.citation: J Mol Biol. 2004 Jan 16;335(3):693-706
references.pmid: 14687567
references.citation: Nat Prod Rep. 2002 Aug;19(4):390-412
references.pmid: 12195810
references.citation: J Biol Chem. 2000 Feb 11;275(6):4060-5
references.pmid: 10660564
references.citation: Biochemistry. 2007 Dec 25;46(51):14838-44
references.pmid: 18044969
references.citation: J Mol Biol. 2003 Aug 8;331(2):407-16
references.pmid: 12888348
references.citation: J Biol Chem. 1995 Aug 4;270(31):18484-90
references.pmid: 7629176
references.citation: Acta Crystallogr B. 1993 Aug 1;49 ( Pt 4):738-44
references.pmid: 8397982
references.citation: Trends Biochem Sci. 2007 Mar;32(3):101-10
references.pmid: 17291766
references.citation: J Biomol Struct Dyn. 1996 Apr;13(5):727-39
references.pmid: 8723769
references.citation: Q Rev Biophys. 2003 Feb;36(1):91-145
references.pmid: 12643044
references.citation: J Biol Chem. 1999 Nov 12;274(46):32909-14
references.pmid: 10551856
references.citation: J Comput Chem. 2004 Oct;25(13):1605-12
references.pmid: 15264254
references.citation: Biochemistry. 2000 May 30;39(21):6267-74
references.pmid: 10828939
references.citation: J Am Chem Soc. 2007 Mar 21;129(11):3135-47
references.pmid: 17326634
references.citation: N Engl J Med. 2008 Mar 13;358(11):1148-59
references.pmid: 18337604
references.citation: Proc Natl Acad Sci U S A. 2006 Apr 18;103(16):6148-53
references.pmid: 16606828
references.citation: J Org Chem. 2008 Feb 1;73(3):889-99
references.pmid: 18179229
references.citation: Biochemistry. 1996 Feb 27;35(8):2586-96
references.pmid: 8611562
references.citation: J Biol Chem. 1987 Apr 25;262(12):5609-15
references.pmid: 3553181
references.citation: Biochemistry. 2004 Feb 24;43(7):1821-31
references.pmid: 14967023
references.citation: Int J Biochem Cell Biol. 2000 Apr;32(4):391-5
references.pmid: 10762064
references.citation: Annu Rev Biochem. 1975;44:435-51
references.pmid: 1094914
references.citation: Acc Chem Res. 2002 Mar;35(3):139-48
references.pmid: 11900517
references.citation: J Gastroenterol Hepatol. 2008 Mar;23 Suppl 1:S73-7
references.pmid: 18336669
references.citation: Cancer Res. 1988 Feb 15;48(4):759-74
references.pmid: 3123052
references.citation: Biochemistry. 2002 Jul 30;41(30):9358-69
references.pmid: 12135357
references.citation: Cell Mol Life Sci. 2009 Feb;66(4):636-48
references.pmid: 18953685
references.citation: J Am Chem Soc. 2006 Feb 1;128(4):1272-8
references.pmid: 16433545
references.citation: Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16141-6
references.pmid: 17053070
references.citation: J Biol Chem. 1995 Aug 4;270(31):18277-84
references.pmid: 7629147
references.citation: J Biol Chem. 1980 Oct 10;255(19):9082-92
references.pmid: 6251075
references.citation: J Biol Inorg Chem. 2001 Mar;6(3):209-26
references.pmid: 11315557
references.citation: Annu Rev Biophys Biomol Struct. 2003;32:425-43
references.pmid: 12574064
references.citation: J Biol Chem. 2007 Jan 26;282(4):2596-605
references.pmid: 17121823
references.citation: Biochemistry. 2002 Jun 18;41(24):7636-46
references.pmid: 12056895
references.citation: Biochemistry. 2008 Mar 4;47(9):2743-8
references.pmid: 18260647
references.citation: Biochemistry. 2001 Jan 16;40(2):361-74
references.pmid: 11148030
references.citation: Annu Rev Phys Chem. 2005;56:389-427
references.pmid: 15796706
references.citation: Biochemistry. 1991 Jul 16;30(28):6948-56
references.pmid: 2069953
references.citation: J Biol Chem. 1997 Mar 28;272(13):8105-8
references.pmid: 9139042
references.citation: Chem Rev. 2006 Aug;106(8):3210-35
references.pmid: 16895325
references.citation: Annu Rev Biochem. 1984;53:749-90
references.pmid: 6206782
references.citation: Biochemistry. 1993 Apr 27;32(16):4338-43
references.pmid: 8476863
references.citation: J Am Chem Soc. 2002 Apr 17;124(15):4097-107
references.pmid: 11942849
references.citation: Biochemistry. 1998 May 5;37(18):6247-55
references.pmid: 9572839
references.citation: Curr Opin Chem Biol. 2007 Apr;11(2):182-7
references.pmid: 17307018
references.citation: Biochemistry. 1998 Sep 29;37(39):13499-506
references.pmid: 9753435
references.citation: Biochemistry. 2006 Dec 19;45(50):14917-25
references.pmid: 17154529
references.citation: J Biol Chem. 2000 Feb 11;275(6):4055-9
references.pmid: 10660563
references.citation: J Comput Chem. 2006 Sep;27(12):1324-37
references.pmid: 16788908