title: Catalysis in glycine N-methyltransferase: testing the electrostatic stabilization and compression hypothesis.
abstract: Glycine N-methyltransferase (GNMT) is an S-adenosyl-l-methionine dependent enzyme that catalyzes glycine transformation to sarcosine. Here, we present a hybrid quantum mechanics/molecular mechanics (QM/MM) computational study of the reaction compared to the counterpart process in water. The process takes place through an SN2 mechanism in both media with a transition state in which the transferring methyl group is placed in between the donor (SAM) and the acceptor (the amine group of glycine). Comparative analysis of structural, electrostatic, and electronic characteristics of the in-solution and enzymatic transition states allows us to get a deeper insight into the origins of the enzyme's catalytic power. We found that the enzyme is able to stabilize the substrate in its more active basic form by means of a positively charged residue (Arg175) placed in the active site. However, the maximum stabilization is attained for the transition state. In this case, the enzyme is able to form stronger hydrogen bonds with the positively charged amine group. Finally, we show that in agreement with previous computational studies on other methyltransferases, there is no computational evidence for the compression hypothesis, as was formulated by Schowen (Hegazi, M. F., Borchardt, R. T., and Schowen, R. L. (1979) J. Am. Chem. Soc. 101, 4359-4365).
authors.affiliation: Departament de Ciències Experimentals, Universitat Jaume I, 12071 Castellón, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Soriano
authors.forename: Raquel
authors.initials: R
authors.lastname: Castillo
authors.forename: Christo
authors.initials: C
authors.lastname: Christov
authors.forename: Juan
authors.initials: J
authors.lastname: Andrés
authors.forename: Vicente
authors.initials: V
authors.lastname: Moliner
authors.forename: Iñaki
authors.initials: I
authors.lastname: Tuñón
mesh_terms: D002384:Catalysis; D050938:Glycine N-Methyltransferase / Q000737:chemistry*; D008956:Models, Chemical; D012436:S-Adenosylmethionine / Q000737:chemistry*; D055672:Static Electricity
chemical_list: D012436:S-Adenosylmethionine; D050938:Glycine N-Methyltransferase