Understanding general acid-base catalysis of enzyme-catalyzed reactions from computer simulations: Serine-carboxyl peptidases

BIOL 282

Hong Guo, hguo1@utk.edu1, Haobo Guo, hguo2@utk.edu1, Qin Xu1, and Alex Wlodawer2. (1) Department of Biocehmistry & Cellular & Molecular Biology, University of Tennessee, M407 Walters Life Sciences, University of Tennessee, Knoxville, TN 37996, (2) Protein Structure Section, Macromolecular Crystallography Laboratory, National Cancer Institute at Frederick, Frederick, MD 21702
General acid-base transition-state stabilization is one of the most important strategies that enzymes use to catalyze chemical reactions and is used by a variety of enzymes including sedolisins (serine-carboxyl peptidases), a recently characterized family of proteolytic enzymes. Sedolisins have a fold resembling that of subtilisin and a maximal activity at low pH. The defining features of this family are a unique catalytic triad, Ser-Glu-Asp, as well as the presence of an aspartic acid residue that occupies the same position as Asn155 of subtilisin, a residue that creates the oxyanion hole in that classical serine protease. We demonstrate from quantum mechanical/molecular mechanical (QM/MM) molecular dynamics (MD) simulations that unlike serine proteases that use the oxyanion-hole interactions to achieve the electrostatic stabilization of the tetrahedral intermediate and adduct, the members of sedolisin family may stabilize the tetrahedral intermediate and adduct primarily through a general acid-base mechanism (i.e., similar to the mechanism proposed for aspartic proteases).
 

Enzymes
4:30 PM-6:30 PM, Wednesday, 13 September 2006 Moscone Center -- Hall D, Poster

Division of Biological Chemistry

The 232nd ACS National Meeting, San Francisco, CA, September 10-14, 2006