Intrinsic evolutionary constraints on protease structure, enzyme acylation, and the identity of the catalytic triad.

ABSTRACT: The study of proteolysis lies at the heart of our understanding of biocatalysis, enzyme evolution, and drug development. To understand the degree of natural variation in protease active sites, we systematically evaluated simple active site features from all serine, cysteine and threonine proteases of independent lineage. This convergent evolutionary analysis revealed several interrelated and previously unrecognized relationships. The reactive rotamer of the nucleophile determines which neighboring amide can be used in the local oxyanion hole. Each rotamer-oxyanion hole combination limits the location of the moiety facilitating proton transfer and, combined together, fixes the stereochemistry of catalysis. All proteases that use an acyl-enzyme mechanism naturally divide into two classes acc

SUBMITTER: Buller AR 

PROVIDER: S-EPMC3581919 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature