Theoretical and Mechanistic Validation of Global Kinetic Parameters of the Inactivation of GABA Aminotransferase by OV329 and CPP-115.

ABSTRACT: ((S)-3-Amino-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid (OV329) is a recently discovered inactivator of γ-aminobutyric acid aminotransferase (GABA-AT), which has 10 times better inactivation efficiency than its predecessor, CPP-115, despite the only structural difference being an endocyclic double bond in OV329. Both compounds are mechanism-based enzyme inactivators (MBEIs), which inactivate GABA-AT by a similar mechanism. Here, a combination of a variety of computational chemistry tools and experimental methods, including quantum mechanical (QM) calculations, molecular dynamic simulations, progress curve analysis, and deuterium kinetic isotope effect (KIE) experiments, are utilized to comprehensively study the mechanism of inactivation of GABA-AT by CPP-115 and OV329 and

SUBMITTER: Weerawarna PM 

PROVIDER: S-EPMC8371712 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature