?-Keto and ?-hydroxyphosphonate analogs of biotin-5'-AMP are inhibitors of holocarboxylase synthetase.

ABSTRACT: Holocarboxylase synthetase (HLCS) catalyzes the covalent attachment of biotin to cytoplasmic and mitochondrial carboxylases, nuclear histones, and over a hundred human proteins. Nonhydrolyzable ketophosphonate (?-ketoP) and hydroxyphosphonate (?-hydroxyP) analogs of biotin-5'-AMP inhibit holocarboxylase synthetase (HLCS) with IC50 values of 39.7 ?M and 203.7 ?M. By comparison, an IC50 value of 7 ?M was observed with the previously reported biotinol-5'-AMP. The Ki values, 3.4 ?M and 17.3 ?M, respectively, are consistent with the IC50 results, and close to the Ki obtained for biotinol-5'-AMP (7 ?M). The ?-ketoP and ?-hydroxyP molecules are competitive inhibitors of HLCS while biotinol-5'-AMP inhibited HLCS by a mixed mechanism.

SUBMITTER: Sittiwong W 

PROVIDER: S-EPMC4255142 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature