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?-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

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

Sittiwong Wantanee W Cordonier Elizabeth L EL Zempleni Janos J Dussault Patrick H PH

Bioorganic & medicinal chemistry letters 20141107 24

Holocarboxylase synthetase (HLCS) catalyzes the covalent attachment of biotin to cytoplasmic and mitochondrial carboxylases, nuclear histones, and over a hundred human proteins. Nonhydrolyzable ketophosphonate (β-ketoP) and hydroxyphosphonate (β-hydroxyP) analogs of biotin-5'-AMP inhibit holocarboxylase synthetase (HLCS) with IC50 values of 39.7 μM and 203.7 μM. By comparison, an IC50 value of 7 μM was observed with the previously reported biotinol-5'-AMP. The Ki values, 3.4 μM and 17.3 μM, resp ...[more]

PMID: 25466176

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