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

Authors

Wantanee Sittiwong, University of Nebraska - LincolnFollow
Elizabeth Cordonier, University of Nebraska-LincolnFollow
Janos Zempleni, University of Nebraska - LincolnFollow
Patrick Dussault, University of Nebraska-LincolnFollow

Date of this Version

2014

Citation

Bioorg Med Chem Lett. 2014 December 15; 24(24): 5568–5571.

Comments

Copyright 2009 Elsevier Ltd. All rights reserved

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 (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 K_i values, 3.4 μM and 17.3 μM, respectively, are consistent with the IC50 results, and close to the K_i obtained for biotinol-5'-AMP (7 μM). The β-ketoP and β-hydroxyP molecules are competitive inhibitors of HLCS while biotinol-5'-AMP inhibited HLCS by a mixed mechanism.