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

Bioorg Med Chem Lett. 2014 Dec 15;24(24):5568-5571. doi: 10.1016/j.bmcl.2014.11.010. Epub 2014 Nov 7.

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 Ki values, 3.4 μM and 17.3 μM, respectively, are consistent with the IC50 results, and close to the Ki 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.

Keywords: Biotin-5′-AMP; Biotinylation; Holocarboxylase synthetase; β-Hydroxyphosphonate; β-Ketophosphonate.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Monophosphate / chemistry*
  • Biotin / chemistry*
  • Carbon-Nitrogen Ligases / antagonists & inhibitors*
  • Carbon-Nitrogen Ligases / metabolism
  • Humans
  • Ketones / chemistry
  • Kinetics
  • Organophosphonates / chemical synthesis
  • Organophosphonates / chemistry*
  • Organophosphonates / metabolism
  • Protein Binding

Substances

  • Ketones
  • Organophosphonates
  • Adenosine Monophosphate
  • Biotin
  • Carbon-Nitrogen Ligases
  • holocarboxylase synthetases