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

Wantanee Sittiwong, Elizabeth L. Cordonier, Janos Zempleni, Patrick H. Dussault

Research output: Contribution to journalArticle

7 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)5568-5571
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume24
Issue number24
DOIs
StatePublished - Dec 15 2014

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Keywords

  • Biotin-50-AMP
  • Biotinylation
  • Holocarboxylase synthetase
  • β-Hydroxyphosphonate
  • β-Ketophosphonate

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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