title: β-Keto and β-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 (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.
authors.affiliation: Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588-0304, USA.
authors.forename: Wantanee
authors.initials: W
authors.lastname: Sittiwong
authors.affiliation: Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583-0806, USA.
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Cordonier
authors.affiliation: Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583-0806, USA. Electronic address: jzempleni2@unl.edu.
authors.forename: Janos
authors.initials: J
authors.lastname: Zempleni
authors.affiliation: Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588-0304, USA. Electronic address: pdussault1@unl.edu.
authors.forename: Patrick H
authors.initials: PH
authors.lastname: Dussault
mesh_terms: D000249:Adenosine Monophosphate / Q000737:chemistry*; D001710:Biotin / Q000737:chemistry*; D019731:Carbon-Nitrogen Ligases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007659:Ketones / Q000737:chemistry; D007700:Kinetics; D063065:Organophosphonates / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding
chemical_list: D007659:Ketones; D063065:Organophosphonates; D000249:Adenosine Monophosphate; D001710:Biotin; D019731:Carbon-Nitrogen Ligases; C023312:holocarboxylase synthetases
keywords: Biotin-5′-AMP; Biotinylation; Holocarboxylase synthetase; β-Hydroxyphosphonate; β-Ketophosphonate