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

doi:10.1016/j.bmcl.2014.11.010

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 journal › Article

9 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 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.

Original language	English (US)
Pages (from-to)	5568-5571
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	24
Issue number	24
DOIs	https://doi.org/10.1016/j.bmcl.2014.11.010
State	Published - Dec 15 2014

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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Sittiwong, W., Cordonier, E. L., Zempleni, J., & Dussault, P. H. (2014). β-Keto and β-hydroxyphosphonate analogs of biotin-5′-AMP are inhibitors of holocarboxylase synthetase. Bioorganic and Medicinal Chemistry Letters, 24(24), 5568-5571. https://doi.org/10.1016/j.bmcl.2014.11.010

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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.",

keywords = "Biotin-50-AMP, Biotinylation, Holocarboxylase synthetase, β-Hydroxyphosphonate, β-Ketophosphonate",

author = "Wantanee Sittiwong and Cordonier, {Elizabeth L.} and Janos Zempleni and Dussault, {Patrick H.}",

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AU - Sittiwong, Wantanee

AU - Cordonier, Elizabeth L.

AU - Zempleni, Janos

AU - Dussault, Patrick H.

PY - 2014/12/15

Y1 - 2014/12/15

N2 - 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.

AB - 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.

KW - Biotin-50-AMP

KW - Biotinylation

KW - Holocarboxylase synthetase

KW - β-Hydroxyphosphonate

KW - β-Ketophosphonate

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