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 › peer-review

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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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.}",

note = "Funding Information: A contribution of the University of Nebraska Agricultural Research Division , supported in part by funds provided through the Hatch Act (to P.D. and J.Z.). Additional support was provided by NIH grants DK063945 and P20GM104320 (to J.Z.). Research was conducted, in part, in facilities remodeled with support from NIH ( RR016544 ). ",

year = "2014",

month = dec,

day = "15",

doi = "10.1016/j.bmcl.2014.11.010",

language = "English (US)",

volume = "24",

pages = "5568--5571",

journal = "Bioorganic and Medicinal Chemistry Letters",

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TY - JOUR

T1 - β-Keto and β-hydroxyphosphonate analogs of biotin-5′-AMP are inhibitors of holocarboxylase synthetase

AU - Sittiwong, Wantanee

AU - Cordonier, Elizabeth L.

AU - Zempleni, Janos

AU - Dussault, Patrick H.

N1 - Funding Information: A contribution of the University of Nebraska Agricultural Research Division , supported in part by funds provided through the Hatch Act (to P.D. and J.Z.). Additional support was provided by NIH grants DK063945 and P20GM104320 (to J.Z.). Research was conducted, in part, in facilities remodeled with support from NIH ( RR016544 ).

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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