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 Citations (Scopus)

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

Fingerprint

Adenosine Monophosphate
Inhibitory Concentration 50
Biotin
Histones
Molecules
5'-AMP-biotin
holocarboxylase synthetases
Proteins

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

Cite this

β-Keto and β-hydroxyphosphonate analogs of biotin-5′-AMP are inhibitors of holocarboxylase synthetase. / Sittiwong, Wantanee; Cordonier, Elizabeth L.; Zempleni, Janos; Dussault, Patrick H.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 24, No. 24, 15.12.2014, p. 5568-5571.

Research output: Contribution to journalArticle

@article{cd85df749a2a43989d22bbbf8437d4ee,
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}",
year = "2014",
month = "12",
day = "15",
doi = "10.1016/j.bmcl.2014.11.010",
language = "English (US)",
volume = "24",
pages = "5568--5571",
journal = "Bioorganic and Medicinal Chemistry Letters",
issn = "0960-894X",
publisher = "Elsevier Limited",
number = "24",

}

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

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

UR - http://www.scopus.com/inward/record.url?scp=84911891567&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84911891567&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2014.11.010

DO - 10.1016/j.bmcl.2014.11.010

M3 - Article

VL - 24

SP - 5568

EP - 5571

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

SN - 0960-894X

IS - 24

ER -