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 ).
Publisher Copyright:
© 2014 Elsevier Ltd. All rights reserved.
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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U2 - 10.1016/j.bmcl.2014.11.010
DO - 10.1016/j.bmcl.2014.11.010
M3 - Article
C2 - 25466176
AN - SCOPUS:84911891567
VL - 24
SP - 5568
EP - 5571
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
SN - 0960-894X
IS - 24
ER -