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Chem Biol. 2010 Aug 27;17(8):892-902. doi: 10.1016/j.chembiol.2010.06.006.

Modulation of pantothenate kinase 3 activity by small molecules that interact with the substrate/allosteric regulatory domain.

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  • 1Department of Infectious Diseases, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.

Abstract

Pantothenate kinase (PanK) catalyzes the rate-controlling step in coenzyme A (CoA) biosynthesis. PanK3 is stringently regulated by acetyl-CoA and uses an ordered kinetic mechanism with ATP as the leading substrate. Biochemical analysis of site-directed mutants indicates that pantothenate binds in a tunnel adjacent to the active site that is occupied by the pantothenate moiety of the acetyl-CoA regulator in the PanK3acetyl-CoA binary complex. A high-throughput screen for PanK3 inhibitors and activators was applied to a bioactive compound library. Thiazolidinediones, sulfonylureas and steroids were inhibitors, and fatty acyl-amides and tamoxifen were activators. The PanK3 activators and inhibitors either stimulated or repressed CoA biosynthesis in HepG2/C3A cells. The flexible allosteric acetyl-CoA regulatory domain of PanK3 also binds the substrates, pantothenate and pantetheine, and small molecule inhibitors and activators to modulate PanK3 activity.

Copyright (c) 2010 Elsevier Ltd. All rights reserved.

PMID:
20797618
[PubMed - indexed for MEDLINE]
PMCID:
PMC2929395
Free PMC Article
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