Chemical knockout of pantothenate kinase reveals the metabolic and genetic program responsible for hepatic coenzyme A homeostasis.

Published

Journal Article

Coenzyme A (CoA) is the major acyl group carrier in intermediary metabolism. Hopantenate (HoPan), a competitive inhibitor of the pantothenate kinases, was used to chemically antagonize CoA biosynthesis. HoPan dramatically reduced liver CoA and mice developed severe hypoglycemia. Insulin was reduced, glucagon and corticosterone were elevated, and fasting accelerated hypoglycemia. Metabolic profiling revealed a large increase in acylcarnitines, illustrating the role of carnitine in buffering acyl groups to maintain the nonesterified CoASH level. HoPan triggered significant changes in hepatic gene expression that substantially increased the thioesterases, which liberate CoASH from acyl-CoA, and increased pyruvate dehydrogenase kinase 1, which prevents the conversion of CoASH to acetyl-CoA. These results identify the metabolic rearrangements that maintain the CoASH pool which is critical to mitochondrial functions, including gluconeogenesis, fatty acid oxidation, and the tricarboxylic acid and urea cycles.

Full Text

Duke Authors

Cited Authors

  • Zhang, Y-M; Chohnan, S; Virga, KG; Stevens, RD; Ilkayeva, OR; Wenner, BR; Bain, JR; Newgard, CB; Lee, RE; Rock, CO; Jackowski, S

Published Date

  • March 2007

Published In

Volume / Issue

  • 14 / 3

Start / End Page

  • 291 - 302

PubMed ID

  • 17379144

Pubmed Central ID

  • 17379144

International Standard Serial Number (ISSN)

  • 1074-5521

Digital Object Identifier (DOI)

  • 10.1016/j.chembiol.2007.01.013

Language

  • eng

Conference Location

  • United States