Participation of two members of the very long-chain acyl-CoA synthetase family in bile acid synthesis and recycling

J Biol Chem. 2002 Jul 5;277(27):24771-9. doi: 10.1074/jbc.M203295200. Epub 2002 Apr 29.

Abstract

Bile acids are synthesized de novo in the liver from cholesterol and conjugated to glycine or taurine via a complex series of reactions involving multiple organelles. Bile acids secreted into the small intestine are efficiently reabsorbed and reutilized. Activation by thioesterification to CoA is required at two points in bile acid metabolism. First, 3alpha,7alpha,12alpha-trihydroxy-5beta-cholestanoic acid, the 27-carbon precursor of cholic acid, must be activated to its CoA derivative before side chain cleavage via peroxisomal beta-oxidation. Second, reutilization of cholate and other C24 bile acids requires reactivation prior to re-conjugation. We reported previously that homolog 2 of very long-chain acyl-CoA synthetase (VLCS) can activate cholate (Steinberg, S. J., Mihalik, S. J., Kim, D. G., Cuebas, D. A., and Watkins, P. A. (2000) J. Biol. Chem. 275, 15605-15608). We now show that this enzyme also activates chenodeoxycholate, the secondary bile acids deoxycholate and lithocholate, and 3alpha,7alpha,12alpha-trihydroxy-5beta-cholestanoic acid. In contrast, VLCS activated 3alpha,7alpha,12alpha-trihydroxy-5beta-cholestanoate, but did not utilize any of the C24 bile acids as substrates. We hypothesize that the primary function of homolog 2 is in the reactivation and recycling of C24 bile acids, whereas VLCS participates in the de novo synthesis pathway. Results of in situ hybridization, topographic orientation, and inhibition studies are consistent with the proposed roles of these enzymes in bile acid metabolism.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Bile Acids and Salts / biosynthesis
  • Bile Acids and Salts / metabolism*
  • Chenodeoxycholic Acid / metabolism
  • Cholic Acid / pharmacology
  • Cloning, Molecular
  • Coenzyme A Ligases / antagonists & inhibitors
  • Coenzyme A Ligases / genetics
  • Coenzyme A Ligases / metabolism*
  • DNA Primers
  • Humans
  • Kinetics
  • Liver / enzymology
  • Molecular Sequence Data
  • Open Reading Frames
  • Polymerase Chain Reaction
  • Recombinant Proteins / metabolism
  • Repressor Proteins*
  • Saccharomyces cerevisiae Proteins*
  • Stereoisomerism
  • Substrate Specificity

Substances

  • Bile Acids and Salts
  • DNA Primers
  • Recombinant Proteins
  • Repressor Proteins
  • Saccharomyces cerevisiae Proteins
  • Chenodeoxycholic Acid
  • Coenzyme A Ligases
  • FAA2 protein, S cerevisiae
  • long-chain-fatty-acid-CoA ligase
  • Cholic Acid

Associated data

  • GENBANK/AF033031