Participation of two members of the very long-chain acyl-CoA synthetase family in bile acid synthesis and recycling.
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.
Mihalik
Stephanie J
SJ
Kennedy Krieger Institute and the Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Steinberg
Steven J
SJ
Pei
Zhengtong
Z
Park
Joseph
J
Kim
Do G
DG
Heinzer
Ann K
AK
Dacremont
Georges
G
Wanders
Ronald J A
RJ
Cuebas
Dean A
DA
Smith
Kirby D
KD
Watkins
Paul A
PA
D001647:Bile Acids and Salts / Q000096:biosynthesis / Q000378:metabolism*; D002635:Chenodeoxycholic Acid / Q000378:metabolism; D019826:Cholic Acid / Q000494:pharmacology; D003001:Cloning, Molecular; D003066:Coenzyme A Ligases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008969:Molecular Sequence Data; D016366:Open Reading Frames; D016133:Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000378:metabolism; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D013237:Stereoisomerism; D013379:Substrate Specificity; D000098859:Long-Chain-Fatty-Acid-CoA Ligase
D001647:Bile Acids and Salts; D017931:DNA Primers; D011994:Recombinant Proteins; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D002635:Chenodeoxycholic Acid; D003066:Coenzyme A Ligases; C090799:FAA2 protein, S cerevisiae; D000098859:Long-Chain-Fatty-Acid-CoA Ligase; D019826:Cholic Acid