Biosynthesis of Chenodeoxycholic Acid in Man

Shefer, Sarah; Cheng, F. W.; Batta, Ashok K.; Dayal, B.; Tint, G. S.; Salen, Gerald

doi:10.1172/jci109158

Cited by 35 publications

(6 citation statements)

References 20 publications

(8 reference statements)

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“…Because mitochondrial oxidation of the cholesterol side chain specifically affords the (25R) enantiomer [13], racemization seems to be an essential step in bile acid formation. Apart from its biological function, α-methylacyl-CoA racemase might also be interesting from a mechanistic point of view because it seems to act without any cofactor or prosthetic group.…”

Section: Introductionmentioning

confidence: 99%

Molecular cloning of cDNA species for rat and mouse liver α-methylacyl-CoA racemases

Schmitz

Helander

Hiltunen

et al. 1997

Biochemical Journal

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cDNA species coding for alpha-methylacyl-CoA racemase were cloned from rat and mouse liver cDNA libraries and characterized. The rat liver lambdagt11 cDNA expression library was screened with anti-racemase IgG [Schmitz, Albers, Fingerhut and Conzelmann (1995) Eur. J. Biochem.231, 815-822]. Several full-length clones were obtained that contained an open reading frame of 1083 bp, coding for a protein of 361 amino acid residues with a predicted molecular mass of 39679 Da. The sequences of three peptides that were isolated by HPLC from a tryptic digest of purified rat liver racemase fully matched the cDNA-derived amino acid sequence. The cDNA coding for mouse racemase was cloned from a mouse liver lambdaZAP cDNA expression library and sequenced. The coding region of 1080 bp codes for a 360-residue protein (molecular mass 39558 Da) that shares 89.7% similarity with the rat protein. Expression of the rat racemase as are combinant protein in Escherichia coli with the pTrcHisB-expression vector yielded enzymically active protein. The amino acid sequences of alpha-methylacyl-CoA racemases do not resemble any known sequence of beta-oxidation or auxiliary enzymes, supporting the view of a highly diverse evolutionary origin of enzymes acting on fatty acyl-CoA S-esters.

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Section: Introductionmentioning

confidence: 99%

Molecular cloning of cDNA species for rat and mouse liver α-methylacyl-CoA racemases

Schmitz

Helander

Hiltunen

et al. 1997

Biochemical Journal

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“…Sterol 27-hydroxylase, like most enzymes, recognizes the nonequivalence of the two methyl groups and catalyzes a stereospecific hydroxylation event, producing almost exclusively the 25(R) isomer (67,68). After activation of intermediates with coenzyme A by the bile acid ligase, the 25(R) isomers must be converted into 25(S) isomers before subsequent steps in side chain shortening can take place.…”

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confidence: 99%

The Enzymes, Regulation, and Genetics of Bile Acid Synthesis

Russell

2003

Annu. Rev. Biochem.

1,695

1,464

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The synthesis and excretion of bile acids comprise the major pathway of cholesterol catabolism in mammals. Synthesis provides a direct means of converting cholesterol, which is both hydrophobic and insoluble, into a water-soluble and readily excreted molecule, the bile acid. The biosynthetic steps that accomplish this transformation also confer detergent properties to the bile acid, which are exploited by the body to facilitate the secretion of cholesterol from the liver. This role in the elimination of cholesterol is counterbalanced by the ability of bile acids to solubilize dietary cholesterol and essential nutrients and to promote their delivery to the liver. The synthesis of a full complement of bile acids requires 17 enzymes. The expression of selected enzymes in the pathway is tightly regulated by nuclear hormone receptors and other transcription factors, which ensure a constant supply of bile acids in an ever changing metabolic environment. Inherited mutations that impair bile acid synthesis cause a spectrum of human disease; this ranges from liver failure in early childhood to progressive neuropathy in adults.

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“…The side chain of the diol is hydroxylated by mitochondrial sterol 27-hydroxylase (CYP27) (1)(2)(3) and finally transformed to chenodeoxycholic acid. On the other hand, the side chain of 5␤-cholestane-3␣,7␣,12␣-triol is hydroxylated by either mitochondrial CYP27 (2-4) or microsomal 5␤-cholestane-3␣,7␣,12␣-triol 25-hydroxylase (2,5,6), and the formed tetrols (5␤-cholestane-3␣,7␣,12␣,27-tetrol or 5␤-cholestane-3␣,7␣,12␣,25-tetrol) are eventually converted into cholic acid.…”

mentioning

confidence: 99%

“…Cerebrotendinous xanthomatosis (CTX) 1 is recessively inherited and caused by mutations in the CYP27 gene located on human chromosome 2 (10 -12). Clinical features in patients are tendon and brain xanthomas, premature atherosclerosis, and nervous system dysfunction including mental retardation, dementia, cerebellar ataxia, epileptic seizures, and peripheral neuropathy (13).…”

mentioning

confidence: 99%

Side Chain Hydroxylations in Bile Acid Biosynthesis Catalyzed by CYP3A Are Markedly Up-regulated in Cyp27 Mice but Not in Cerebrotendinous Xanthomatosis

Honda¹,

Salen²,

Matsuzaki³

et al. 2001

Journal of Biological Chemistry

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The accumulation of various 25-hydroxylated C 27 -bile alcohols in blood and their excretion in urine are characteristic features of cerebrotendinous xanthomatosis (CTX) a recessively inherited inborn error of bile acid synthesis caused by mutations in the mitochondrial sterol 27-hydroxylase (CYP27) gene. These bile alcohols may be intermediates in the alternative cholic acid side chain cleavage pathway. The present study was undertaken to identify enzymes and reactions responsible for the formation of these bile alcohols and to explain why Cyp27 ؊/؊ mice do not show CTX-related abnormalities. Microsomal activities of 5␤-cholestane-3␣,7␣,12␣-triol 25-and 26-hydroxylases, 5␤-cholestane-3␣,7␣,12␣,25-tetrol 23R-, 24S-, and 27-hydroxylases and testosterone 6␤-hydroxylase, a marker enzyme for CYP3A, in Cyp27 ؊/؊ mice livers were markedly up-regulated (5.5-, 3.5-, 6.5-, 7.5-, 2.9-, and 5.4-fold, respectively). In contrast, these enzyme activities were not increased in CTX. The activities of 5␤-cholestane-3␣,7␣,12␣-triol 25-and 26-hydroxylases and 5␤-cholestane-3␣,7␣,12␣,25-tetrol 23R-, 24R-, 24S-, and 27-hydroxylases were strongly correlated with the activities of testosterone 6␤-hydroxylase in control human liver microsomes from eight unrelated donors. Troleandomycin, a specific inhibitor of CYP3A, markedly suppressed these microsomal side chain hydroxylations in both mouse and human livers in a dosedependent manner. In addition, experiments using recombinant overexpressed human CYP3A4 confirmed that these microsomal side chain hydroxylations were catalyzed by a single enzyme, CYP3A4. The results demonstrate that microsomal 25-and 26-hydroxylations of 5␤-cholestane-3␣,7␣,12␣-triol and microsomal 23R-, 24R-, 24S-, and 27-hydroxylations of 5␤-cholestane-3␣,7␣,12␣,25-tetrol are mainly catalyzed by CYP3A in both mice and humans. Unlike Cyp27 ؊/؊ mice, CYP3A activity was not up-regulated despite marked accumulation of 5␤-cholestane-3␣,7␣,12␣-triol in CTX.

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Biosynthesis of Chenodeoxycholic Acid in Man

Cited by 35 publications

References 20 publications

Molecular cloning of cDNA species for rat and mouse liver α-methylacyl-CoA racemases

Molecular cloning of cDNA species for rat and mouse liver α-methylacyl-CoA racemases

The Enzymes, Regulation, and Genetics of Bile Acid Synthesis

Side Chain Hydroxylations in Bile Acid Biosynthesis Catalyzed by CYP3A Are Markedly Up-regulated in Cyp27 Mice but Not in Cerebrotendinous Xanthomatosis

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