title: The role of alpha-methylacyl-CoA racemase in bile acid synthesis.
abstract: According to current views, the second peroxisomal beta-oxidation pathway is responsible for the degradation of the side chain of bile acid intermediates. Peroxisomal multifunctional enzyme type 2 [peroxisomal multifunctional 2-enoyl-CoA hydratase/(R)-3-hydroxyacyl-CoA dehydrogenase; MFE-2] catalyses the second (hydration) and third (dehydrogenation) reactions of the pathway. Deficiency of MFE-2 leads to accumulation of very-long-chain fatty acids, 2-methyl-branched fatty acids and C(27) bile acid intermediates in plasma, but bile acid synthesis is not blocked completely. In this study we describe an alternative pathway, which allows MFE-2 deficiency to be overcome. The alternative pathway consists of alpha-methylacyl-CoA racemase and peroxisomal multifunctional enzyme type 1 [peroxisomal multifunctional 2-enoyl-CoA hydratase/(S)-3-hydroxyacyl-CoA dehydrogenase; MFE-1]. (24E)-3alpha,7alpha,12alpha-Trihydroxy-5beta-cholest-24-enoyl-CoA, the presumed physiological isomer, is hydrated by MFE-1 with the formation of (24S,25S)-3alpha,7alpha,12alpha,24-tetrahydroxy-5beta-cholestanoyl-CoA [(24S,25S)-24-OH-THCA-CoA], which after conversion by a alpha-methylacyl-CoA racemase into the (24S,25R) isomer can again be dehydrogenated by MFE-1 to 24-keto-3alpha,7alpha,12alpha-trihydroxycholestanoyl-CoA, a physiological intermediate in cholic acid synthesis. The discovery of the alternative pathway of cholesterol side-chain oxidation will improve diagnosis of peroxisomal deficiencies by identification of serum 24-OH-THCA-CoA diastereomer profiles.
authors.affiliation: Department of Chemistry, Southwest Missouri State University, Springfield, MO 65804, USA.
authors.forename: Dean A
authors.initials: DA
authors.lastname: Cuebas
authors.forename: Christopher
authors.initials: C
authors.lastname: Phillips
authors.forename: Werner
authors.initials: W
authors.lastname: Schmitz
authors.forename: Ernst
authors.initials: E
authors.lastname: Conzelmann
authors.forename: Dmitry K
authors.initials: DK
authors.lastname: Novikov
mesh_terms: D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000378:metabolism / Q000502:physiology; D000214:Acyl Coenzyme A / Q000378:metabolism; D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis*; D002784:Cholesterol / Q000031:analogs & derivatives* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004746:Enoyl-CoA Hydratase / Q000378:metabolism / Q000502:physiology; D007535:Isomerases / Q000502:physiology; D008956:Models, Chemical; D009097:Multienzyme Complexes / Q000378:metabolism / Q000502:physiology; D063994:Peroxisomal Bifunctional Enzyme; D019998:Racemases and Epimerases / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D013237:Stereoisomerism
chemical_list: D000214:Acyl Coenzyme A; D001647:Bile Acids and Salts; D009097:Multienzyme Complexes; C059108:3,7,12-trihydroxycholest-24-enoic acid; D002784:Cholesterol; D015094:3-Hydroxyacyl CoA Dehydrogenases; D004746:Enoyl-CoA Hydratase; D063994:Peroxisomal Bifunctional Enzyme; D007535:Isomerases; D019998:Racemases and Epimerases; C108352:alpha-methylacyl-CoA racemase