Cuebas Dean A, Phillips Christopher, Schmitz Werner, Conzelmann Ernst, Novikov Dmitry K
Department of Chemistry, Southwest Missouri State University, Springfield, MO 65804, USA.
Biochem J. 2002 May 1;363(Pt 3):801-7. doi: 10.1042/0264-6021:3630801.
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.
根据目前的观点，第二条过氧化物酶体β-氧化途径负责胆汁酸中间体侧链的降解。过氧化物酶体多功能酶2型[过氧化物酶体多功能2-烯酰辅酶A水合酶/(R)-3-羟酰基辅酶A脱氢酶；MFE-2]催化该途径的第二步（水合）和第三步（脱氢）反应。MFE-2缺乏会导致血浆中极长链脂肪酸、2-甲基支链脂肪酸和C(27)胆汁酸中间体的积累，但胆汁酸合成并未完全受阻。在本研究中，我们描述了一条替代途径，该途径可以克服MFE-2缺乏。替代途径由α-甲基酰基辅酶A消旋酶和过氧化物酶体多功能酶1型[过氧化物酶体多功能2-烯酰辅酶A水合酶/(S)-3-羟酰基辅酶A脱氢酶；MFE-1]组成。推测的生理异构体(24E)-3α,7α,12α-三羟基-5β-胆甾-24-烯酰辅酶A由MFE-1水合形成(24S,25S)-3α,7α,12α,24-四羟基-5β-胆甾烷酰辅酶A[(24S,25S)-24-OH-THCA-CoA]，其经α-甲基酰基辅酶A消旋酶转化为(24S,25R)异构体后，可再次被MFE-1脱氢生成24-酮-3α,7α,12α-三羟基胆甾烷酰辅酶A，这是胆酸合成中的一种生理中间体。胆固醇侧链氧化替代途径的发现将通过鉴定血清24-OH-THCA-CoA非对映体谱来改善过氧化物酶体缺乏症的诊断。
