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标题：Aberrant pathways in the late stages of cholesterol biosynthesis in the rat: origin and metabolic fate of unsaturated sterols relevant to the Smith-Lemli-Opitz syndrome
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作者：Benfang Ruan ; James Tsai ; William K. Wilson 等
期刊名称：JLR Papers In Press
印刷版ISSN：0022-2275
电子版ISSN：1539-7262
出版年度：2000
卷号：41
期号：11
页码：1772-1782
语种：English
出版社：American Society for Biochemistry and Molecular Biology
摘要：Minor aberrant pathways of cholesterol biosynthesis normally produce only trace levels of abnormal sterol metabolites but may assume major importance when an essential biosynthetic step is blocked. Cholesta-5,8-dien-3β-ol, its Δ^5,7 isomer, and other noncholesterol sterols accumulate in subjects with the Smith-Lemli-Opitz syndrome (SLOS), a severe developmental disorder caused by a defective Δ⁷ sterol reductase gene. We have explored the formation and metabolism of unsaturated sterols relevant to SLOS by incubating tritium-labeled Δ^5,8, Δ^6,8, Δ^6,8(14), Δ^5,8(14), and Δ⁸ sterols with rat liver preparations. More than 60 different incubations were carried out with washed microsomes or the 10,000 g supernatant under aerobic or anaerobic conditions; some experiments included addition of cofactors, fenpropimorph (a Δ⁸–Δ⁷ isomerase inhibitor), and/or AY-9944 (a Δ⁷ reductase inhibitor). The tritium-labeled metabolites from each incubation were identified by silver ion high performance liquid chromatography on the basis of their coelution with unlabeled authentic standards, as free sterols and/or acetate derivatives. The Δ^5,8 sterol was converted slowly to cholesterol via the Δ^5,7 sterol, which also slowly isomerized back to the Δ^5,8 sterol. The Δ^6,8 sterol was metabolized rapidly to cholesterol by an oxygen-requiring pathway via the Δ^7,9(11), Δ⁸, Δ⁷, and Δ^5,7 sterols as well as by an oxygen-independent route involving initial isomerization to the Δ^5,7 sterol. The Δ⁸ sterol was partially metabolized to Δ^5,8, Δ^6,8, Δ^7,9(11), and Δ^5,7,9(11) sterols when isomerization to Δ⁷ was blocked. The combined results were used to formulate a scheme of normal and aberrant biosynthetic pathways that illuminate the origin and metabolic fate of abnormal sterols observed in SLOS and chondrodysplasia punctata. —Ruan, B., J. Tsai, W. K. Wilson, and G. J. Schroepfer, Jr. Aberrant pathways in the late stages of cholesterol biosynthesis in the rat: origin and metabolic fate of unsaturated sterols relevant to the Smith-Lemli-Opitz syndrome. J. Lipid Res. 2000. 41: 1772–1782.
关键词：cholesta-5,8-dien-3β-ol ; Ag⁺-HPLC ; microsomes ; tritium-labeled substrates ; Δ⁸–Δ⁷ sterol isomerase ; Δ⁵desaturase ; Δ⁷ reductase ; SLOS