| 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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MedLine Citation:
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PMID: 11060346 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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-3beta-ol, its Delta(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 Delta(7) sterol reductase gene. We have explored the formation and metabolism of unsaturated sterols relevant to SLOS by incubating tritium-labeled Delta(5,8), Delta(6, 8), Delta(6,8(14)), Delta(5,8(14)), and Delta(8) 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 Delta(8);-Delta(7) isomerase inhibitor), and/or AY-9944 (a Delta(7) 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 Delta(5,8) sterol was converted slowly to cholesterol via the Delta(5,7) sterol, which also slowly isomerized back to the Delta(5,8) sterol. The Delta(6,8) sterol was metabolized rapidly to cholesterol by an oxygen-requiring pathway via the Delta(7,9(11)), Delta(8), Delta(7), and Delta(5,7) sterols as well as by an oxygen-independent route involving initial isomerization to the Delta(5,7) sterol. The Delta(8) sterol was partially metabolized to Delta(5,8), Delta(6,8), Delta(7,9(11)), and Delta(5,7,9(11)) sterols when isomerization to Delta(7) 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. |
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Authors:
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B Ruan; J Tsai; W K Wilson; G J Schroepfer |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Journal of lipid research Volume: 41 ISSN: 0022-2275 ISO Abbreviation: J. Lipid Res. Publication Date: 2000 Nov |
Date Detail:
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Created Date: 2000-11-29 Completed Date: 2001-02-08 Revised Date: 2012-05-25 |
Medline Journal Info:
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Nlm Unique ID: 0376606 Medline TA: J Lipid Res Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 1772-82 Citation Subset: IM |
Affiliation:
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Department of Biochemistry and Cell Biology, Rice University, Houston, TX 77005, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Aerobiosis Anaerobiosis Animals Cholesterol / biosynthesis*, metabolism Chromatography, High Pressure Liquid Dehydrocholesterols / metabolism Enzyme Inhibitors / pharmacology Female Magnetic Resonance Spectroscopy Microsomes, Liver / enzymology Oxidoreductases / antagonists & inhibitors, metabolism Oxidoreductases Acting on CH-CH Group Donors* Rats Rats, Sprague-Dawley Smith-Lemli-Opitz Syndrome / metabolism* Sterols / metabolism* Tritium |
| Grant Support | |
ID/Acronym/Agency:
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HL-49122/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Dehydrocholesterols; 0/Enzyme Inhibitors; 0/Sterols; 10028-17-8/Tritium; 57-88-5/Cholesterol; 80-99-9/lathosterol; EC 1.-/Oxidoreductases; EC 1.14.21.6/lathosterol delta-5-dehydrogenase; EC 1.3.-/Oxidoreductases Acting on CH-CH Group Donors |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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