This research program concerns multiple ongoing projects dealing with the biochemistry, chemistry, and actions of sterols, sphingolipid bases (and their derivatives), and isoprenoid alcohols and acids as well as potential interrelationships in their metabolism and actions. One major project concerns the chemistry, actions, and metabolism of certain 4,4-dimethylsterols very recently found to affect meiosis in mammalian oocytes. Another major focus involves the chemical nature and metabolism of C27 sterols found to accumulate in tissues of subjects with the Smith-Lemli-Opitz syndrome, an hereditary disorder of development associated with a defect in the late stage of cholesterol biosynthesis. Another hereditary disorder of development, suggested to be a defect in squalene epoxidase, is also being studied. Several projects involve studies of the biochemistry and actions of different oxysterols as potential inducers of calcification in specialized cells of arteries (calcifying vascular cells), a subject of importance in the pathogenesis and detection of atherosclerotic lesions. Also included are fundamental studies of the actions of a variety of oxysterols on cholesterol esterification and their actions on acyl coenzyme A-cholesterol acyltransferase, studies of relevance to the intestinal absorption of cholesterol and the pathogenesis of atherosclerosis. Other studies concern the effects of selected oxysterols on the nuclear orphan receptor LXRalpha, recently shown to be important in the in vivo regulation of cholesterol metabolism. Another exciting project concerns studies directed towards determination of the chemical nature of the endogenous inducer(s) of cytochrome P450BM-3 in Bacillus megaterium, with potential for transfer of knowledge from this system to the control of the induction of drug-metabolizing enzymes in humans. Isoprenoid alcohols and acids, regulators of cell growth and apoptosis, will be studied with regard to their syntheses, methods for their separation, and studies of their actions. Sphingolipid bases and their 1-phosphate derivatives, of considerable current interest in biology and medicine, will be studied with regard to their chemistry, methods for their quantitation, and selected actions.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL049122-06
Application #
2842305
Study Section
Physiological Chemistry Study Section (PC)
Project Start
1994-05-01
Project End
2001-06-30
Budget Start
1999-07-23
Budget End
2000-06-30
Support Year
6
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Rice University
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
050299031
City
Houston
State
TX
Country
United States
Zip Code
77005
Guo, Li-Wei; Wilson, William K; Pang, Jihai et al. (2003) Chemical synthesis of 7- and 8-dehydro derivatives of pregnane-3,17alpha,20-triols, potential steroid metabolites in Smith-Lemli-Opitz syndrome. Steroids 68:31-42
Shan, Hui; Pang, Jihai; Li, Shengrong et al. (2003) Chromatographic behavior of oxygenated derivatives of cholesterol. Steroids 68:221-33
Xu, Ran; Wilson, William K; Matsuda, Seiichi P T (2002) Production of meiosis-activating sterols from metabolically engineered yeast. J Am Chem Soc 124:918-9
Xiong, Quanbo; Ruan, Benfang; Whitby, Frank G et al. (2002) A colorimetric assay for 7-dehydrocholesterol with potential application to screening for Smith-Lemli-Opitz syndrome. Chem Phys Lipids 115:1-15
Shan, Hui; Wilson, William K (2002) Ternary gradient elution markedly improves silver-ion high performance liquid chromatography of unsaturated sterols. Steroids 67:917-23
Ruan, Benfang; Lai, Peggy S; Yeh, Christine W et al. (2002) Alternative pathways of sterol synthesis in yeast. Use of C(27) sterol tracers to study aberrant double-bond migrations and evaluate their relative importance. Steroids 67:1109-19
Downs, S M; Ruan, B; Schroepfer Jr, G J (2001) Meiosis-activating sterol and the maturation of isolated mouse oocytes. Biol Reprod 64:80-9
Gardner, R G; Shan, H; Matsuda, S P et al. (2001) An oxysterol-derived positive signal for 3-hydroxy- 3-methylglutaryl-CoA reductase degradation in yeast. J Biol Chem 276:8681-94
Lindenthal, B; Holleran, A L; Aldaghlas, T A et al. (2001) Progestins block cholesterol synthesis to produce meiosis-activating sterols. FASEB J 15:775-84
Guo, L W; Shackleton, C H; Wilson, W K (2001) Synthesis of ring B unsaturated estriols. Confirming the structure of a diagnostic analyte for Smith-Lemli-Opitz syndrome. Org Lett 3:2547-50

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