Textbook Reading: Voet & Voet, Biochemistry, 3rd Edition, p. 942-958.
Some recent articles
E. S. Istvan & J. Deisenhofer (2000) "The structure of the catalytic portion of human HMG-CoA reductase," Biochim. Biophys. Acta 1529: 9-18.
H. Mo & C. E. Elson (2004) "Studies of the isoprenoid-mediated inhibition of mevalonate synthesis applied to cancer chemotherapy and chemoprevention," Exp. Biol. Med. 229: 567-585.
G. A. Holdgate, W. H. J. Ward & F. McTaggart (2003) "Molecular mechanism for inhibition of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase by rosuvastatin," Biochem. Soc. Trans. 31: 528-531.
R. Rawson (2003) "The SREBP pathway - insights from Insigs and insects," Nature Rev. Molec. Cell Biol. 4: 631-640.
R. G. W. Anderson (2003) "Joe Goldstein and Mike Brown: from cholesterol homeostasis to new paradigms in membrane biology," Trends in Cell Biol. 13: 534-539.
M. J. Coon (2005) "Cytochrome P450: nature's most versatile biological catalyst," Annu. Rev. Pharmacol. Toxicol. 45: 1-25.
D. Eberlé, B. Hegarty, P. Bossard, P. Ferré & F. Foufelle (2004) "SREBP transcription factors: master regulators of lipid homeostasis," Biochimie 86: 839-848.
J. Shepherd (2004) "Lipids in health and disease," Biochem. Soc. Trans. 32: 1051-1056.
D. J. Reinert, G. Balliano & G. E. Schulz (2004) "Conversion of squalene to the pentacarbocyclic hopene," Chemistry & Biol. 11: 121-126.
R. W. Estabrook (2005) "Steroid hydroxylations: A paradigm for cytochrome P450 catalyzed mammalian monooxygenation reactions," Biochem. Biophys. Res. Comm. 338: 290-298.
T. Poulos (2005) "Structural biology of heme monooxygenases," Biochem. Biophys. Res. Comm. 338: 337-345.
E. Swiezewska & W. Danikiewicz (2005) "Polyisoprenoids: Structure, biosynthesis and function," Progr. in Lipid Res. 44: 235-258.
P. J. Espenshade (2006) "SREBPs: sterol-regulated transcription factors," J. Cell Sci. 119: 973-976.
A. D. Basso, P. Kirschmeier & W. R. Bishop (2006) "Farnesyl transferase inhibitors," J. Lipid Res. 47: 15-31.
M. Seliskar & D. Rozman (2007) "Mammalian cytochromes P450 - Importance of tissue specificity," Biochim. Biophys. Acta 1770: 458-466.
I. Buhaescu & H. Izzedine (2007) "Mevalonate pathway: A review of clinical and therapeutical implications," Clinical Biochem. 40: 575-584.
1a. Write out the reaction catalyzed by
Hydroxymethylglutaryl-Coenzyme A Reductase (HMG-CoA Reductase), giving
names and structures of reactant and product and names of relevant coenzymes. What is the
significance of this enzyme to the overall pathway of cholesterol synthesis?
b. Describe how activity of SREBP-2 is regulated by cholesterol concentration, including the roles of SCAP, Insig, S1P and S2P. What is the function of the released SREBP-2?
c. Speculate on the basis of known mechanisms of regulation of HMG-CoA Reductase whether a decrease in dietary cholesterol is likely to substantially affect cholesterol levels in the body. Mention at lease two regulatory processes on which your conclusion is based.
d. Describe the mechanism of action of one of the drugs used to inhibit HMG-CoA Reductase. What could be the danger of consuming an HMG-CoA reductase inhibitor in combination with a low-cholesterol diet? Why must dosage and diet be carefully controlled?
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