Which of the following drugs reduces cholesterol levels by inhibiting HMG CoA reductase the enzyme that catalyzes the rate limiting step in the synthesis of cholesterol?

1. Laule O, Furholz A, Chang HS, Zhu T, Wang X, Heifetz PB, Gruissem W, Lange M: Crosstalk between cytosolic and plastidial pathways of isoprenoid biosynthesis in Arabidopsis thaliana. Proc Natl Acad Sci USA. 2003, 100: 6866-6871. 10.1073/pnas.1031755100. A study of the regulation of both mevalonate and mevalonate independent pathways for isoprenoid synthesis in plants.

   Article  PubMed  CAS  PubMed Central  Google Scholar 

2. Bochar DA, Stauffacher CV, Rodwell VW: Sequence comparisons reveal two classes of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Mol Genet Metab. 1999, 66: 122-127. 10.1006/mgme.1998.2786. This article reported the classification of HMG-CoA reductases into Class I and Class II enzymes on the basis of sequence comparison. The authors utilized phylogenetic analysis to analyze a plethora of genomic sequences of various organisms.

   Article  PubMed  CAS  Google Scholar 

3. Hedl M, Tabernero L, Stauffacher CV, Rodwell VW: Class II 3-hydroxy-3-methylglutaryl coenzyme A reductases. J Bacteriol. 2004, 186: 1927-1932. 10.1128/JB.186.7.1927-1932.2004. A review article detailing current research and thought concerning Class II forms of the enzyme, including the HMGRs of many pathogenic bacteria.

   Article  PubMed  CAS  PubMed Central  Google Scholar 

4. Istvan ES, Palnitkar M, Buchanan SK, Deisenhofer J: Crystal structure of the catalytic portion of human HMG-CoA reductase: insights into regulation of activity and catalysis. EMBO J. 2000, 19: 819-830. 10.1093/emboj/19.5.819. This article and [5] reported the crystal structure of the human HMG-CoA reductase catalytic domain, providing numerous insights into catalysis by a Class I HMG-CoA reductase.

   Article  PubMed  CAS  PubMed Central  Google Scholar 

5. Istvan ES, Deisenhofer J: The structure of the catalytic portion of human HMG-CoA reductase. Biochim Biophys Acta. 2000, 1529: 9-18. See [4]

   Article  PubMed  CAS  Google Scholar 

6. Lawrence CM, Rodwell VW, Stauffacher CV: The crystal structure of Pseudomonas mevalonii HMG-CoA reductase at 3.0 Å resolution. Science. 1995, 268: 1758-1762. This article reports the first HMG-CoA reductase structure that was solved.

   Article  PubMed  CAS  Google Scholar 

7. Tabernero LD, Bochar DA, Rodwell VW, Stauffacher CV: Substrate-induced closure of the flap domain in the ternary complex structures provides new insights into the mechanism of catalysis by 3-hydroxy-3-methylglutaryl-CoA reductase. Proc Natl Acad Sci USA. 1999, 96: 7167-7171. 10.1073/pnas.96.13.7167. The original structure of P. mevalonii HMG-CoA reductase [6] lacked a portion of the enzyme known to be critical for catalysis. This article provided insight into the catalytic mechanism by solving the structure of the original missing region.

   Article  PubMed  CAS  PubMed Central  Google Scholar 

8. Istvan ES, Deisenhofer J: Structural mechanism for statin inhibition of HMG-CoA reductase. Science. 2001, 292: 1160-1164. 10.1126/science.1059344. This article reports a structural explanation for inhibition of human HMG-CoA reductase by statins, which are widely prescribed drugs for hypercholesterolemia.

   Article  PubMed  CAS  Google Scholar 

9. Tabernero L, Rodwell VW, Stauffacher CV: Crystal structure of a statin bound to a class II hydroxymethylglutaryl-CoA reductase. J Biol Chem. 2003, 278: 19933-19938. 10.1074/jbc.M213006200. The authors detail the interaction of P. mevalonii HMG-CoA reductase, a Class II enzyme, with statins.

   Article  PubMed  CAS  Google Scholar 

10. Istvan ES: Bacterial and mammalian HMG-CoA reductases: related enzymes with distinct architectures. Curr Opin Struct Biol. 2001, 11: 746-751. 10.1016/S0959-440X(01)00276-7. A review that provides insight into the relationships between Class I and Class II HMG-CoA reductases, both in terms of structure and evolution.

    Article  PubMed  CAS  Google Scholar 

11. Bochar DA, Friesen JA, Stauffacher CV, Rodwell VW: Biosynthesis of mevalonic acid from acetyl-CoA. Isoprenoids Including Carotenoids and Steroids. Edited by: Cane D. 1999, New York: Pergamon Press, 15-44. A comprehensive review article detailing the catalysis, structure, and regulation of HMG-CoA reductase. It is written from the point of view of natural products synthesis.

    Google Scholar 

12. Goldstein JL, Brown MS: Regulation of the mevalonate pathway. Nature. 1990, 343: 425-430. 10.1038/343425a0. The first major report on the regulation of HMG-CoA reductase.

    Article  PubMed  CAS  Google Scholar 

13. Horton JD, Goldstein JL, Brown MS: SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest. 2002, 109: 1125-1131. 10.1172/JCI200215593. A recent review detailing the role of sterol regulatory element binding proteins (SREBPs) in the regulation of cholesterol biosynthesis. This is the transcriptional control for HMG-CoA reductase.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

14. Mitropoulos KA, Venkatesan S: Membrane-mediated control of HMG-CoA reductase activity. In Regulation of HMG-CoA Reductase. Edited by: Preiss B. 1985, Orlando: Academic Press, 1-48. A classical review article summarizing the role of the membrane anchor domain in HMG-CoA reductase degradation.

    Chapter  Google Scholar 

15. Jingami H, Brown MS, Goldstein JL, Anderson RJ, Luskey KL: Partial deletion of membrane-bound domain of 3-hydroxy-3-methylglutaryl coenzyme A reductase eliminates sterol-enhanced degradation and prevents formation of crystalloid endoplasmic reticulum. J Cell Biol. 1987, 104: 1693-1704. 10.1083/jcb.104.6.1693. The original report of the sterol-mediated regulation of HMG-CoA reductase degradation and localization of the region responsible for mediating this degradation.

    Article  PubMed  CAS  Google Scholar 

16. Xu L, Simoni RD: The inhibition of degradation of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase by sterol regulatory element binding protein cleavage-activating protein requires four phenylalanine residues in span 6 of HMG-CoA reductase transmembrane domain. Arch Biochem Biophys. 2003, 414: 232-243. 10.1016/S0003-9861(03)00168-1. A study of the structure-function relationships between HMG-CoA reductase degradation and the sterol cleavage activating protein (SCAP).

    Article  PubMed  CAS  Google Scholar 

17. Sever N, Yang T, Brown MS, Goldstein JL, DeBose-Boyd RA: Accelerated degradation of HMG-CoA reductase mediated by binding of insig-1 to its sterol-sensing domain. Mol Cell. 2003, 11: 25-33. 10.1016/S1097-2765(02)00822-5. The authors identified the role of the protein insig-1 in regulation of HMG-CoA reductase by degradation.

    Article  PubMed  CAS  Google Scholar 

18. Sever N, Song BL, Yabe D, Goldstein JL, Brown MS, DeBose-Boyd RA: Insig-dependent ubiquitination and degradation of mammalian 3-hydroxy-3-methylglutaryl-CoA reductase stimulated by sterols and geranylgeraniol. J Biol Chem. 2003, 278: 52479-52490. 10.1074/jbc.M310053200. This study described the relationship between ubiquitination, degradation, and the protein insig-1 in HMG-CoA reductase degradation.

    Article  PubMed  CAS  Google Scholar 

19. Sato R, Goldstein JL, Brown MS: Replacement of serine-871 of hamster 3-hydroxy-3-methylglutaryl-CoA reductase prevents phosphorylation by AMP-activated kinase and blocks inhibition of sterol synthesis induced by ATP depletion. Proc Natl Acad Sci USA. 1993, 90: 9261-9265. In this study, the authors identified the specific amino acid of mammalian HMG-CoA reductase that is phosphorylated and mediates regulation of HMG-CoA reductase by reversible phosphorylation.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

20. Hardie DG: The AMP-activated protein kinase cascade: the key sensor of cellular energy status. Endocrinology. 2003, 144: 5179-5183. 10.1210/en.2003-0982. A review article describing the AMP-activated protein kinase (AMPK) that phosphorylates HMG-CoA reductase.

    Article  PubMed  CAS  Google Scholar 

21. Dale S, Arro M, Becerra B, Morrice NG, Boronat A, Hardie DG, Ferrer A: Bacterial expression of the catalytic domain of 3-hydroxy-3-methylglutaryl-CoA reductase (isoform hmgr1) from Arabidopsis thaliana, and its inactivation by phosphorylation at Ser577 by Brassica oleracea 3-hydroxy-3-methylglutaryl-CoA reductase kinase. Eur J Biochem. 1995, 233: 506-513. 10.1111/j.1432-1033.1995.506_2.x. A study that illustrated that plant HMG-CoA reductases are probably regulated by reversible phosphorylation.

    Article  PubMed  CAS  Google Scholar 

22. Ensembl Human Genome browser. Ensembl information about the human HMG-CoA reductase gene and transcript details., [http://www.ensembl.org/Homo_sapiens/]

23. Higgins D, Thompson J, Gibson T, Thompson JD, Higgins DG, Gibson TJ: CLUSTAL W: Improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res. 1994, 22: 4673-4680. An article describing the CLUSTAL W program, which is used for multiple sequence alignments of amino-acid sequences.

    Article  PubMed  PubMed Central  Google Scholar 

24. TreeTop - Phylogenetic tree prediction. A program for phylogenetic tree generation., [http://www.genebee.msu.su/services/phtree_reduced.html]

25. National Center for Biotechnology Information. The NCBI contains a vast amount of sequence information, including protein and nucleic acid sequences for HMG-CoA reductases and information on the sequencing of genomes of organisms containing HMG-CoA reductase isoforms., [http://www.ncbi.nlm.nih.gov]

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1. *Common names are indicated in parentheses Accession numbers for each sequence are available from sequence databases accessible through the National Center for Biotechnology Information [25].