1dqa Citations

Crystal structure of the catalytic portion of human HMG-CoA reductase: insights into regulation of activity and catalysis.

EMBO J. 19 819-30 (2000)
Related entries: 1dq8, 1dq9

Cited: 87 times
EuropePMC logo PMID: 10698924

Abstract

3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) catalyzes the formation of mevalonate, the committed step in the biosynthesis of sterols and isoprenoids. The activity of HMGR is controlled through synthesis, degradation and phosphorylation to maintain the concentration of mevalonate-derived products. In addition to the physiological regulation of HMGR, the human enzyme has been targeted successfully by drugs in the clinical treatment of high serum cholesterol levels. Three crystal structures of the catalytic portion of human HMGR in complexes with HMG-CoA, with HMG and CoA, and with HMG, CoA and NADP(+), provide a detailed view of the enzyme active site. Catalytic portions of human HMGR form tight tetramers. The crystal structure explains the influence of the enzyme's oligomeric state on the activity and suggests a mechanism for cholesterol sensing. The active site architecture of human HMGR is different from that of bacterial HMGR; this may explain why binding of HMGR inhibitors to bacterial HMGRs has not been reported.

Articles - 1dqa mentioned but not cited (1)



Reviews citing this publication (19)

  1. The 3-hydroxy-3-methylglutaryl coenzyme-A reductases from fungi: a proposal as a therapeutic target and as a study model. Andrade-Pavón D, Sánchez-Sandoval E, Rosales-Acosta B, Ibarra JA, Tamariz J, Hernández-Rodríguez C, Villa-Tanaca L. Rev Iberoam Micol 31 81-85 (2014)
  2. Anomalous diffraction in crystallographic phase evaluation. Hendrickson WA. Q. Rev. Biophys. 47 49-93 (2014)
  3. The increasingly complex mechanism of HMG-CoA reductase. Haines BE, Wiest O, Stauffacher CV. Acc. Chem. Res. 46 2416-2426 (2013)
  4. Dual functions of Insig proteins in cholesterol homeostasis. Dong XY, Tang SQ, Chen JD. Lipids Health Dis 11 173 (2012)
  5. Enzymes of the mevalonate pathway of isoprenoid biosynthesis. Miziorko HM. Arch. Biochem. Biophys. 505 131-143 (2011)
  6. Regulation of HMG-CoA reductase in mammals and yeast. Burg JS, Espenshade PJ. Prog. Lipid Res. 50 403-410 (2011)
  7. Structure and function of AMP-activated protein kinase. Oakhill JS, Scott JW, Kemp BE. Acta Physiol (Oxf) 196 3-14 (2009)
  8. The role of HMGCR alternative splicing in statin efficacy. Medina MW, Krauss RM. Trends Cardiovasc. Med. 19 173-177 (2009)
  9. Regulation of sterol synthesis in eukaryotes. Espenshade PJ, Hughes AL. Annu. Rev. Genet. 41 401-427 (2007)
  10. Protein sensors for membrane sterols. Goldstein JL, DeBose-Boyd RA, Brown MS. Cell 124 35-46 (2006)
  11. Class II 3-hydroxy-3-methylglutaryl coenzyme A reductases. Hedl M, Tabernero L, Stauffacher CV, Rodwell VW. J. Bacteriol. 186 1927-1932 (2004)
  12. The 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductases. Friesen JA, Rodwell VW. Genome Biol. 5 248 (2004)
  13. The lipid and non-lipid effects of statins. Wierzbicki AS, Poston R, Ferro A. Pharmacol. Ther. 99 95-112 (2003)
  14. Management of cellular energy by the AMP-activated protein kinase system. Hardie DG, Scott JW, Pan DA, Hudson ER. FEBS Lett. 546 113-120 (2003)
  15. Structural biology: a high-tech tool for biomedical research. Machius M. Curr. Opin. Nephrol. Hypertens. 12 431-438 (2003)
  16. Structural genomics of proteins from conserved biochemical pathways and processes. Burley SK, Bonanno JB. Curr. Opin. Struct. Biol. 12 383-391 (2002)
  17. Structural mechanism for statin inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Istvan ES. Am. Heart J. 144 S27-32 (2002)
  18. Moving towards the next generation. Starz-Gaiano M, Lehmann R. Mech. Dev. 105 5-18 (2001)
  19. The structure of the catalytic portion of human HMG-CoA reductase. Istvan ES, Deisenhofer J. Biochim. Biophys. Acta 1529 9-18 (2000)

Articles citing this publication (67)

  1. Direct binding of cholesterol to the purified membrane region of SCAP: mechanism for a sterol-sensing domain. Radhakrishnan A, Sun LP, Kwon HJ, Brown MS, Goldstein JL. Mol. Cell 15 259-268 (2004)
  2. Protein kinase substrate recognition studied using the recombinant catalytic domain of AMP-activated protein kinase and a model substrate. Scott JW, Norman DG, Hawley SA, Kontogiannis L, Hardie DG. J. Mol. Biol. 317 309-323 (2002)
  3. Alternative splicing of 3-hydroxy-3-methylglutaryl coenzyme A reductase is associated with plasma low-density lipoprotein cholesterol response to simvastatin. Medina MW, Gao F, Ruan W, Rotter JI, Krauss RM. Circulation 118 355-362 (2008)
  4. Common SNPs in HMGCR in micronesians and whites associated with LDL-cholesterol levels affect alternative splicing of exon13. Burkhardt R, Kenny EE, Lowe JK, Birkeland A, Josowitz R, Noel M, Salit J, Maller JB, Pe'er I, Daly MJ, Altshuler D, Stoffel M, Friedman JM, Breslow JL. Arterioscler. Thromb. Vasc. Biol. 28 2078-2084 (2008)
  5. Regulation of ipsilateral and contralateral bovine oviduct epithelial cell function in the postovulation period: a transcriptomics approach. Bauersachs S, Blum H, Mallok S, Wenigerkind H, Rief S, Prelle K, Wolf E. Biol. Reprod. 68 1170-1177 (2003)
  6. A mutation in zebrafish hmgcr1b reveals a role for isoprenoids in vertebrate heart-tube formation. D'Amico L, Scott IC, Jungblut B, Stainier DY. Curr. Biol. 17 252-259 (2007)
  7. Isoprenoid biosynthesis is required for miRNA function and affects membrane association of ARGONAUTE 1 in Arabidopsis. Brodersen P, Sakvarelidze-Achard L, Schaller H, Khafif M, Schott G, Bendahmane A, Voinnet O. Proc. Natl. Acad. Sci. U.S.A. 109 1778-1783 (2012)
  8. Essentiality, expression, and characterization of the class II 3-hydroxy-3-methylglutaryl coenzyme A reductase of Staphylococcus aureus. Wilding EI, Kim DY, Bryant AP, Gwynn MN, Lunsford RD, McDevitt D, Myers JE, Rosenberg M, Sylvester D, Stauffacher CV, Rodwell VW. J. Bacteriol. 182 5147-5152 (2000)
  9. Epigallocatechin-3-gallate potently inhibits the in vitro activity of hydroxy-3-methyl-glutaryl-CoA reductase. Cuccioloni M, Mozzicafreddo M, Spina M, Tran CN, Falconi M, Eleuteri AM, Angeletti M. J. Lipid Res. 52 897-907 (2011)
  10. Regulation of AMP-activated protein kinase by a pseudosubstrate sequence on the gamma subunit. Scott JW, Ross FA, Liu JK, Hardie DG. EMBO J. 26 806-815 (2007)
  11. Insig regulates HMG-CoA reductase by controlling enzyme phosphorylation in fission yeast. Burg JS, Powell DW, Chai R, Hughes AL, Link AJ, Espenshade PJ. Cell Metab. 8 522-531 (2008)
  12. Indirect stimulation of human Vγ2Vδ2 T cells through alterations in isoprenoid metabolism. Wang H, Sarikonda G, Puan KJ, Tanaka Y, Feng J, Giner JL, Cao R, Mönkkönen J, Oldfield E, Morita CT. J. Immunol. 187 5099-5113 (2011)
  13. Enterococcus faecalis acetoacetyl-coenzyme A thiolase/3-hydroxy-3-methylglutaryl-coenzyme A reductase, a dual-function protein of isopentenyl diphosphate biosynthesis. Hedl M, Sutherlin A, Wilding EI, Mazzulla M, McDevitt D, Lane P, Burgner JW, Lehnbeuter KR, Stauffacher CV, Gwynn MN, Rodwell VW. J. Bacteriol. 184 2116-2122 (2002)
  14. Dislocation of HMG-CoA reductase and Insig-1, two polytopic endoplasmic reticulum proteins, en route to proteasomal degradation. Leichner GS, Avner R, Harats D, Roitelman J. Mol. Biol. Cell 20 3330-3341 (2009)
  15. Cloning and characterization of a root-specific expressing gene encoding 3-hydroxy-3-methylglutaryl coenzyme A reductase from Ginkgo biloba. Shen G, Pang Y, Wu W, Liao Z, Zhao L, Sun X, Tang K. Mol. Biol. Rep. 33 117-127 (2006)
  16. Iridoid biosynthesis in Chrysomelina larvae: Fat body produces early terpenoid precursors. Burse A, Schmidt A, Frick S, Kuhn J, Gershenzon J, Boland W. Insect Biochem. Mol. Biol. 37 255-265 (2007)
  17. Cloning and functional characterization of 3-hydroxy-3-methylglutaryl coenzyme A reductase gene from Withania somnifera: an important medicinal plant. Akhtar N, Gupta P, Sangwan NS, Sangwan RS, Trivedi PK. Protoplasma 250 613-622 (2013)
  18. Chemical and genetic validation of the statin drug target to treat the helminth disease, schistosomiasis. Rojo-Arreola L, Long T, Asarnow D, Suzuki BM, Singh R, Caffrey CR. PLoS ONE 9 e87594 (2014)
  19. Mechanism of action and NAD+-binding mode revealed by the crystal structure of L-histidinol dehydrogenase. Barbosa JA, Sivaraman J, Li Y, Larocque R, Matte A, Schrag JD, Cygler M. Proc. Natl. Acad. Sci. U.S.A. 99 1859-1864 (2002)
  20. Enterococcus faecalis 3-hydroxy-3-methylglutaryl coenzyme A synthase, an enzyme of isopentenyl diphosphate biosynthesis. Sutherlin A, Hedl M, Sanchez-Neri B, Burgner JW, Stauffacher CV, Rodwell VW. J. Bacteriol. 184 4065-4070 (2002)
  21. Enterococcus faecalis phosphomevalonate kinase. Doun SS, Burgner JW, Briggs SD, Rodwell VW. Protein Sci. 14 1134-1139 (2005)
  22. Molecular cloning and functional analysis of the gene encoding 3-hydroxy-3-methylglutaryl coenzyme A reductase from hazel (Corylus avellana L. Gasaway). Wang Y, Guo B, Zhang F, Yao H, Miao Z, Tang K. J. Biochem. Mol. Biol. 40 861-869 (2007)
  23. Genetic and structural analysis of Hmg2p-induced endoplasmic reticulum remodeling in Saccharomyces cerevisiae. Federovitch CM, Jones YZ, Tong AH, Boone C, Prinz WA, Hampton RY. Mol. Biol. Cell 19 4506-4520 (2008)
  24. Sterol metabolism. Benveniste P. Arabidopsis Book 1 e0004 (2002)
  25. 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. Xu L, Simoni RD. Arch. Biochem. Biophys. 414 232-243 (2003)
  26. Exploring Leishmania donovani 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) as a potential drug target by biochemical, biophysical and inhibition studies. Dinesh N, Pallerla DS, Kaur PK, Kishore Babu N, Singh S. Microb. Pathog. 66 14-23 (2014)
  27. Exploration and characterization of genes involved in the synthesis of diterpene defence secretion in nasute termite soldiers. Hojo M, Maekawa K, Saitoh S, Shigenobu S, Miura T, Hayashi Y, Tokuda G, Maekawa H. Insect Mol. Biol. 21 545-557 (2012)
  28. Novel synthetic inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity that inhibit tumor cell proliferation and are structurally unrelated to existing statins. Perchellet JP, Perchellet EM, Crow KR, Buszek KR, Brown N, Ellappan S, Gao G, Luo D, Minatoya M, Lushington GH. Int. J. Mol. Med. 24 633-643 (2009)
  29. Molecular cloning, characterization and function analysis of the gene encoding HMG-CoA reductase from Euphorbia Pekinensis Rupr. Cao X, Zong Z, Ju X, Sun Y, Dai C, Liu Q, Jiang J. Mol. Biol. Rep. 37 1559-1567 (2010)
  30. Role of AMP-activated protein kinase gamma 3 genetic variability in glucose and lipid metabolism in non-diabetic whites. Weyrich P, Machicao F, Staiger H, Simon P, Thamer C, Machann J, Schick F, Guirguis A, Fritsche A, Stefan N, Häring HU. Diabetologia 50 2097-2106 (2007)
  31. Sequence diversity in genes of lipid metabolism. Garcia CK, Mues G, Liao Y, Hyatt T, Patil N, Cohen JC, Hobbs HH. Genome Res. 11 1043-1052 (2001)
  32. A new autophagy-related checkpoint in the degradation of an ERAD-M target. Kario E, Amar N, Elazar Z, Navon A. J. Biol. Chem. 286 11479-11491 (2011)
  33. Effects of statins on the secretion of human serum albumin in cultured HepG2 cells. Ha CE, Ha JS, Theriault AG, Bhagavan NV. J. Biomed. Sci. 16 32 (2009)
  34. Implication of HMGR in homeostasis of sequestered and de novo produced precursors of the iridoid biosynthesis in leaf beetle larvae. Burse A, Frick S, Schmidt A, Buechler R, Kunert M, Gershenzon J, Brandt W, Boland W. Insect Biochem. Mol. Biol. 38 76-88 (2008)
  35. The geometry of interactions between catalytic residues and their substrates. Torrance JW, Holliday GL, Mitchell JB, Thornton JM. J. Mol. Biol. 369 1140-1152 (2007)
  36. Molecular docking of the highly hypolipidemic agent alpha-asarone with the catalytic portion of HMG-CoA reductase. Medina-Franco JL, López-Vallejo F, Rodríguez-Morales S, Castillo R, Chamorro G, Tamariz J. Bioorg. Med. Chem. Lett. 15 989-994 (2005)
  37. Effects of hypocholesterolaemic agents on the expression and activity of 3-hydroxy-3-methylglutaryl-CoA reductase in the fat body of the German cockroach. Zapata R, Martín D, Piulachs MD, Bellés X. Arch. Insect Biochem. Physiol. 49 177-186 (2002)
  38. Kinetic properties and inhibition of Trypanosoma cruzi 3-hydroxy-3-methylglutaryl CoA reductase. Hurtado-Guerrrero R, Peña-Díaz J, Montalvetti A, Ruiz-Pérez LM, González-Pacanowska D. FEBS Lett. 510 141-144 (2002)
  39. Tissue-specific effects of atorvastatin on 3-hydroxy-3-methylglutarylcoenzyme A reductase expression and activity in spontaneously hypertensive rats. Chen GP, Yao L, Lu X, Li L, Hu SJ. Acta Pharmacol. Sin. 29 1181-1186 (2008)
  40. Rapid reverse phase-HPLC assay of HMG-CoA reductase activity. Mozzicafreddo M, Cuccioloni M, Eleuteri AM, Angeletti M. J. Lipid Res. 51 2460-2463 (2010)
  41. Omega-3 as well as caloric restriction prevent the age-related modifications of cholesterol metabolism. Martini C, Pallottini V, De Marinis E, Marino M, Cavallini G, Donati A, Straniero S, Trentalance A. Mech. Ageing Dev. 129 722-727 (2008)
  42. Metabolically regulated endoplasmic reticulum-associated degradation of 3-hydroxy-3-methylglutaryl-CoA reductase: evidence for requirement of a geranylgeranylated protein. Leichner GS, Avner R, Harats D, Roitelman J. J. Biol. Chem. 286 32150-32161 (2011)
  43. Site of pheromone biosynthesis and isolation of HMG-CoA reductase cDNA in the cotton boll weevil, Anthonomus grandis. Taban AH, Fu J, Blake J, Awano A, Tittiger C, Blomquist GJ. Arch. Insect Biochem. Physiol. 62 153-163 (2006)
  44. A mathematical model of the sterol regulatory element binding protein 2 cholesterol biosynthesis pathway. Bhattacharya BS, Sweby PK, Minihane AM, Jackson KG, Tindall MJ. J. Theor. Biol. 349 150-162 (2014)
  45. Glucose-6-phosphate dehydrogenase and NADPH redox regulates cardiac myocyte L-type calcium channel activity and myocardial contractile function. Rawat DK, Hecker P, Watanabe M, Chettimada S, Levy RJ, Okada T, Edwards JG, Gupte SA. PLoS ONE 7 e45365 (2012)
  46. Methyl farnesoate synthesis in the lobster mandibular organ: the roles of HMG-CoA reductase and farnesoic acid O-methyltransferase. Li S, Friesen JA, Holford KC, Borst DW. Comp. Biochem. Physiol., Part A Mol. Integr. Physiol. 155 49-55 (2010)
  47. 3-hydroxy-3-methylglutaryl coenzyme A reductase is sterol-dependently cleaved by cathepsin L-type cysteine protease in the isolated endoplasmic reticulum. Moriyama T, Wada M, Urade R, Kito M, Katunuma N, Ogawa T, Simoni RD. Arch. Biochem. Biophys. 386 205-212 (2001)
  48. In vitro screening for β-hydroxy-β-methylglutaryl-CoA reductase inhibitory and antioxidant activity of sequentially extracted fractions of Ficus palmata Forsk. Iqbal D, Khan MS, Khan A, Khan MS, Ahmad S, Srivastava AK, Bagga P. Biomed Res Int 2014 762620 (2014)
  49. HMG-CoA reductase is negatively associated with PCV2 infection and PCV2-induced apoptotic cell death. Yang X, Ouyang H, Chen F, Pang D, Dong M, Yang S, Liu X, Peng Z, Wang F, Zhang X, Ren L. J. Gen. Virol. 95 1330-1337 (2014)
  50. A novel 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) splice variant with an alternative exon 1 potentially encoding an extended N-terminus. Stormo C, Kringen MK, Grimholt RM, Berg JP, Piehler AP. BMC Mol. Biol. 13 29 (2012)
  51. Molecular modeling of the reaction pathway and hydride transfer reactions of HMG-CoA reductase. Haines BE, Steussy CN, Stauffacher CV, Wiest O. Biochemistry 51 7983-7995 (2012)
  52. Structures of the first representatives of Pfam family PF06938 (DUF1285) reveal a new fold with repeated structural motifs and possible involvement in signal transduction. Han GW, Bakolitsa C, Miller MD, Kumar A, Carlton D, Najmanovich RJ, Abdubek P, Astakhova T, Axelrod HL, Chen C, Chiu HJ, Clayton T, Das D, Deller MC, Duan L, Ernst D, Feuerhelm J, Grant JC, Grzechnik A, Jaroszewski L, Jin KK, Johnson HA, Klock HE, Knuth MW, Kozbial P, Krishna SS, Marciano D, McMullan D, Morse AT, Nigoghossian E, Okach L, Reyes R, Rife CL, Sefcovic N, Tien HJ, Trame CB, van den Bedem H, Weekes D, Xu Q, Hodgson KO, Wooley J, Elsliger MA, Deacon AM, Godzik A, Lesley SA, Wilson IA. Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 66 1218-1225 (2010)
  53. Cloning of the Rhizomucor miehei 3-hydroxy-3-methylglutaryl-coenzyme A reductase gene and its heterologous expression in Mucor circinelloides. Lukács G, Papp T, Somogyvári F, Csernetics A, Nyilasi I, Vágvölgyi C. Antonie Van Leeuwenhoek 95 55-64 (2009)
  54. Anti-hyperlipidemic action of a newly synthesized benzoic acid derivative, S-2E. Ohmori K, Yamada H, Yasuda A, Yamamoto A, Matsuura N, Kiniwa M. Eur. J. Pharmacol. 471 69-76 (2003)
  55. Thyroid-stimulating hormone decreases HMG-CoA reductase phosphorylation via AMP-activated protein kinase in the liver. Zhang X, Song Y, Feng M, Zhou X, Lu Y, Gao L, Yu C, Jiang X, Zhao J. J. Lipid Res. 56 963-971 (2015)
  56. Exploration of virtual candidates for human HMG-CoA reductase inhibitors using pharmacophore modeling and molecular dynamics simulations. Son M, Baek A, Sakkiah S, Park C, John S, Lee KW. PLoS ONE 8 e83496 (2013)
  57. Explaining statin inhibition effectiveness of HMG-CoA reductase by quantum biochemistry computations. da Costa RF, Freire VN, Bezerra EM, Cavada BS, Caetano EW, de Lima Filho JL, Albuquerque EL. Phys Chem Chem Phys 14 1389-1398 (2012)
  58. A comparative analysis of protein targets of withdrawn cardiovascular drugs in human and mouse. Zhao Y, Wang J, Wang Y, Huang J. J Clin Bioinforma 2 10 (2012)
  59. Role of rs3846662 and HMGCR alternative splicing in statin efficacy and baseline lipid levels in familial hypercholesterolemia. Leduc V, Bourque L, Poirier J, Dufour R. Pharmacogenet. Genomics 26 1-11 (2016)
  60. Insight into the mechanism of polyphenols on the activity of HMGR by molecular docking. Islam B, Sharma C, Adem A, Aburawi E, Ojha S. Drug Des Devel Ther 9 4943-4951 (2015)
  61. Kinetic characterization of an oxidative, cooperative HMG-CoA reductase from Burkholderia cenocepacia. Schwarz BH, Driver J, Peacock RB, Dembinski HE, Corson MH, Gordon SS, Watson JM. Biochim. Biophys. Acta 1844 457-464 (2014)
  62. Transcription of the three HMG-CoA reductase genes of Mucor circinelloides. Nagy G, Farkas A, Csernetics Á, Bencsik O, Szekeres A, Nyilasi I, Vágvölgyi C, Papp T. BMC Microbiol. 14 93 (2014)
  63. Effects of rs3846662 Variants on HMGCR mRNA and Protein Levels and on Markers of Alzheimer's Disease Pathology. Leduc V, Théroux L, Dea D, Dufour R, Poirier J. J. Mol. Neurosci. 58 109-119 (2016)
  64. A critical role of mevalonate for peptidoglycan synthesis in Staphylococcus aureus. Matsumoto Y, Yasukawa J, Ishii M, Hayashi Y, Miyazaki S, Sekimizu K. Sci Rep 6 22894 (2016)
  65. HMGCR inhibits the early stage of PCV2 infection, while PKC enhances the infection at the late stage. Ma T, Chen X, Ouyang H, Liu X, Ouyang T, Peng Z, Yang X, Chen F, Pang D, Bai J, Ren L. Virus Res. 229 41-47 (2017)
  66. An Insight Into Structure, Function, and Expression Analysis of 3-Hydroxy-3-Methylglutaryl-CoA Reductase of Cymbopogon winterianus. Devi K, Patar L, Modi MK, Sen P. Bioinform Biol Insights 11 1177932217701735 (2017)
  67. Bacteriostatic Effect of Simvastatin on Selected Oral Streptococci in Vitro. Whitaker EJ, Alshammari A. Contemp Clin Dent 8 59-63 (2017)