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The Info List - HMG-CoA Reductase





1DQ8, 1DQ9, 1DQA, 1HW8, 1HW9, 1HWI, 1HWJ, 1HWK, 1HWL, 2Q1L, 2Q6B, 2Q6C, 2R4F, 3BGL, 3CCT, 3CCW, 3CCZ, 3CD0, 3CD5, 3CD7, 3CDA, 3CDB

Identifiers

Aliases HMGCR, HMG-CoA
HMG-CoA
reductase, Entrez
Entrez
3156, LDLCQ3, 3-hydroxy-3-methylglutaryl-CoA reductase, Hydroxymethylglutaryl-CoA reductase

External IDs OMIM: 142910 MGI: 96159 HomoloGene: 30994 GeneCards: HMGCR

Gene
Gene
location (Human)

Chr. Chromosome
Chromosome
5 (human)[1]

Band 5q13.3 Start 75,336,329 bp[1]

End 75,362,104 bp[1]

Gene
Gene
location (Mouse)

Chr. Chromosome
Chromosome
13 (mouse)[2]

Band 13 D113 50.65 cM Start 96,648,967 bp[2]

End 96,670,936 bp[2]

RNA expression pattern

More reference expression data

Gene
Gene
ontology

Molecular function • oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor • protein homodimerization activity • hydroxymethylglutaryl-CoA reductase (NADPH) activity • protein binding • NADP binding • NADPH
NADPH
binding • coenzyme binding • oxidoreductase activity • hydroxymethylglutaryl-CoA reductase activity

Cellular component • integral component of membrane • endoplasmic reticulum membrane • membrane • intracellular membrane-bounded organelle • peroxisomal membrane • endoplasmic reticulum

Biological process • visual learning • steroid metabolic process • sterol biosynthetic process • negative regulation of striated muscle cell apoptotic process • coenzyme A metabolic process • response to nutrient • positive regulation of skeletal muscle tissue development • lipid metabolic process • positive regulation of cardiac muscle cell apoptotic process • negative regulation of insulin secretion involved in cellular response to glucose stimulus • aging • negative regulation of apoptotic process • cholesterol metabolic process • protein tetramerization • isoprenoid biosynthetic process • negative regulation of MAP kinase activity • positive regulation of cell proliferation • positive regulation of ERK1 and ERK2 cascade • negative regulation of wound healing • cholesterol biosynthetic process • ubiquinone metabolic process • myoblast differentiation • response to ethanol • oxidation-reduction process • positive regulation of stress-activated MAPK cascade • positive regulation of smooth muscle cell proliferation • steroid biosynthetic process • regulation of lipid metabolic process • regulation of cholesterol biosynthetic process • negative regulation of blood vessel diameter

Sources:Amigo / QuickGO

Orthologs

Species Human Mouse

Entrez

3156

15357

Ensembl

ENSG00000113161

ENSMUSG00000021670

UniProt

P04035

Q01237

RefSeq (mRNA)

NM_000859 NM_001130996

NM_008255 NM_001360165 NM_001360166

RefSeq (protein)

NP_000850 NP_001124468 NP_000850.1

NP_032281 NP_001347094 NP_001347095

Location (UCSC) Chr 5: 75.34 – 75.36 Mb Chr 13: 96.65 – 96.67 Mb

PubMed
PubMed
search [3] [4]

Wikidata

View/Edit Human View/Edit Mouse

HMG-CoA
HMG-CoA
reductase

EC number EC_number

Gene
Gene
Ontology AmiGO / QuickGO

hydroxymethylglutaryl-CoA reductase

Identifiers

EC number 1.1.1.88

CAS number 37250-24-1

Databases

IntEnz IntEnz view

BRENDA BRENDA
BRENDA
entry

ExPASy NiceZyme view

KEGG KEGG
KEGG
entry

MetaCyc metabolic pathway

PRIAM profile

PDB structures RCSB PDB PDBe PDBsum

Gene
Gene
Ontology AmiGO / QuickGO

Search

PMC articles

PubMed articles

NCBI proteins

hydroxymethylglutaryl-CoA reductase

Identifiers

EC number 1.1.1.34

Databases

IntEnz IntEnz view

BRENDA BRENDA
BRENDA
entry

ExPASy NiceZyme view

KEGG KEGG
KEGG
entry

MetaCyc metabolic pathway

PRIAM profile

PDB structures RCSB PDB PDBe PDBsum

Search

PMC articles

PubMed articles

NCBI proteins

HMG-CoA
HMG-CoA
reductase (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, officially abbreviated HMGCR) is the rate-controlling enzyme (NADH-dependent, EC 1.1.1.88; NADPH-dependent, EC 1.1.1.34) of the mevalonate pathway, the metabolic pathway that produces cholesterol and other isoprenoids. Normally in mammalian cells this enzyme is suppressed by cholesterol derived from the internalization and degradation of low density lipoprotein (LDL) via the LDL receptor
LDL receptor
as well as oxidized species of cholesterol. Competitive inhibitors of the reductase induce the expression of LDL receptors in the liver, which in turn increases the catabolism of plasma LDL and lowers the plasma concentration of cholesterol, which is considered, by those who accept the standard lipid hypothesis, an important determinant of atherosclerosis.[5] This enzyme is thus the target of the widely available cholesterol-lowering drugs known collectively as the statins. HMG-CoA
HMG-CoA
reductase is anchored in the membrane of the endoplasmic reticulum, and was long regarded as having seven transmembrane domains, with the active site located in a long carboxyl terminal domain in the cytosol. More recent evidence shows it to contain eight transmembrane domains.[6] In humans, the gene for HMG-CoA
HMG-CoA
reductase is located on the long arm of the fifth chromosome (5q13.3-14).[7] Related enzymes having the same function are also present in other animals, plants and bacteria.

Contents

1 Structure 2 Function

2.1 Interactive pathway map

3 Inhibitors

3.1 Drugs 3.2 Hormones

4 Clinical significance 5 Regulation

5.1 Transcription of the reductase gene 5.2 Translation of mRNA 5.3 Degradation of reductase 5.4 Phosphorylation
Phosphorylation
of reductase

6 See also 7 References 8 Further reading 9 External links

Structure[edit] The main isoform (isoform 1) of HMG-CoA
HMG-CoA
reductase in humans is 888 amino acids long. It is a polytopic transmembrane protein (meaning it possesses many alpha helical transmembrane segments). It contains two main domains:

an N-terminal sterol-sensing domain (amino acid interval: 88-218), which binds sterol groups. Cholesterol
Cholesterol
binding at this region inhibits the activity of the catalytic domain. a C-terminal catalytic domain (amino acid interval: 489-871), namely the 3-hydroxy-3-methyl-glutaryl-CoA reductase domain. This domain is required for the proper enzymatic activity of the protein.

Isoform 2 is 835 amino acids long. This variant is shorter because it lacks an exon in the middle region. This does not affect any of the aforementioned domains. Function[edit] HMGCR
HMGCR
catalyses the conversion of HMG-CoA
HMG-CoA
to mevalonic acid, a necessary step in the biosynthesis of cholesterol:

Interactive pathway map[edit] Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

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pxalt=Statin Pathway edit]]

Statin Pathway edit

^ The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430". 

Inhibitors[edit] Drugs[edit] Drugs that inhibit HMG-CoA
HMG-CoA
reductase, known collectively as HMG-CoA reductase inhibitors (or "statins"), are used to lower serum cholesterol as a means of reducing the risk for cardiovascular disease.[8] These drugs include rosuvastatin (CRESTOR), lovastatin (Mevacor), atorvastatin (Lipitor), pravastatin (Pravachol), fluvastatin (Lescol), pitavastatin (Livalo), and simvastatin (Zocor).[9] Red yeast rice extract, one of the fungal sources from which the statins were discovered, contains several naturally occurring cholesterol-lowering molecules known as monacolins. The most active of these is monacolin K, or lovastatin (previously sold under the trade name Mevacor, and now available as generic lovastatin).[10] Vytorin
Vytorin
is drug that combines the use simvastatin and ezetimibe, which slows the formation of cholesterol by every cell in the body, along with ezetimibe reducing absorption of cholesterol, typically by about 53%, from the intestines.[11] Hormones[edit] HMG-CoA
HMG-CoA
reductase is active when blood glucose is high. The basic functions of insulin and glucagon are to maintain glucose homeostasis. Thus, in controlling blood sugar levels, they indirectly affect the activity of HMG-CoA
HMG-CoA
reductase, but a decrease in activity of the enzyme is caused by AMP-activated protein kinase[12], which responds to an increase in AMP concentration, and also to leptin Clinical significance[edit] Since the reaction catalysed by HMG-CoA
HMG-CoA
reductase is the rate-limiting step in cholesterol synthesis, this enzyme represents the sole major drug target for contemporary cholesterol-lowering drugs in humans. The medical significance of HMG-CoA
HMG-CoA
reductase has continued to expand beyond its direct role in cholesterol synthesis following the discovery that statins can offer cardiovascular health benefits independent of cholesterol reduction.[13] Statins
Statins
have been shown to have anti-inflammatory properties,[14] most likely as a result of their ability to limit production of key downstream isoprenoids that are required for portions of the inflammatory response. It can be noted that blocking of isoprenoid synthesis by statins has shown promise in treating a mouse model of multiple sclerosis, an inflammatory autoimmune disease.[15] HMG-CoA
HMG-CoA
reductase is an important developmental enzyme. Inhibition of its activity and the concomitant lack of isoprenoids that yields can lead to germ cell migration defects [16] as well as intracerebral hemorrhage.[17] Regulation[edit]

HMG-CoA
HMG-CoA
reductase-Substrate complex (Blue: Coenzyme
Coenzyme
A, red:HMG, green:NADP)

Regulation of HMG-CoA
HMG-CoA
reductase is achieved at several levels: transcription, translation, degradation and phosphorylation. Transcription of the reductase gene[edit] Transcription of the reductase gene is enhanced by the sterol regulatory element binding protein (SREBP). This protein binds to the sterol regulatory element (SRE), located on the 5' end of the reductase gene after controlled proteolytic processing. When SREBP is inactive, it is bound to the ER or nuclear membrane with another protein called SREBP cleavage-activating protein (SCAP). SCAP senses low cholesterol concentration and transports SREBP to the Golgi membrane where a consecutive proteolysis by S1P and S2P cleaves SREBP into a active nuclear form, nSREBP. nSREBPs migrate to the nucleus and activate transcription of SRE-containing genes. The nSREBP transcription factor is short-lived. If cholesterol levels rise, SCAP retains SREBP in the ER membrane. Translation of mRNA[edit] Translation of mRNA is inhibited by a mevalonate derivative, which has been reported to be the isoprenoid farnesol,[18][19] although this role has been disputed.[20] Degradation of reductase[edit] Rising levels of sterols increase the susceptibility of the reductase enzyme to ER-associated degradation (ERAD) and proteolysis. Helices 2-6 (total of 8) of the HMG-CoA
HMG-CoA
reductase transmembrane domain sense the higher levels of cholesterol, which leads to the exposure of Lysine 248. This lysine residue can become ubiquinated by the E3 ligase AMFR, serving as a signal for proteolytic degradation. Phosphorylation
Phosphorylation
of reductase[edit] Short-term regulation of HMG-CoA
HMG-CoA
reductase is achieved by inhibition by phosphorylation (of Serine 872, in humans[21]). Decades ago it was believed that a cascade of enzymes controls the activity of HMG-CoA reductase: an HMG-CoA
HMG-CoA
reductase kinase was thought to inactivate the enzyme, and the kinase in turn was held to be activated via phosphorylation by HMG-CoA
HMG-CoA
reductase kinase kinase. An excellent review on regulation of the mevalonate pathway by Nobel Laureates Joseph Goldstein and Michael Brown adds specifics: HMG-CoA
HMG-CoA
reductase is phosphorylated and inactivated by an AMP-activated protein kinase, which also phosphorylates and inactivates acetyl-CoA carboxylase, the rate-limiting enzyme of fatty acid biosynthesis.[22] Thus, both pathways utilizing acetyl-CoA for lipid synthesis are inactivated when energy charge is low in the cell, and concentrations of AMP rise. There has been a great deal of research on the identity of upstream kinases that phosphorylate and activate the AMP-activated protein kinase.[23] Fairly recently, LKB1 has been identified as a likely AMP kinase kinase,[24] which appears to involve calcium/calmodulin signaling. This pathway likely transduces signals from leptin, adiponectin, and other signaling molecules.[23] See also[edit]

Oxidoreductase

References[edit]

^ a b c GRCh38: Ensembl
Ensembl
release 89: ENSG00000113161 - Ensembl, May 2017 ^ a b c GRCm38: Ensembl
Ensembl
release 89: ENSMUSG00000021670 - Ensembl, May 2017 ^ "Human PubMed
PubMed
Reference:".  ^ "Mouse PubMed
PubMed
Reference:".  ^ " Entrez
Entrez
Gene: HMGCR
HMGCR
3-hydroxy-3-methylglutaryl- Coenzyme
Coenzyme
A reductase".  ^ Roitelman J, Olender EH, Bar-Nun S, Dunn WA, Simoni RD (Jun 1992). "Immunological evidence for eight spans in the membrane domain of 3-hydroxy-3-methylglutaryl coenzyme A reductase: implications for enzyme degradation in the endoplasmic reticulum". The Journal of Cell Biology. 117 (5): 959–73. doi:10.1083/jcb.117.5.959. PMC 2289486 . PMID 1374417.  ^ Lindgren V, Luskey KL, Russell DW, Francke U (Dec 1985). "Human genes involved in cholesterol metabolism: chromosomal mapping of the loci for the low density lipoprotein receptor and 3-hydroxy-3-methylglutaryl-coenzyme A reductase with cDNA probes". Proceedings of the National Academy of Sciences of the United States of America. 82 (24): 8567–71. Bibcode:1985PNAS...82.8567L. doi:10.1073/pnas.82.24.8567. PMC 390958 . PMID 3866240.  ^ Farmer JA (1998). "Aggressive lipid therapy in the statin era". Progress in Cardiovascular Diseases. 41 (2): 71–94. doi:10.1016/S0033-0620(98)80006-6. PMID 9790411.  ^ "Is there a "best" statin drug?". The Johns Hopkins Medical Letter Health After 50. 15 (11): 4–5. Jan 2004. PMID 14983817.  ^ Lin YL, Wang TH, Lee MH, Su NW (Jan 2008). "Biologically active components and nutraceuticals in the Monascus-fermented rice: a review". Applied Microbiology and Biotechnology. 77 (5): 965–73. doi:10.1007/s00253-007-1256-6. PMID 18038131.  ^ Flores NA (Sep 2004). " Ezetimibe
Ezetimibe
+ simvastatin (Merck/Schering-Plough)". Current Opinion in Investigational Drugs. 5 (9): 984–92. PMID 15503655.  ^ Hardie DG (February 1992). "Regulation of fatty acid and cholesterol metabolism by the AMP-activated protein kinase". Biochimica et Biophysica Acta. 1123 (3): 231–8. doi:10.1016/0005-2760(92)90001-c. PMID 1536860.  ^ Arnaud C, Veillard NR, Mach F (Apr 2005). "Cholesterol-independent effects of statins in inflammation, immunomodulation and atherosclerosis". Current Drug Targets. Cardiovascular & Haematological Disorders. 5 (2): 127–34. doi:10.2174/1568006043586198. PMID 15853754.  ^ Sorrentino S, Landmesser U (Dec 2005). "Nonlipid-lowering effects of statins". Current Treatment Options in Cardiovascular Medicine. 7 (6): 459–466. doi:10.1007/s11936-005-0031-1. PMID 16283973.  ^ Stüve O, Youssef S, Steinman L, Zamvil SS (Jun 2003). " Statins
Statins
as potential therapeutic agents in neuroinflammatory disorders". Current Opinion in Neurology. 16 (3): 393–401. doi:10.1097/00019052-200306000-00021. PMID 12858078.  ^ Thorpe JL, Doitsidou M, Ho SY, Raz E, Farber SA (Feb 2004). "Germ cell migration in zebrafish is dependent on HMGCoA reductase activity and prenylation". Developmental Cell. 6 (2): 295–302. doi:10.1016/S1534-5807(04)00032-2. PMID 14960282.  ^ Eisa-Beygi S, Hatch G, Noble S, Ekker M, Moon TW (Jan 2013). "The 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) pathway regulates developmental cerebral-vascular stability via prenylation-dependent signalling pathway". Developmental Biology. 373 (2): 258–266. doi:10.1016/j.ydbio.2012.11.024. PMID 23206891.  ^ Meigs TE, Roseman DS, Simoni RD (Apr 1996). "Regulation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase degradation by the nonsterol mevalonate metabolite farnesol in vivo". The Journal of Biological Chemistry. 271 (14): 7916–22. doi:10.1074/jbc.271.14.7916. PMID 8626470.  ^ Meigs TE, Simoni RD (Sep 1997). " Farnesol
Farnesol
as a regulator of HMG-CoA reductase degradation: characterization and role of farnesyl pyrophosphatase". Archives of Biochemistry and Biophysics. 345 (1): 1–9. doi:10.1006/abbi.1997.0200. PMID 9281305.  ^ Keller RK, Zhao Z, Chambers C, Ness GC (Apr 1996). " Farnesol
Farnesol
is not the nonsterol regulator mediating degradation of HMG-CoA
HMG-CoA
reductase in rat liver". Archives of Biochemistry and Biophysics. 328 (2): 324–30. doi:10.1006/abbi.1996.0180. PMID 8645011.  ^ Istvan ES, Palnitkar M, Buchanan SK, Deisenhofer J (Mar 2000). "Crystal structure of the catalytic portion of human HMG-CoA reductase: insights into regulation of activity and catalysis". The EMBO Journal. 19 (5): 819–30. doi:10.1093/emboj/19.5.819. PMC 305622 . PMID 10698924.  ^ Goldstein JL, Brown MS (Feb 1990). "Regulation of the mevalonate pathway". Nature. 343 (6257): 425–30. Bibcode:1990Natur.343..425G. doi:10.1038/343425a0. PMID 1967820.  ^ a b Hardie DG, Scott JW, Pan DA, Hudson ER (Jul 2003). "Management of cellular energy by the AMP-activated protein kinase
AMP-activated protein kinase
system". FEBS Letters. 546 (1): 113–20. doi:10.1016/S0014-5793(03)00560-X. PMID 12829246.  ^ Witters LA, Kemp BE, Means AR (Jan 2006). "Chutes and Ladders: the search for protein kinases that act on AMPK". Trends in Biochemical Sciences. 31 (1): 13–6. doi:10.1016/j.tibs.2005.11.009. PMID 16356723. 

Further reading[edit]

Hodge VJ, Gould SJ, Subramani S, Moser HW, Krisans SK (Dec 1991). "Normal cholesterol synthesis in human cells requires functional peroxisomes". Biochemical and Biophysical Research Communications. 181 (2): 537–41. doi:10.1016/0006-291X(91)91222-X. PMID 1755834.  Ramharack R, Tam SP, Deeley RG (Nov 1990). "Characterization of three distinct size classes of human 3-hydroxy-3-methylglutaryl coenzyme A reductase mRNA: expression of the transcripts in hepatic and nonhepatic cells". DNA and Cell Biology. 9 (9): 677–90. doi:10.1089/dna.1990.9.677. PMID 1979742.  Clarke PR, Hardie DG (Aug 1990). "Regulation of HMG-CoA
HMG-CoA
reductase: identification of the site phosphorylated by the AMP-activated protein kinase in vitro and in intact rat liver". The EMBO Journal. 9 (8): 2439–46. PMC 552270 . PMID 2369897.  Luskey KL, Stevens B (Aug 1985). "Human 3-hydroxy-3-methylglutaryl coenzyme A reductase. Conserved domains responsible for catalytic activity and sterol-regulated degradation". The Journal of Biological Chemistry. 260 (18): 10271–7. PMID 2991281.  Humphries SE, Tata F, Henry I, Barichard F, Holm M, Junien C, Williamson R (1986). "The isolation, characterisation, and chromosomal assignment of the gene for human 3-hydroxy-3-methylglutaryl coenzyme A reductase, ( HMG-CoA
HMG-CoA
reductase)". Human Genetics. 71 (3): 254–8. doi:10.1007/BF00284585. PMID 2998972.  Beg ZH, Stonik JA, Brewer HB (Sep 1987). " Phosphorylation
Phosphorylation
and modulation of the enzymic activity of native and protease-cleaved purified hepatic 3-hydroxy-3-methylglutaryl-coenzyme A reductase by a calcium/calmodulin-dependent protein kinase". The Journal of Biological Chemistry. 262 (27): 13228–40. PMID 3308873.  Osborne TF, Goldstein JL, Brown MS (Aug 1985). "5' end of HMG CoA reductase gene contains sequences responsible for cholesterol-mediated inhibition of transcription". Cell. 42 (1): 203–12. doi:10.1016/S0092-8674(85)80116-1. PMID 3860301.  Lindgren V, Luskey KL, Russell DW, Francke U (Dec 1985). "Human genes involved in cholesterol metabolism: chromosomal mapping of the loci for the low density lipoprotein receptor and 3-hydroxy-3-methylglutaryl-coenzyme A reductase with cDNA probes". Proceedings of the National Academy of Sciences of the United States of America. 82 (24): 8567–71. Bibcode:1985PNAS...82.8567L. doi:10.1073/pnas.82.24.8567. PMC 390958 . PMID 3866240.  Lehoux JG, Kandalaft N, Belisle S, Bellabarba D (Oct 1985). "Characterization of 3-hydroxy-3-methylglutaryl coenzyme A reductase in human adrenal cortex". Endocrinology. 117 (4): 1462–8. doi:10.1210/endo-117-4-1462. PMID 3896758.  Boguslawski W, Sokolowski W (1984). " HMG-CoA
HMG-CoA
reductase activity in the microsomal fraction from human placenta in early and term pregnancy". The International Journal of Biochemistry. 16 (9): 1023–6. doi:10.1016/0020-711X(84)90120-4. PMID 6479432.  Harwood HJ, Schneider M, Stacpoole PW (Sep 1984). "Measurement of human leukocyte microsomal HMG-CoA
HMG-CoA
reductase activity". Journal of Lipid Research. 25 (9): 967–78. PMID 6491541.  Nguyen LB, Salen G, Shefer S, Bullock J, Chen T, Tint GS, Chowdhary IR, Lerner S (Jul 1994). "Deficient ileal 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in sitosterolemia: sitosterol is not a feedback inhibitor of intestinal cholesterol biosynthesis". Metabolism. 43 (7): 855–9. doi:10.1016/0026-0495(94)90266-6. PMID 8028508.  Bennis F, Favre G, Le Gaillard F, Soula G (Oct 1993). "Importance of mevalonate-derived products in the control of HMG-CoA
HMG-CoA
reductase activity and growth of human lung adenocarcinoma cell line A549". International Journal of Cancer. 55 (4): 640–5. doi:10.1002/ijc.2910550421. PMID 8406993.  Van Doren M, Broihier HT, Moore LA, Lehmann R (Dec 1998). "HMG-CoA reductase guides migrating primordial germ cells". Nature. 396 (6710): 466–9. Bibcode:1998Natur.396..466V. doi:10.1038/24871. PMID 9853754.  Cargill M, Altshuler D, Ireland J, Sklar P, Ardlie K, Patil N, Shaw N, Lane CR, Lim EP, Kalyanaraman N, Nemesh J, Ziaugra L, Friedland L, Rolfe A, Warrington J, Lipshutz R, Daley GQ, Lander ES (Jul 1999). "Characterization of single-nucleotide polymorphisms in coding regions of human genes". Nature Genetics. 22 (3): 231–8. doi:10.1038/10290. PMID 10391209.  Aboushadi N, Engfelt WH, Paton VG, Krisans SK (Sep 1999). "Role of peroxisomes in isoprenoid biosynthesis". The Journal of Histochemistry and Cytochemistry. 47 (9): 1127–32. doi:10.1177/002215549904700904. PMID 10449533.  Honda A, Salen G, Honda M, Batta AK, Tint GS, Xu G, Chen TS, Tanaka N, Shefer S (Feb 2000). "3-Hydroxy-3-methylglutaryl-coenzyme A reductase activity is inhibited by cholesterol and up-regulated by sitosterol in sitosterolemic fibroblasts". The Journal of Laboratory and Clinical Medicine. 135 (2): 174–9. doi:10.1067/mlc.2000.104459. PMID 10695663.  Istvan ES, Palnitkar M, Buchanan SK, Deisenhofer J (Mar 2000). "Crystal structure of the catalytic portion of human HMG-CoA reductase: insights into regulation of activity and catalysis". The EMBO Journal. 19 (5): 819–30. doi:10.1093/emboj/19.5.819. PMC 305622 . PMID 10698924.  Istvan ES, Deisenhofer J (May 2001). "Structural mechanism for statin inhibition of HMG-CoA
HMG-CoA
reductase". Science. 292 (5519): 1160–4. Bibcode:2001Sci...292.1160I. doi:10.1126/science.1059344. PMID 11349148.  Rasmussen LM, Hansen PR, Nabipour MT, Olesen P, Kristiansen MT, Ledet T (Dec 2001). "Diverse effects of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase on the expression of VCAM-1 and E-selectin in endothelial cells". The Biochemical Journal. 360 (Pt 2): 363–70. doi:10.1042/0264-6021:3600363. PMC 1222236 . PMID 11716764. 

External links[edit]

Cholesterol
Cholesterol
Synthesis - has some good regulatory details Proteopedia HMG-CoA_Reductase - the HMG-CoA
HMG-CoA
Reductase Structure in Interactive 3D

v t e

PDB gallery

1dq8: COMPLEX OF THE CATALYTIC PORTION OF HUMAN HMG-COA REDUCTASE WITH HMG AND COA 

1dq9: COMPLEX OF CATALYTIC PORTION OF HUMAN HMG-COA REDUCTASE WITH HMG-COA 

1dqa: COMPLEX OF THE CATALYTIC PORTION OF HUMAN HMG-COA REDUCTASE WITH HMG, COA, AND NADP+ 

1hw8: COMPLEX OF THE CATALYTIC PORTION OF HUMAN HMG-COA REDUCTASE WITH COMPACTIN (ALSO KNOWN AS MEVASTATIN) 

1hw9: COMPLEX OF THE CATALYTIC PORTION OF HUMAN HMG-COA REDUCTASE WITH SIMVASTATIN 

1hwi: COMPLEX OF THE CATALYTIC PORTION OF HUMAN HMG-COA REDUCTASE WITH FLUVASTATIN 

1hwj: COMPLEX OF THE CATALYTIC PORTION OF HUMAN HMG-COA REDUCTASE WITH CERIVASTATIN 

1hwk: COMPLEX OF THE CATALYTIC PORTION OF HUMAN HMG-COA REDUCTASE WITH ATORVASTATIN 

1hwl: COMPLEX OF THE CATALYTIC PORTION OF HUMAN HMG-COA REDUCTASE WITH ROSUVASTATIN (FORMALLY KNOWN AS ZD4522) 

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Metabolism: lipid metabolism – ketones/cholesterol synthesis enzymes/steroid metabolism

Mevalonate
Mevalonate
pathway

To HMG-CoA

Acetyl- Coenzyme A
Coenzyme A
acetyltransferase HMG-CoA
HMG-CoA
synthase (regulated step)

Ketogenesis

HMG-CoA
HMG-CoA
lyase 3-hydroxybutyrate dehydrogenase Thiophorase

To Mevalonic acid

HMG-CoA
HMG-CoA
reductase

To DMAPP

Mevalonate
Mevalonate
kinase Phosphomevalonate kinase Pyrophosphomevalonate decarboxylase Isopentenyl-diphosphate delta isomerase

Geranyl-

Dimethylallyltranstransferase Geranyl pyrophosphate

To cholesterol

To lanosterol

Farnesyl-diphosphate farnesyltransferase Squalene
Squalene
monooxygenase Lanosterol
Lanosterol
synthase

7-Dehydrocholesterol
7-Dehydrocholesterol
path

Lanosterol
Lanosterol
14α-demethylase Sterol-C5-desaturase-like 7-Dehydrocholesterol
7-Dehydrocholesterol
reductase

Desmosterol
Desmosterol
path

24-Dehydrocholesterol reductase

To Bile acids

Cholesterol
Cholesterol
7α-hydroxylase Sterol
Sterol
27-hydroxylase

Steroidogenesis

To pregnenolone

Cholesterol
Cholesterol
side-chain cleavage

To corticosteroids

aldosterone: 18-Hydroxylase

cortisol/cortisone: 17α-Hydroxylase 11β-HSD

1 2

both: 3β-HSD

1 2

21-Hydroxylase 11β-Hydroxylase

To sex hormones

To androgens

17α-Hydroxylase 17,20-Lyase 3β-HSD 17β-HSD 5α-Reductase

1 2

To estrogens

Aromatase 17β-HSD

Other/ungrouped

Steroid metabolism: sulfatase

Steroid sulfatase

sulfotransferase

SULT1A1 SULT2A1

Steroidogenic acute regulatory protein Cholesterol
Cholesterol
total synthesis Reverse cholesterol transport

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Oxidoreductases: alcohol oxidoreductases (EC 1.1)

1.1.1: NAD/NADP acceptor

3-hydroxyacyl-CoA dehydrogenase 3-hydroxybutyryl-CoA dehydrogenase Alcohol dehydrogenase Aldo-keto reductase

1A1 1B1 1B10 1C1 1C3 1C4 7A2

Aldose reductase Beta-Ketoacyl ACP reductase Carbohydrate dehydrogenases Carnitine dehydrogenase D-malate dehydrogenase (decarboxylating) DXP reductoisomerase Glucose-6-phosphate dehydrogenase Glycerol-3-phosphate dehydrogenase HMG-CoA
HMG-CoA
reductase IMP dehydrogenase Isocitrate dehydrogenase Lactate dehydrogenase L-threonine dehydrogenase L-xylulose reductase Malate dehydrogenase Malate dehydrogenase
Malate dehydrogenase
(decarboxylating) Malate dehydrogenase
Malate dehydrogenase
(NADP+) Malate dehydrogenase
Malate dehydrogenase
(oxaloacetate-decarboxylating) Malate dehydrogenase
Malate dehydrogenase
(oxaloacetate-decarboxylating) (NADP+) Phosphogluconate dehydrogenase Sorbitol dehydrogenase

Hydroxysteroid dehydrogenase: 3β

3β-HSD NSDHL

11β

11β-HSD1 11β-HSD2

17β

1.1.2: cytochrome acceptor

D-lactate dehydrogenase (cytochrome) D-lactate dehydrogenase (cytochrome c-553) Mannitol dehydrogenase (cytochrome)

1.1.3: oxygen acceptor

Glucose oxidase L-gulonolactone oxidase Xanthine oxidase

1.1.4: disulfide as acceptor

Vitamin K epoxide reductase Vitamin-K-epoxide reductase (warfarin-insensitive)

1.1.5: quinone/similar acceptor

Malate dehydrogenase
Malate dehydrogenase
(quinone) Quinoprotein glucose dehydrogenase

1.1.99: other acceptors

Choline dehydrogenase L2HGDH

v t e

Enzymes

Activity

Active site Binding site Catalytic triad Oxyanion hole Enzyme
Enzyme
promiscuity Catalytically perfect enzyme Coenzyme Cofactor Enzyme
Enzyme
catalysis

Regulation

Allosteric regulation Cooperativity Enzyme
Enzyme
inhibitor

Classification

EC number Enzyme
Enzyme
superfamily Enzyme
Enzyme
family List of enzymes

Kinetics

Enzyme
Enzyme
kinetics Eadie–Hofstee diagram Hanes–Woolf plot Lineweaver–Burk plot Michaelis–Menten kinetics

Types

EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list)

Molecular and Cellular Bi

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