HMG-CoA reductase

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HMGCR
Protein HMGCR PDB 1dq8.png
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesHMGCR, HMG-CoA reductase, Entrez 3156, LDLCQ3, 3-hydroxy-3-methylglutaryl-CoA reductase, Hydroxymethylglutaryl-CoA reductase
External IDsOMIM: 142910 MGI: 96159 HomoloGene: 30994 GeneCards: HMGCR
Gene location (Human)
Chromosome 5 (human)
Chr.Chromosome 5 (human)[1]
Chromosome 5 (human)
Genomic location for HMGCR
Genomic location for HMGCR
Band5q13.3Start75,336,329 bp[1]
End75,362,104 bp[1]
RNA expression pattern
PBB GE HMGCR 202540 s at fs.png

PBB GE HMGCR 202539 s at fs.png
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_000859
NM_001130996
NM_001364187

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 MbChr 13: 96.65 – 96.67 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
HMG-CoA reductase
EC number{{{EC_number}}}
Gene OntologyAmiGO / QuickGO
hydroxymethylglutaryl-CoA reductase
Identifiers
EC number1.1.1.88
CAS number37250-24-1
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
hydroxymethylglutaryl-CoA reductase
Identifiers
EC number1.1.1.34
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum

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 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 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 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.

Structure[edit]

The main isoform (isoform 1) of 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:

  • a conserved N-terminal sterol-sensing domain (SSD, amino acid interval: 88–218). The related SSD of SCAP has been shown to bind cholesterol.[8][9]
  • 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 (amino acids 522–574). This does not affect any of the aforementioned domains.

Function[edit]

HMGCR catalyses the conversion of HMG-CoA to mevalonic acid, a necessary step in the biosynthesis of cholesterol:

Mevalonate pathway

Interactive pathway map[edit]

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

[[File:
Statin_Pathway_WP430go to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to article
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Statin_Pathway_WP430go to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to article
|px|alt=Statin Pathway edit]]
Statin Pathway edit
  1. ^ The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430".

Inhibitors[edit]

Drugs[edit]

Drugs that inhibit 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.[10]

These drugs include rosuvastatin (CRESTOR), lovastatin (Mevacor), atorvastatin (Lipitor), pravastatin (Pravachol), fluvastatin (Lescol), pitavastatin (Livalo), and simvastatin (Zocor).[11] 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).[12]

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.[13]

Hormones[edit]

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 reductase, but a decrease in activity of the enzyme is caused by AMP-activated protein kinase,[14] which responds to an increase in AMP concentration, and also to leptin

Clinical significance[edit]

Since the reaction catalysed by 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 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.[15] Statins have been shown to have anti-inflammatory properties,[16] 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.[17]

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 [18] as well as intracerebral hemorrhage.[19]

Regulation[edit]

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

Regulation of HMG-CoA reductase is achieved at several levels: transcription, translation, degradation and phosphorylation.

Transcription[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 an active nuclear form, nSREBP. nSREBPs migrate to the nucleus and activate transcription of SRE-containing genes. The nSREBP transcription factor is short-lived. When cholesterol levels rise, Insigs retains the SCAP-SREBP complex in the ER membrane by preventing its incorporation into COPII vesicles.[20][21]

Translation[edit]

Translation of mRNA is inhibited by a mevalonate derivative, which has been reported to be the isoprenoid farnesol,[22][23] although this role has been disputed.[24]

Degradation[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 reductase transmembrane domain are thought to sense increased cholesterol levels (direct sterol binding to the SSD of HMG-CoA reductase has not been demonstrated). Lysine residues 89 and 248 can become ubiquinated by ER-resident E3 ligases. The identity of the multiple E3 ligases involved in HMG-CoA degradation is controversial, with suggested candidates being AMFR,[25] Trc8,[26] and RNF145[27] The involvement of AMFR and Trc8 has been contested.[28]

Phosphorylation[edit]

Short-term regulation of HMG-CoA reductase is achieved by inhibition by phosphorylation (of Serine 872, in humans[29]). Decades ago it was believed that a cascade of enzymes controls the activity of HMG-CoA reductase: an 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 reductase kinase kinase. An excellent review on regulation of the mevalonate pathway by Nobel Laureates Joseph Goldstein and Michael Brown adds specifics: 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.[30] 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.[31]

Fairly recently, LKB1 has been identified as a likely AMP kinase kinase,[32] which appears to involve calcium/calmodulin signaling. This pathway likely transduces signals from leptin, adiponectin, and other signaling molecules.[31]

See also[edit]

References[edit]

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000113161 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000021670 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:".
  4. ^ "Mouse PubMed Reference:".
  5. ^ "Entrez Gene: HMGCR 3-hydroxy-3-methylglutaryl-Coenzyme A reductase".
  6. ^ Roitelman J, Olender EH, Bar-Nun S, Dunn WA, Simoni RD (June 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.
  7. ^ Lindgren V, Luskey KL, Russell DW, Francke U (December 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.
  8. ^ Brown MS, Radhakrishnan A, Goldstein JL (August 2017). "Retrospective on Cholesterol Homeostasis: The Central Role of Scap". Annual Review of Biochemistry. doi:10.1146/annurev-biochem-062917-011852. PMC 5828883. PMID 28841344.
  9. ^ Radhakrishnan A, Sun LP, Kwon HJ, Brown MS, Goldstein JL (July 2004). "Direct binding of cholesterol to the purified membrane region of SCAP: mechanism for a sterol-sensing domain". Molecular Cell. 15 (2): 259–68. doi:10.1016/j.molcel.2004.06.019. PMID 15260976.
  10. ^ 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.
  11. ^ "Is there a "best" statin drug?". The Johns Hopkins Medical Letter Health After 50. 15 (11): 4–5. January 2004. PMID 14983817.
  12. ^ Lin YL, Wang TH, Lee MH, Su NW (January 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.
  13. ^ Flores NA (September 2004). "Ezetimibe + simvastatin (Merck/Schering-Plough)". Current Opinion in Investigational Drugs. 5 (9): 984–92. PMID 15503655.
  14. ^ 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.
  15. ^ Arnaud C, Veillard NR, Mach F (April 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.
  16. ^ Sorrentino S, Landmesser U (December 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.
  17. ^ Stüve O, Youssef S, Steinman L, Zamvil SS (June 2003). "Statins as potential therapeutic agents in neuroinflammatory disorders". Current Opinion in Neurology. 16 (3): 393–401. doi:10.1097/00019052-200306000-00021. PMID 12858078.
  18. ^ Thorpe JL, Doitsidou M, Ho SY, Raz E, Farber SA (February 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.
  19. ^ Eisa-Beygi S, Hatch G, Noble S, Ekker M, Moon TW (January 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.
  20. ^ Sun LP, Seemann J, Goldstein JL, Brown MS (April 2007). "Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi: Insig renders sorting signal in Scap inaccessible to COPII proteins". Proceedings of the National Academy of Sciences of the United States of America. 104 (16): 6519–26. Bibcode:2007PNAS..104.6519S. doi:10.1073/pnas.0700907104. PMC 1851663. PMID 17428919.
  21. ^ Sun LP, Li L, Goldstein JL, Brown MS (July 2005). "Insig required for sterol-mediated inhibition of Scap/SREBP binding to COPII proteins in vitro". The Journal of Biological Chemistry. 280 (28): 26483–90. doi:10.1074/jbc.M504041200. PMID 15899885.
  22. ^ Meigs TE, Roseman DS, Simoni RD (April 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.
  23. ^ Meigs TE, Simoni RD (September 1997). "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.
  24. ^ Keller RK, Zhao Z, Chambers C, Ness GC (April 1996). "Farnesol is not the nonsterol regulator mediating degradation of HMG-CoA reductase in rat liver". Archives of Biochemistry and Biophysics. 328 (2): 324–30. doi:10.1006/abbi.1996.0180. PMID 8645011.
  25. ^ Song BL, Sever N, DeBose-Boyd RA (September 2005). "Gp78, a membrane-anchored ubiquitin ligase, associates with Insig-1 and couples sterol-regulated ubiquitination to degradation of HMG CoA reductase". Molecular Cell. 19 (6): 829–40. doi:10.1016/j.molcel.2005.08.009. PMID 16168377.
  26. ^ Jo Y, Lee PC, Sguigna PV, DeBose-Boyd RA (December 2011). "Sterol-induced degradation of HMG CoA reductase depends on interplay of two Insigs and two ubiquitin ligases, gp78 and Trc8". Proceedings of the National Academy of Sciences of the United States of America. 108 (51): 20503–8. Bibcode:2011PNAS..10820503J. doi:10.1073/pnas.1112831108. PMC 3251157. PMID 22143767.
  27. ^ Jiang LY, Jiang W, Tian N, Xiong YN, Liu J, Wei J, Wu KY, Luo J, Shi XJ, Song BL (March 2018). "Ring finger protein 145 (RNF145) is a ubiquitin ligase for sterol-induced degradation of HMG-CoA reductase". The Journal of Biological Chemistry. 293 (11): 4047–4055. doi:10.1074/jbc.RA117.001260. PMC 5857978. PMID 29374057.
  28. ^ Tsai YC, Leichner GS, Pearce MM, Wilson GL, Wojcikiewicz RJ, Roitelman J, Weissman AM (December 2012). "Differential regulation of HMG-CoA reductase and Insig-1 by enzymes of the ubiquitin-proteasome system". Molecular Biology of the Cell. 23 (23): 4484–94. doi:10.1091/mbc.E12-08-0631. PMC 3510011. PMID 23087214.
  29. ^ Istvan ES, Palnitkar M, Buchanan SK, Deisenhofer J (March 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.
  30. ^ Goldstein JL, Brown MS (February 1990). "Regulation of the mevalonate pathway". Nature. 343 (6257): 425–30. Bibcode:1990Natur.343..425G. doi:10.1038/343425a0. PMID 1967820.
  31. ^ a b Hardie DG, Scott JW, Pan DA, Hudson ER (July 2003). "Management of cellular energy by the AMP-activated protein kinase system". FEBS Letters. 546 (1): 113–20. doi:10.1016/S0014-5793(03)00560-X. PMID 12829246.
  32. ^ Witters LA, Kemp BE, Means AR (January 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]

External links[edit]