View source for HMG-CoA reductase

{{Short description|Mammalian protein found in Homo sapiens}}
{{Use dmy dates|date=June 2018}}
{{Infobox_gene}}
{{enzyme
| Name = hydroxymethylglutaryl-CoA reductase (NADH)
| EC_number = 1.1.1.88
| CAS_number = 37250-24-1
| GO_code = 0042282
| image = 
| width = 
| caption = 
}}
{{enzyme
| Name = hydroxymethylglutaryl-CoA reductase (NADPH)
| EC_number = 1.1.1.34
| CAS_number = 
| GO_code = 0004420
| image = 1dqa.jpg
| width = 270
| caption = HMG-CoA reductase (NADPH), Human
}}

'''HMG-CoA reductase''' ('''3-hydroxy-3-methyl-glutaryl-coenzyme A reductase''', official symbol '''HMGCR''') is the rate-limiting [[enzyme]] (NADH-dependent, {{EC number|1.1.1.88}}; NADPH-dependent, {{EC number|1.1.1.34}}) of the [[mevalonate pathway]], the metabolic pathway that produces [[cholesterol]] and other [[isoprenoids]]. HMGCR [[catalysis|catalyzes]] the conversion of [[HMG-CoA]] to [[mevalonic acid]], a necessary step in the [[biosynthesis]] of cholesterol. Normally in [[mammal]]ian cells this enzyme is competitively suppressed so that its effect is controlled. This enzyme is the target of the widely available cholesterol-lowering drugs known collectively as the [[statin]]s, which help treat [[dyslipidemia]].

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.<ref name="pmid1374417">{{cite journal | vauthors = Roitelman J, Olender EH, Bar-Nun S, Dunn WA, Simoni RD | title = 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 | journal = The Journal of Cell Biology | volume = 117 | issue = 5 | pages = 959–973 | date = June 1992 | pmid = 1374417 | pmc = 2289486 | doi = 10.1083/jcb.117.5.959 }}</ref>

In humans, the gene for HMG-CoA reductase (NADPH) is located on the long arm of the fifth [[chromosome]] (5q13.3-14).<ref name="pmid3866240">{{cite journal | vauthors = Lindgren V, Luskey KL, Russell DW, Francke U | title = 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 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 82 | issue = 24 | pages = 8567–8571 | date = December 1985 | pmid = 3866240 | pmc = 390958 | doi = 10.1073/pnas.82.24.8567 | doi-access = free | bibcode = 1985PNAS...82.8567L }}</ref> Related enzymes having the same function are also present in other animals, plants and bacteria.

== Structure ==
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 helix|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.<ref>{{cite journal | vauthors = Brown MS, Radhakrishnan A, Goldstein JL | title = Retrospective on Cholesterol Homeostasis: The Central Role of Scap | journal = Annual Review of Biochemistry | volume = 87 | pages = 783–807 | date = June 2018 | pmid = 28841344 | pmc = 5828883 | doi = 10.1146/annurev-biochem-062917-011852 }}</ref><ref>{{cite journal | vauthors = Radhakrishnan A, Sun LP, Kwon HJ, Brown MS, Goldstein JL | title = Direct binding of cholesterol to the purified membrane region of SCAP: mechanism for a sterol-sensing domain | journal = Molecular Cell | volume = 15 | issue = 2 | pages = 259–268 | date = July 2004 | pmid = 15260976 | doi = 10.1016/j.molcel.2004.06.019 | doi-access = free }}</ref>
*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.<ref>{{cite journal | vauthors = Costa CH, Oliveira AR, Dos Santos AM, da Costa KS, Lima AH, Alves CN, Lameira J | title = Computational study of conformational changes in human 3-hydroxy-3-methylglutaryl coenzyme reductase induced by substrate binding | journal = Journal of Biomolecular Structure & Dynamics | volume = 37 | issue = 16 | pages = 4374–4383 | date = October 2019 | pmid = 30470158 | doi = 10.1080/07391102.2018.1549508 | s2cid = 53717806 }}</ref>

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 ==
HMGCR catalyses the conversion of [[HMG-CoA]] to [[mevalonic acid]], a necessary step in the [[biosynthesis]] of cholesterol:
{|
|[[Image:Mevalonate pathway.svg|450px|left|[[Mevalonate pathway]]]]
|}

Normally in mammalian cells this enzyme is competitively 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]].<ref name="entrez">{{cite web | title = Entrez Gene: HMGCR 3-hydroxy-3-methylglutaryl-Coenzyme A reductase| url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=3156}}</ref> This enzyme is thus the target of the widely available cholesterol-lowering drugs known collectively as the [[statins]] (see ''[[#Drugs|Drugs]]'' section for more).

In ''Drosophila melanogaster'', Hmgcr is the homolog of Human HMGCR, and plays crucial roles in regulating energy metabolism and food intake but also sleep homeostasis through the central mechanisms according to these studies.{{Citation needed|date=October 2025}} 

===Interactive pathway map===
{{StatinPathway_WP430|highlight=HMGCR}}

== Inhibitors ==

=== Drugs ===
Drugs that inhibit HMG-CoA reductase, known collectively as [[HMG-CoA reductase inhibitor]]s (or "statins"), are used to lower serum [[cholesterol]] as a means of reducing the risk for [[heart disease|cardiovascular disease]].<ref name="pmid9790411">{{cite journal | vauthors = Farmer JA | title = Aggressive lipid therapy in the statin era | journal = Progress in Cardiovascular Diseases | volume = 41 | issue = 2 | pages = 71–94 | year = 1998 | pmid = 9790411 | doi = 10.1016/S0033-0620(98)80006-6 }}</ref>

These drugs include [[rosuvastatin]] (CRESTOR), [[lovastatin]] (Mevacor), [[atorvastatin]] (Lipitor), [[pravastatin]] (Pravachol), [[fluvastatin]] (Lescol), [[pitavastatin]] (Livalo), and [[simvastatin]] (Zocor).<ref name="pmid14983817">{{cite journal | vauthors =  | title = Is there a "best" statin drug? | journal = The Johns Hopkins Medical Letter Health After 50 | volume = 15 | issue = 11 | pages = 4–5 | date = January 2004 | pmid = 14983817 }}</ref> [[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).<ref name="pmid18038131">{{cite journal | vauthors = Lin YL, Wang TH, Lee MH, Su NW | title = Biologically active components and nutraceuticals in the Monascus-fermented rice: a review | journal = Applied Microbiology and Biotechnology | volume = 77 | issue = 5 | pages = 965–973 | date = January 2008 | pmid = 18038131 | doi = 10.1007/s00253-007-1256-6 | s2cid = 33299544 | url = http://ntur.lib.ntu.edu.tw/bitstream/246246/215068/-1/b.pdf }}</ref>

[[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.<ref name="pmid15503655">{{cite journal | vauthors = Flores NA | title = Ezetimibe + simvastatin (Merck/Schering-Plough) | journal = Current Opinion in Investigational Drugs | volume = 5 | issue = 9 | pages = 984–992 | date = September 2004 | pmid = 15503655 }}</ref>

Statins, HMG-CoA reductase inhibitors, are competent in lowering cholesterol levels and reducing cardiac-related diseases. However, there have been controversies surrounding the potential of statins increasing the risk of new-onset diabetes mellitus (NOD). Experiments have demonstrated that glucose and cholesterol homeostasis are regulated by statins. The HMG-CoA reductase (HMGCR), converts HMG-CoA into mevalonic acid. Thus, when HMGCR activities are reduced, the cell associated cholesterols are also reduced. This results in the activation of SREBP-2-mediated signaling pathways. SREBP-2 activation for cholesterol homeostasis is crucial for the upregulation of low density lipoprotein (LDL) receptor (LDLR). The removal of LDL particles from blood circulation is enhanced when the number of LDLR on hepatocytes increases. Due to the removal of atherogenic lipoprotein particles, such as LDLs and intermediate density lipoproteins, HMGCR inhibitors have been proven to be efficient in reducing cardiovascular diseases from the blood circulation, which is represented by the reduction of LDL-cholesterol levels. In many studies, lipophilic statins are shown as more diabetogenic, possibly due to the fact that they can easily diffuse into cells and inhibit the production of isoprenoids which become more potent. Additionally, statins have been shown to change glucose levels as well.<ref>{{cite journal | vauthors = Han KH | title = Functional Implications of HMG-CoA Reductase Inhibition on Glucose Metabolism | journal = Korean Circulation Journal | volume = 48 | issue = 11 | pages = 951–963 | date = November 2018 | pmid = 30334382 | pmc = 6196158 | doi = 10.4070/kcj.2018.0307 | publisher = The Korean Society of Cardiology }}</ref>

=== Hormones ===
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]],<ref>{{cite journal | vauthors = Hardie DG | title = Regulation of fatty acid and cholesterol metabolism by the AMP-activated protein kinase | journal = Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism | volume = 1123 | issue = 3 | pages = 231–238 | date = February 1992 | pmid = 1536860 | doi = 10.1016/0005-2760(92)90001-c }}</ref> which responds to an increase in [[Adenosine monophosphate|AMP]] concentration, and also to [[leptin]].

== Clinical significance ==
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.<ref name=pmid15853754>{{cite journal | vauthors = Arnaud C, Veillard NR, Mach F | title = Cholesterol-independent effects of statins in inflammation, immunomodulation and atherosclerosis | journal = Current Drug Targets. Cardiovascular & Hematological Disorders| volume = 5 | issue = 2 | pages = 127–134 | date = April 2005 | pmid = 15853754 | doi = 10.2174/1568006043586198 }}</ref> Statins have been shown to have anti-inflammatory properties,<ref name=pmid16283973>{{cite journal | vauthors = Sorrentino S, Landmesser U | title = Nonlipid-lowering effects of statins | journal = Current Treatment Options in Cardiovascular Medicine | volume = 7 | issue = 6 | pages = 459–466 | date = December 2005 | pmid = 16283973 | doi = 10.1007/s11936-005-0031-1 | author-link2 = Ulf Landmesser | s2cid = 44918429 }}</ref> 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.<ref name="pmid12858078">{{cite journal | vauthors = Stüve O, Youssef S, Steinman L, Zamvil SS | title = Statins as potential therapeutic agents in neuroinflammatory disorders | journal = Current Opinion in Neurology | volume = 16 | issue = 3 | pages = 393–401 | date = June 2003 | pmid = 12858078 | doi = 10.1097/00019052-200306000-00021 }}</ref>

Inhibition of HMG-CoA reductase by statins is lessened in patients with [[type 2 diabetes]], which results in lessened inhibition of [[Coronary artery disease|coronary]] [[Atheroma|atheromatous plaque]], development.<ref name="pmid33834073">{{cite journal | vauthors = Mashayekhi-Sardoo H, Atkin SL, Montecucco F, Sahebkar A | title = Potential Alteration of Statin-Related Pharmacological Features in Diabetes Mellitus | journal = BioMed Research International | volume = 2021 | article-number = 6698743 | year = 2021 | pmid = 33834073 | pmc = 8018846 | doi = 10.1155/2021/6698743 | doi-access = free }}</ref>

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<ref name="pmid14960282">{{cite journal | vauthors = Thorpe JL, Doitsidou M, Ho SY, Raz E, Farber SA | title = Germ cell migration in zebrafish is dependent on HMGCoA reductase activity and prenylation | journal = Developmental Cell | volume = 6 | issue = 2 | pages = 295–302 | date = February 2004 | pmid = 14960282 | doi = 10.1016/S1534-5807(04)00032-2 | doi-access = free | hdl = 11858/00-001M-0000-0012-EE5B-7 | hdl-access = free }}</ref> as well as intracerebral hemorrhage.<ref name="pmid23206891">{{cite journal | vauthors = Eisa-Beygi S, Hatch G, Noble S, Ekker M, Moon TW | title = The 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) pathway regulates developmental cerebral-vascular stability via prenylation-dependent signalling pathway | journal = Developmental Biology | volume = 373 | issue = 2 | pages = 258–266 | date = January 2013 | pmid = 23206891 | doi = 10.1016/j.ydbio.2012.11.024 | doi-access = free }}</ref>

Homozygous mutation of HMGCR can lead to a form of limb girdle myopathy that may share features with mild statin-induced myopathy.  The clinical syndrome was partially reversed in a model system by supplementation with the downstream metabolite mevalonolactone.<ref>{{cite journal |vauthors=Yogev Y, Shorer Z, Koifman A, Wormser O, Drabkin M, Halperin D, Dolgin V, Proskorovski-Ohayon R, Hadar N, Davidov G, Nudelman H, Zarivach R, Shelef I, Perez Y, Birk OS |title=Limb girdle muscular disease caused by HMGCR mutation and statin myopathy treatable with mevalonolactone |journal=Proc Natl Acad Sci U S A |volume=120 |issue=7 |article-number=e2217831120 |date=February 2023 |pmid=36745799 |doi=10.1073/pnas.2217831120 |pmc=9963716 |bibcode=2023PNAS..12017831Y |url=|doi-access=free }}</ref>

The presence of anti HMG-CoA reductase [[antibodies]] is seen in people with [[statin-associated autoimmune myopathy]], which is a very rare form of [[myopathy|muscle damage]] caused by the [[immune system]] in people who take [[statin]] medications.<ref name="Thompson2016">{{cite journal | vauthors = Thompson PD, Panza G, Zaleski A, Taylor B | title = Statin-Associated Side Effects | journal = Journal of the American College of Cardiology | volume = 67 | issue = 20 | pages = 2395–2410 | date = May 2016 | pmid = 27199064 | doi = 10.1016/j.jacc.2016.02.071 | type = Review | doi-access =  }}</ref> The exact mechanism is unclear. A combination of consistent findings on physical examination, the presence of anti HMG-CoA reductase antibodies in a person with [[myopathy]], evidence of muscle breakdown, and [[muscle biopsy]] diagnose SAAM.<ref name="Mammen2016">{{cite journal | vauthors = Mammen AL | title = Statin-Associated Autoimmune Myopathy | journal = The New England Journal of Medicine | volume = 374 | issue = 7 | pages = 664–669 | date = February 2016 | pmid = 26886523 | doi = 10.1056/NEJMra1515161 | type = Review }}</ref>

== Regulation ==
[[Image:HMGCOA-1DQA.png|thumb|HMG-CoA reductase-[[substrate (biochemistry)|Substrate]] complex (Blue:[[Coenzyme A]], red:HMG, green:[[NADPH|NADP]])]]
Regulation of HMG-CoA reductase is achieved at several levels: transcription, translation, degradation and phosphorylation.

=== Transcription ===
[[Transcription (genetics)|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 [[sterol regulatory element binding protein|SREBP]] is inactive, it is bound to the [[Endoplasmic reticulum|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.<ref>{{cite journal | vauthors = Sun LP, Seemann J, Goldstein JL, Brown MS | title = Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi: Insig renders sorting signal in Scap inaccessible to COPII proteins | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 16 | pages = 6519–6526 | date = April 2007 | pmid = 17428919 | pmc = 1851663 | doi = 10.1073/pnas.0700907104 | doi-access = free | bibcode = 2007PNAS..104.6519S }}</ref><ref>{{cite journal | vauthors = Sun LP, Li L, Goldstein JL, Brown MS | title = Insig required for sterol-mediated inhibition of Scap/SREBP binding to COPII proteins in vitro | journal = The Journal of Biological Chemistry | volume = 280 | issue = 28 | pages = 26483–26490 | date = July 2005 | pmid = 15899885 | doi = 10.1074/jbc.M504041200 | doi-access = free }}</ref>

=== Translation ===
[[Translation (genetics)|Translation]] of [[mRNA]] is inhibited by a [[mevalonate]] derivative, which has been reported to be the isoprenoid [[farnesol]],<ref name="pmid8626470">{{cite journal | vauthors = Meigs TE, Roseman DS, Simoni RD | title = Regulation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase degradation by the nonsterol mevalonate metabolite farnesol in vivo | journal = The Journal of Biological Chemistry | volume = 271 | issue = 14 | pages = 7916–7922 | date = April 1996 | pmid = 8626470 | doi = 10.1074/jbc.271.14.7916 | doi-access = free }}</ref><ref name="pmid9281305">{{cite journal | vauthors = Meigs TE, Simoni RD | title = Farnesol as a regulator of HMG-CoA reductase degradation: characterization and role of farnesyl pyrophosphatase | journal = Archives of Biochemistry and Biophysics | volume = 345 | issue = 1 | pages = 1–9 | date = September 1997 | pmid = 9281305 | doi = 10.1006/abbi.1997.0200 | doi-access = free }}</ref> although this role has been disputed.<ref name="pmid8645011">{{cite journal | vauthors = Keller RK, Zhao Z, Chambers C, Ness GC | title = Farnesol is not the nonsterol regulator mediating degradation of HMG-CoA reductase in rat liver | journal = Archives of Biochemistry and Biophysics | volume = 328 | issue = 2 | pages = 324–330 | date = April 1996 | pmid = 8645011 | doi = 10.1006/abbi.1996.0180 }}</ref>

=== Degradation ===
Rising levels of [[sterol]]s 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,<ref>{{cite journal | vauthors = Song BL, Sever N, DeBose-Boyd RA | title = Gp78, a membrane-anchored ubiquitin ligase, associates with Insig-1 and couples sterol-regulated ubiquitination to degradation of HMG CoA reductase | journal = Molecular Cell | volume = 19 | issue = 6 | pages = 829–840 | date = September 2005 | pmid = 16168377 | doi = 10.1016/j.molcel.2005.08.009 | doi-access = free }}</ref> Trc8,<ref>{{cite journal | vauthors = Jo Y, Lee PC, Sguigna PV, DeBose-Boyd RA | title = Sterol-induced degradation of HMG CoA reductase depends on interplay of two Insigs and two ubiquitin ligases, gp78 and Trc8 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 51 | pages = 20503–20508 | date = December 2011 | pmid = 22143767 | pmc = 3251157 | doi = 10.1073/pnas.1112831108 | doi-access = free | bibcode = 2011PNAS..10820503J }}</ref> and RNF145<ref>{{cite journal | vauthors = Jiang LY, Jiang W, Tian N, Xiong YN, Liu J, Wei J, Wu KY, Luo J, Shi XJ, Song BL | display-authors = 6 | title = Ring finger protein 145 (RNF145) is a ubiquitin ligase for sterol-induced degradation of HMG-CoA reductase | journal = The Journal of Biological Chemistry | volume = 293 | issue = 11 | pages = 4047–4055 | date = March 2018 | pmid = 29374057 | pmc = 5857978 | doi = 10.1074/jbc.RA117.001260 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Menzies SA, Volkmar N, van den Boomen DJ, Timms RT, Dickson AS, Nathan JA, Lehner PJ | title = The sterol-responsive RNF145 E3 ubiquitin ligase mediates the degradation of HMG-CoA reductase together with gp78 and Hrd1 | journal = eLife | volume = 7 | date = December 2018 | article-number = e40009 | pmid = 30543180 | pmc = 6292692 | doi = 10.7554/eLife.40009 | doi-access = free }}</ref> The involvement of AMFR and Trc8 has been contested.<ref>{{cite journal | vauthors = Tsai YC, Leichner GS, Pearce MM, Wilson GL, Wojcikiewicz RJ, Roitelman J, Weissman AM | title = Differential regulation of HMG-CoA reductase and Insig-1 by enzymes of the ubiquitin-proteasome system | journal = Molecular Biology of the Cell | volume = 23 | issue = 23 | pages = 4484–4494 | date = December 2012 | pmid = 23087214 | pmc = 3510011 | doi = 10.1091/mbc.E12-08-0631 }}</ref>

=== Phosphorylation ===
Short-term regulation of HMG-CoA reductase is achieved by inhibition by [[phosphorylation]] (of Serine 872, in humans<ref name="pmid10698924">{{cite journal | vauthors = Istvan ES, Palnitkar M, Buchanan SK, Deisenhofer J | title = Crystal structure of the catalytic portion of human HMG-CoA reductase: insights into regulation of activity and catalysis | journal = The EMBO Journal | volume = 19 | issue = 5 | pages = 819–830 | date = March 2000 | pmid = 10698924 | pmc = 305622 | doi = 10.1093/emboj/19.5.819 }}</ref>). 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.<ref name="pmid1967820">{{cite journal | vauthors = Goldstein JL, Brown MS | title = Regulation of the mevalonate pathway | journal = Nature | volume = 343 | issue = 6257 | pages = 425–430 | date = February 1990 | pmid = 1967820 | doi = 10.1038/343425a0 | s2cid = 30477478 | bibcode = 1990Natur.343..425G }}</ref> Thus, both pathways utilizing acetyl-CoA for lipid synthesis are inactivated when energy charge is low in the cell, and concentrations of [[Adenosine monophosphate|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]].<ref name="pmid12829246">{{cite journal | vauthors = Hardie DG, Scott JW, Pan DA, Hudson ER | title = Management of cellular energy by the AMP-activated protein kinase system | journal = FEBS Letters | volume = 546 | issue = 1 | pages = 113–120 | date = July 2003 | pmid = 12829246 | doi = 10.1016/S0014-5793(03)00560-X | s2cid = 42881381 | doi-access = free | bibcode = 2003FEBSL.546..113H }}</ref>

Fairly recently, LKB1 has been identified as a likely AMP kinase kinase,<ref name="pmid16356723">{{cite journal | vauthors = Witters LA, Kemp BE, Means AR | title = Chutes and Ladders: the search for protein kinases that act on AMPK | journal = Trends in Biochemical Sciences | volume = 31 | issue = 1 | pages = 13–16 | date = January 2006 | pmid = 16356723 | doi = 10.1016/j.tibs.2005.11.009 }}</ref> which appears to involve calcium/calmodulin signaling. This pathway likely transduces signals from [[leptin]], [[adiponectin]], and other signaling molecules.<ref name="pmid12829246"/>

== See also ==
* [[Oxidoreductase]]

== References ==
{{reflist|33em}}

== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = Hodge VJ, Gould SJ, Subramani S, Moser HW, Krisans SK | title = Normal cholesterol synthesis in human cells requires functional peroxisomes | journal = Biochemical and Biophysical Research Communications | volume = 181 | issue = 2 | pages = 537–541 | date = December 1991 | pmid = 1755834 | doi = 10.1016/0006-291X(91)91222-X | bibcode = 1991BBRC..181..537H }}
* {{cite journal | vauthors = Ramharack R, Tam SP, Deeley RG | title = 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 | journal = DNA and Cell Biology | volume = 9 | issue = 9 | pages = 677–690 | date = November 1990 | pmid = 1979742 | doi = 10.1089/dna.1990.9.677 }}
* {{cite journal | vauthors = Clarke PR, Hardie DG | title = Regulation of HMG-CoA reductase: identification of the site phosphorylated by the AMP-activated protein kinase in vitro and in intact rat liver | journal = The EMBO Journal | volume = 9 | issue = 8 | pages = 2439–2446 | date = August 1990 | pmid = 2369897 | pmc = 552270 | doi = 10.1002/j.1460-2075.1990.tb07420.x }}
* {{cite journal | vauthors = Luskey KL, Stevens B | title = Human 3-hydroxy-3-methylglutaryl coenzyme A reductase. Conserved domains responsible for catalytic activity and sterol-regulated degradation | journal = The Journal of Biological Chemistry | volume = 260 | issue = 18 | pages = 10271–10277 | date = August 1985 | pmid = 2991281 | doi = 10.1016/S0021-9258(17)39242-6 | doi-access = free }}
* {{cite journal | vauthors = Humphries SE, Tata F, Henry I, Barichard F, Holm M, Junien C, Williamson R | title = The isolation, characterisation, and chromosomal assignment of the gene for human 3-hydroxy-3-methylglutaryl coenzyme A reductase, (HMG-CoA reductase) | journal = Human Genetics | volume = 71 | issue = 3 | pages = 254–258 | year = 1986 | pmid = 2998972 | doi = 10.1007/BF00284585 | s2cid = 10619592 }}
* {{cite journal | vauthors = Beg ZH, Stonik JA, Brewer HB | title = 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 | journal = The Journal of Biological Chemistry | volume = 262 | issue = 27 | pages = 13228–13240 | date = September 1987 | pmid = 3308873 | doi = 10.1016/S0021-9258(18)45191-5 | doi-access = free }}
* {{cite journal | vauthors = Osborne TF, Goldstein JL, Brown MS | title = 5' end of HMG CoA reductase gene contains sequences responsible for cholesterol-mediated inhibition of transcription | journal = Cell | volume = 42 | issue = 1 | pages = 203–212 | date = August 1985 | pmid = 3860301 | doi = 10.1016/S0092-8674(85)80116-1 | s2cid = 37319421 }}
* {{cite journal | vauthors = Lindgren V, Luskey KL, Russell DW, Francke U | title = 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 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 82 | issue = 24 | pages = 8567–8571 | date = December 1985 | pmid = 3866240 | pmc = 390958 | doi = 10.1073/pnas.82.24.8567 | doi-access = free | bibcode = 1985PNAS...82.8567L }}
* {{cite journal | vauthors = Lehoux JG, Kandalaft N, Belisle S, Bellabarba D | title = Characterization of 3-hydroxy-3-methylglutaryl coenzyme A reductase in human adrenal cortex | journal = Endocrinology | volume = 117 | issue = 4 | pages = 1462–1468 | date = October 1985 | pmid = 3896758 | doi = 10.1210/endo-117-4-1462 }}
* {{cite journal | vauthors = Boguslawski W, Sokolowski W | title = HMG-CoA reductase activity in the microsomal fraction from human placenta in early and term pregnancy | journal = The International Journal of Biochemistry | volume = 16 | issue = 9 | pages = 1023–1026 | year = 1984 | pmid = 6479432 | doi = 10.1016/0020-711X(84)90120-4 }}
* {{cite journal | vauthors = Harwood HJ, Schneider M, Stacpoole PW | title = Measurement of human leukocyte microsomal HMG-CoA reductase activity | journal = Journal of Lipid Research | volume = 25 | issue = 9 | pages = 967–978 | date = September 1984 | pmid = 6491541 | doi = 10.1016/S0022-2275(20)37733-6 | doi-access = free }}
* {{cite journal | vauthors = Nguyen LB, Salen G, Shefer S, Bullock J, Chen T, Tint GS, Chowdhary IR, Lerner S | display-authors = 6 | title = Deficient ileal 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in sitosterolemia: sitosterol is not a feedback inhibitor of intestinal cholesterol biosynthesis | journal = Metabolism | volume = 43 | issue = 7 | pages = 855–859 | date = July 1994 | pmid = 8028508 | doi = 10.1016/0026-0495(94)90266-6 }}
* {{cite journal | vauthors = Bennis F, Favre G, Le Gaillard F, Soula G | title = Importance of mevalonate-derived products in the control of HMG-CoA reductase activity and growth of human lung adenocarcinoma cell line A549 | journal = International Journal of Cancer | volume = 55 | issue = 4 | pages = 640–645 | date = October 1993 | pmid = 8406993 | doi = 10.1002/ijc.2910550421 | s2cid = 23842867 }}
* {{cite journal | vauthors = Van Doren M, Broihier HT, Moore LA, Lehmann R | title = HMG-CoA reductase guides migrating primordial germ cells | journal = Nature | volume = 396 | issue = 6710 | pages = 466–469 | date = December 1998 | pmid = 9853754 | doi = 10.1038/24871 | s2cid = 4430351 | bibcode = 1998Natur.396..466V }}
* {{cite journal | vauthors = 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 | display-authors = 6 | title = Characterization of single-nucleotide polymorphisms in coding regions of human genes | journal = Nature Genetics | volume = 22 | issue = 3 | pages = 231–238 | date = July 1999 | pmid = 10391209 | doi = 10.1038/10290 | s2cid = 195213008 }}
* {{cite journal | vauthors = Aboushadi N, Engfelt WH, Paton VG, Krisans SK | title = Role of peroxisomes in isoprenoid biosynthesis | journal = The Journal of Histochemistry and Cytochemistry | volume = 47 | issue = 9 | pages = 1127–1132 | date = September 1999 | pmid = 10449533 | doi = 10.1177/002215549904700904 | s2cid = 1596555 | doi-access =  }}
* {{cite journal | vauthors = Honda A, Salen G, Honda M, Batta AK, Tint GS, Xu G, Chen TS, Tanaka N, Shefer S | display-authors = 6 | title = 3-Hydroxy-3-methylglutaryl-coenzyme A reductase activity is inhibited by cholesterol and up-regulated by sitosterol in sitosterolemic fibroblasts | journal = The Journal of Laboratory and Clinical Medicine | volume = 135 | issue = 2 | pages = 174–179 | date = February 2000 | pmid = 10695663 | doi = 10.1067/mlc.2000.104459 }}
* {{cite journal | vauthors = Istvan ES, Deisenhofer J | title = Structural mechanism for statin inhibition of HMG-CoA reductase | journal = Science | volume = 292 | issue = 5519 | pages = 1160–1164 | date = May 2001 | pmid = 11349148 | doi = 10.1126/science.1059344 | s2cid = 37686043 | bibcode = 2001Sci...292.1160I }}
* {{cite journal | vauthors = Rasmussen LM, Hansen PR, Nabipour MT, Olesen P, Kristiansen MT, Ledet T | title = Diverse effects of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase on the expression of VCAM-1 and E-selectin in endothelial cells | journal = The Biochemical Journal | volume = 360 | issue = Pt 2 | pages = 363–370 | date = December 2001 | pmid = 11716764 | pmc = 1222236 | doi = 10.1042/0264-6021:3600363 }}
{{refend}}

== External links ==
* [http://www.rpi.edu/dept/bcbp/molbiochem/MBWeb/mb2/part1/cholesterol.htm Cholesterol Synthesis] {{Webarchive|url=https://web.archive.org/web/20170704121951/http://www.rpi.edu/dept/bcbp/molbiochem/MBWeb/mb2/part1/cholesterol.htm |date=4 July 2017 }} - has some good regulatory details
* {{Proteopedia|HMG-CoA_Reductase}} - the HMG-CoA Reductase Structure in Interactive 3D
* {{PDBe-KB2|P04035|3-hydroxy-3-methylglutaryl-coenzyme A reductase}}

{{PDB Gallery|geneid=3156}}
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[[Category:EC 1.1.1]]