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HM G-CoA reductase
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3-hydroxy-3-methylglutaryl-CoA reductase

PDB rendering based on 1dq8.

Available structures
Ortholog search: PDBe, RCSB
PDB
[show]List of PDB id codes

I dentifiers

Symbols HMGCR (; LDLCQ3)

OMIM: 142910 MGI: 96159
External
HomoloGene: 30994 ChEMBL: 402
I Ds
GeneCards: HMGCR Gene

EC
1.1.1.34
number

[show]Gene Ontology

RNA expression pattern

More reference expression data

Orthologs
Species Human M ouse

Entrez 3156 15357

Ensembl ENSG00000113161 ENSMUSG00000021670

UniProt P04035 Q01237

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RefSeq NM_000859 NM_008255

(mRNA)

RefSeq
NP_000850 NP_032281
(protein)
Location Chr 5: Chr 13:
(UCSC) 74.63 – 74.66 Mb 96.65 – 96.67 Mb
PubM ed
[1] [2]
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HM G-CoA reductase
EC number { { { EC_number} } }
Gene Ontology AmiGO / EGO

hydroxymethylglutaryl-CoA reductase
I dentifiers
EC number 1.1.1.88
CAS number 37250-24-1
Databases
I ntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
M etaCyc metabolic pathway
PRI AM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO
[show]Search
hydroxymethylglutaryl-CoA reductase
I dentifiers
EC number 1.1.1.34
Databases
I ntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
M etaCyc metabolic pathway
PRI AM profile
PDB structures RCSB PDB PDBe PDBsum
[show]Search

HM G-CoA reductase (or 3-hydroxy-3-methyl-glutaryl-CoA reductase or HM GCR) is the rate-controlling enzyme (EC
1.1.1.88& 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

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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, an important determinant of atherosclerosis.[1] 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.[2]

The enzyme commission designation is EC 1.1.1.34 for the NADPH-dependent enzyme, whereas 1.1.1.88 links to an NADH-
dependent enzyme.

In humans, the gene for HMG-CoA reductase is located on the long arm of the fifth chromosome (5q13.3-14).[3] Related
enzymes having the same function are also present in other animals, plants and bacteria.

Contents
[hide]

1 Reaction
2 Interactive pathway map
3 Inhibitors
◦ 3.1 Drugs
◦ 3.2 Hormones
4 Importance
5 Regulation
◦ 5.1 Transcription of the reductase gene
◦ 5.2 Translation of mRNA
◦ 5.3 Degradation of reductase
◦ 5.4 Phosphorylation of reductase
6 See also
7 References
8 Further reading

Reaction[edit]
HMGCR converts HMG-CoA to mevalonic acid:

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I nteractive pathway map[edit]

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

Statin Pathway edit

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

I nhibitors[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.[4]

These drugs include rosuvastatin (CRESTOR), lovastatin (Mevacor), atorvastatin (Lipitor), pravastatin (Pravachol), fluvastatin
(Lescol), pitavastatin (Livalo), and simvastatin (Zocor).[5] 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).[6]

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.[7]

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 an AMP-activated protein kinase, which responds to an increase in AMP concentration, and
also to leptin (see 4.4, Phosphorylation of reductase).

I mportance[edit]
HMG-CoA reductase is a transmembrane protein which is polytopic (meaning it many alpha helix transmembrane segments [8] ),
and catalyzes a key step in the mevalonate pathway (MetaCyc mevalonate pathway), which is involved in the synthesis of
sterols, isoprenoids and other lipids. In humans, HMG-CoA reductase is the rate-limiting step in cholesterol synthesis and
represents the sole major drug target for contemporary cholesterol-lowering drugs.

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.[9] Statins have
been shown to have anti-inflammatory properties,[10] 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.
[11]

HMG-CoA reductase is also an important developmental enzyme. Inhibition of its activity and the concomitant lack of
isoprenoids that yields can lead to germ cell migration defects [12] as well as intracerebral hemorrhage. [13]

Regulation[edit]

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

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Regulation of 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. When SREBP is inactive, it is bound to the ER
or nuclear membrane with another protein called SREBP cleavage-activating protein (SCAP). When cholesterol levels fall,
SREBP is released from the membrane by proteolysis and migrates to the nucleus, where it binds to the SRE and transcription is
enhanced. If cholesterol levels rise, proteolytic cleavage of SREBP from the membrane ceases and any proteins in the nucleus
are quickly degraded.

Translation of mRNA[edit]

Translation of mRNA is inhibited by a mevalonate derivative, which has been reported to be farnesol,[14][15] although this role
has been disputed.[16]

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 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 of reductase[edit]

Short-term regulation of HMG-CoA reductase is achieved by inhibition by phosphorylation (of Serine 872, in humans[17] ).
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.[18] 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.[19]

Fairly recently, LKB1 has been identified as a likely AMP kinase kinase,[20] which appears to involve calcium/calmodulin
signaling. This pathway likely transduces signals from leptin, adiponectin, and other signaling molecules.[19]

See also[edit]
Oxidoreductase

References[edit]
1. ^ "Entrez Gene: HMGCR 3-hydroxy-3-methylglutaryl-
Coenzyme A reductase".
2. ^ 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". J.
Cell Biol. 117 (5): 959–73. doi:10.1083/jcb.117.5.959.
PMC 2289486. PMID 1374417.
3. ^ 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". Proc. Natl. Acad. Sci. U.S.A. 82 (24):
8567–71. doi:10.1073/pnas.82.24.8567. PMC 390958.
PMID 3866240.
4. ^ Farmer JA (1998). "Aggressive lipid therapy in the
statin era". Prog. Cardiovasc. Dis. 41 (2): 71–94.
doi:10.1016/S0033-0620(98)80006-6. PMID 9790411.
5. ^ "Is there a "best" statin drug?". Johns Hopkins Med.
Lett. Health After 50 15 (11): 4–5. January 2004.
PMID 14983817.
6. ^ Lin YL, Wang TH, Lee MH, Su NW (January 2008).
"Biologically active components and nutraceuticals in
the Monascus-fermented rice: a review". Appl.
Microbiol. Biotechnol. 77 (5): 965–73.
doi:10.1007/s00253-007-1256-6. PMID 18038131.

http://en.wikipedia.org/wiki/HMG-CoA_reductase 3/31/2014
HMG-CoA reductase - Wikipedia, the free encyclopedia
7. ^ Flores NA (September 2004). "Ezetimibe +
simvastatin (Merck/Schering-Plough)". Current Opinion
in Investigational Drugs 5 (9): 984–92.
PMID 15503655.
8. ^ Department of Chemistry and Biochemistry (October
1998). "Biophysical Methods - Lecture 3: Membrane
Proteins". University of Guelph. Retrieved 30 December
2013.
9. ^ Arnaud C, Veillard NR, Mach F (April 2005).
"Cholesterol-independent effects of statins in
inflammation, immunomodulation and atherosclerosis".
Curr. Drug Targets Cardiovasc. Haematol. Disord. 5
(2): 127–34. doi:10.2174/1568006043586198.
PMID 15853754.
10. ^ Sorrentino, Sajoscha; Landmesser, Ulf (December
2005). "Nonlipid-lowering effects of statins". Curr.
Treat. Options Cardiovasc. Med. 7 (6): 459–466.
doi:10.1007/s11936-005-0031-1. PMID 16283973.
11. ^ 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:10.1097/01.wco.0000073942.19076.d1 (inactive
2009-11-26). PMID 12858078.
12. ^ 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". Dev. Cell 6 (2): 295–302.
doi:10.1016/S1534-5807(04)00032-2. PMID 14960282.
13. ^ Eisa-Beygi S, Hatch G, Noble S, Ekker M, Moon TM
(January 2013). "The 3-hydroxy-3-methylglutaryl-CoA
reductase (HMGCR) pathway regulates developmental
cerebral-vascular stability via prenylation-dependent
signalling pathway". Dev. Biol. 373 (2): 258–266.
doi:10.1016/j.ydbio.2012.11.024. PMID 23206891.
Further reading[edit]
Hodge VJ, Gould SJ, Subramani S et al. (1992).
"Normal cholesterol synthesis in human cells requires
functional peroxisomes". Biochem. Biophys. Res.
Commun. 181 (2): 537–41. doi:10.1016/0006-291X(91)
91222-X. PMID 1755834.
Ramharack R, Tam SP, Deeley RG (1991).
"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 Cell Biol. 9 (9): 677–90.
doi:10.1089/dna.1990.9.677. PMID 1979742.
Clarke PR, Hardie DG (1990). "Regulation of HMG-
CoA reductase: identification of the site phosphorylated
by the AMP-activated protein kinase in vitro and in
intact rat liver". EMBO J. 9 (8): 2439–46. PMC 552270.
PMID 2369897.
Luskey KL, Stevens B (1985). "Human 3-hydroxy-3-
methylglutaryl coenzyme A reductase. Conserved
domains responsible for catalytic activity and sterol-
regulated degradation". J. Biol. Chem. 260 (18): 10271
–7. PMID 2991281.
http://en.wikipedia.org/wiki/HMG-CoA_reductase
Page 7 of 10
14. ^ 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". J. Biol. Chem. 271 (14):
7916–22. doi:10.1074/jbc.271.14.7916. PMID 8626470.
15. ^ Meigs TE, Simoni RD (September 1997). "Farnesol as
a regulator of HMG-CoA reductase degradation:
characterization and role of farnesyl pyrophosphatase".
Arch. Biochem. Biophys. 345 (1): 1–9.
doi:10.1006/abbi.1997.0200. PMID 9281305.
16. ^ 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". Arch.
Biochem. Biophys. 328 (2): 324–30.
doi:10.1006/abbi.1996.0180. PMID 8645011.
17. ^ 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". EMBO J. 19 (5): 819–30.
doi:10.1093/emboj/19.5.819. PMC 305622.
PMID 10698924.
18. ^ Goldstein JL, Brown MS (February 1990).
"Regulation of the mevalonate pathway". Nature 343
(6257): 425–30. doi:10.1038/343425a0. PMID 1967820.
19. ^ a b Hardie DG, Scott JW, Pan DA, Hudson ER (July
2003). "Management of cellular energy by the AMP-
activated protein kinase system". FEBS Lett. 546 (1):
113–20. doi:10.1016/S0014-5793(03)00560-X.
PMID 12829246.
20. ^ Witters LA, Kemp BE, Means AR (January 2006).
"Chutes and Ladders: the search for protein kinases that
act on AMPK". Trends Biochem. Sci. 31 (1): 13–6.
doi:10.1016/j.tibs.2005.11.009. PMID 16356723.
Humphries SE, Tata F, Henry I et al. (1986). "The
isolation, characterisation, and chromosomal assignment
of the gene for human 3-hydroxy-3-methylglutaryl
coenzyme A reductase, (HMG-CoA reductase)". Hum.
Genet. 71 (3): 254–8. doi:10.1007/BF00284585.
PMID 2998972.
Beg ZH, Stonik JA, Brewer HB (1987).
"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". J. Biol.
Chem. 262 (27): 13228–40. PMID 3308873.
Osborne TF, Goldstein JL, Brown MS (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
(1986). "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". Proc. Natl. Acad. Sci. U.S.A. 82 (24): 8567–71.
3/31/2014
HMG-CoA reductase - Wikipedia, the free encyclopedia Page 8 of 10

doi:10.1073/pnas.82.24.8567. PMC 390958. Cargill M, Altshuler D, Ireland J et al. (1999).

PMID 3866240.
Lehoux JG, Kandalaft N, Belisle S, Bellabarba D
(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
reductase activity in the microsomal fraction from
human placenta in early and term pregnancy". Int. J.
Biochem. 16 (9): 1023–6. doi:10.1016/0020-711X(84)
90120-4. PMID 6479432.
Harwood HJ, Schneider M, Stacpoole PW (1984).
"Measurement of human leukocyte microsomal HMG-
CoA reductase activity". J. Lipid Res. 25 (9): 967–78.
PMID 6491541.
Nguyen LB, Salen G, Shefer S et al. (1994). "Deficient
ileal 3-hydroxy-3-methylglutaryl coenzyme A reductase
activity in sitosterolemia: sitosterol is not a feedback
inhibitor of intestinal cholesterol biosynthesis". Metab.
Clin. Exp. 43 (7): 855–9. doi:10.1016/0026-0495(94)
90266-6. PMID 8028508.
Bennis F, Favre G, Le Gaillard F, Soula G (1993).
"Importance of mevalonate-derived products in the
control of HMG-CoA reductase activity and growth of
human lung adenocarcinoma cell line A549". Int. J.
Cancer 55 (4): 640–5. doi:10.1002/ijc.2910550421.
PMID 8406993.
Van Doren M, Broihier HT, Moore LA, Lehmann R
(1998). "HMG-CoA reductase guides migrating
primordial germ cells". Nature 396 (6710): 466–9.
doi:10.1038/24871. PMID 9853754.
"Characterization of single-nucleotide polymorphisms in
coding regions of human genes". Nat. Genet. 22 (3): 231
–8. doi:10.1038/10290. PMID 10391209.
Aboushadi N, Engfelt WH, Paton VG, Krisans SK
(1999). "Role of peroxisomes in isoprenoid
biosynthesis". J. Histochem. Cytochem. 47 (9): 1127
–32. doi:10.1177/002215549904700904.
PMID 10449533.
Honda A, Salen G, Honda M et al. (2000). "3-Hydroxy-
3-methylglutaryl-coenzyme A reductase activity is
inhibited by cholesterol and up-regulated by sitosterol in
sitosterolemic fibroblasts". J. Lab. Clin. Med. 135 (2):
174–9. doi:10.1067/mlc.2000.104459. PMID 10695663.
Istvan ES, Palnitkar M, Buchanan SK, Deisenhofer J
(2000). "Crystal structure of the catalytic portion of
human HMG-CoA reductase: insights into regulation of
activity and catalysis". EMBO J. 19 (5): 819–30.
doi:10.1093/emboj/19.5.819. PMC 305622.
PMID 10698924.
Istvan ES, Deisenhofer J (2001). "Structural mechanism
for statin inhibition of HMG-CoA reductase". Science
292 (5519): 1160–4. doi:10.1126/science.1059344.
PMID 11349148.
Rasmussen LM, Hansen PR, Nabipour MT et al. (2002).
"Diverse effects of inhibition of 3-hydroxy-3-
methylglutaryl-CoA reductase on the expression of
VCAM-1 and E-selectin in endothelial cells". Biochem.
J. 360 (Pt 2): 363–70. doi:10.1042/0264-6021:3600363.
PMC 1222236. PMID 11716764.

== External links ==

Cholesterol Synthesis - has some good regulatory details

Proteopedia HMG-CoA_Reductase - the HMG-CoA Reductase Structure in Interactive 3D

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Oxidoreductases: alcohol oxidoreductases (EC 1.1)

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M etabolism: lipid metabolism – ketones/cholesterol synthesisenzymes/steroid metabolism

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