HMG-CoA reductase
Encyclopedia
HMG-CoA reductase is the rate-controlling enzyme
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, an important determinant of atherosclerosis. 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.
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). Related enzymes having the same function are also present in other animals, plants and bacteria.
to mevalonic acid
:
as a means of reducing the risk for cardiovascular disease
.
These drugs include rosuvastatin
(CRESTOR), lovastatin
(Mevacor), atorvastatin
(Lipitor), pravastatin
(Pravachol), fluvastatin
(Lescol), pitavastatin
(Livalo), and simvastatin
(Zocor). Red yeast rice extract contains several naturally occurring cholesterol-lowering statins 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).
Vytorin is drug that combines the use simvastatin
and ezetimibe
, which blocks the formation of cholesterol by the body, along with the absorption of cholesterol in the intestines.
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).
The medical significance of HMG-CoA reductase has continued to expand beyond its direct role in cholesterol synthesis following the discovery that it can offer cardiovascular health benefits independent of cholesterol reduction. Statins have been shown to have anti-inflammatory properties, 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.
HMG-CoA reductase is also an important developmental enzyme. Inhibition of its activity and the concomitant lack of isoprenoids that yields can lead to morphological defects.
Regulation of HMG-CoA reductase is achieved at several levels: transcription, translation, degradation and phosphorylation.
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. 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.
of mRNA is inhibited by a mevalonate derivative, which has been reported to be farnesol
,although this role has been disputed.
s increase the susceptibility of the reductase enzyme to ER-assosiated 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.
(of Serine 872, in humans). 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. 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
.
Fairly recently, LKB1 has been identified as a likely AMP kinase kinase, which appears to involve calcium/calmodulin signaling. This pathway likely transduces signals from leptin
, adiponectin
, and other signaling molecules.
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
of the mevalonate pathway, the metabolic pathway
Metabolic pathway
In biochemistry, metabolic pathways are series of chemical reactions occurring within a cell. In each pathway, a principal chemical is modified by a series of chemical reactions. Enzymes catalyze these reactions, and often require dietary minerals, vitamins, and other cofactors in order to function...
that produces cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
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, an important determinant of atherosclerosis. 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
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
, 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.
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
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
(5q13.3-14). Related enzymes having the same function are also present in other animals, plants and bacteria.
Reaction
HMGCR converts HMG-CoAHMG-CoA
HMG-CoA is an intermediate in the Mevalonate pathway. It is formed from acetyl CoA and acetoacetyl CoA by HMG-CoA synthase.HMG-CoA reductase converts it into mevalonic acid....
to mevalonic acid
Mevalonic acid
Mevalonic acid is a key organic compound in biochemistry. The anion of mevalonic acid, the predominant form in biological media, is known as mevalonate. This compound is of major pharmaceutical importance...
:
 |
Drugs
Drugs that inhibit HMG-CoA reductase, known collectively as HMG-CoA reductase inhibitors (or "statins"), are used to lower serum cholesterolCholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
as a means of reducing the risk for cardiovascular disease
Heart disease
Heart disease, cardiac disease or cardiopathy is an umbrella term for a variety of diseases affecting the heart. , it is the leading cause of death in the United States, England, Canada and Wales, accounting for 25.4% of the total deaths in the United States.-Types:-Coronary heart disease:Coronary...
.
These drugs include rosuvastatin
Rosuvastatin
Rosuvastatin is a member of the drug class of statins, used to treat high cholesterol and related conditions, and to prevent cardiovascular disease. It was developed by Shionogi.-Medical uses:The primary uses of rosuvastatin is for the treatment of dyslipidemia...
(CRESTOR), lovastatin
Lovastatin
Lovastatin is a member of the drug class of statins, used for lowering cholesterol in those with hypercholesterolemia and so preventing cardiovascular disease...
(Mevacor), atorvastatin
Atorvastatin
Atorvastatin , sold by Pfizer under the trade name Lipitor, is a member of the drug class known as statins, used for lowering blood cholesterol. It also stabilizes plaque and prevents strokes through anti-inflammatory and other mechanisms...
(Lipitor), pravastatin
Pravastatin
Pravastatin is a member of the drug class of statins, used for lowering cholesterol and preventing cardiovascular disease. Initially known as CS-514, it was originally identified in a bacterium called Nocardia autotrophica by researchers of the Sankyo Pharma Inc....
(Pravachol), fluvastatin
Fluvastatin
Fluvastatin is a member of the drug class of statins, used to treat hypercholesterolemia and to prevent cardiovascular disease....
(Lescol), pitavastatin
Pitavastatin
Pitavastatin is a member of the medication class of statins, marketed in the United States under the trade name Livalo. Like other statins, it is an inhibitor of HMG-CoA reductase, the enzyme that catalyses the first step of cholesterol synthesis. It has been available in Japan since 2003, and is...
(Livalo), and simvastatin
Simvastatin
Simvastatin is a hypolipidemic drug used to control elevated cholesterol, or hypercholesterolemia. Simvastatin is a member of the statin class of pharmaceuticals, is a synthetic derivate of a fermentation product of Aspergillus terreus.-Medical uses:The primary uses of simvastatin is for the...
(Zocor). Red yeast rice extract contains several naturally occurring cholesterol-lowering statins known as monacolins. The most active of these is monacolin K, or lovastatin
Lovastatin
Lovastatin is a member of the drug class of statins, used for lowering cholesterol in those with hypercholesterolemia and so preventing cardiovascular disease...
(previously sold under the trade name Mevacor, and now available as generic lovastatin).
Vytorin is drug that combines the use simvastatin
Simvastatin
Simvastatin is a hypolipidemic drug used to control elevated cholesterol, or hypercholesterolemia. Simvastatin is a member of the statin class of pharmaceuticals, is a synthetic derivate of a fermentation product of Aspergillus terreus.-Medical uses:The primary uses of simvastatin is for the...
and ezetimibe
Ezetimibe
Ezetimibe is a drug that lowers cholesterol. It acts by decreasing cholesterol absorption in the intestine. It may be used alone , when other cholesterol-lowering medications are not tolerated, or together with statins when statins alone do not control cholesterol.Even though ezetimibe decreases...
, which blocks the formation of cholesterol by the body, along with the absorption of cholesterol in the intestines.
Hormones
HMG-CoA reductase is active when blood glucose is high. The basic functions of insulinInsulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
and glucagon
Glucagon
Glucagon, a hormone secreted by the pancreas, raises blood glucose levels. Its effect is opposite that of insulin, which lowers blood glucose levels. The pancreas releases glucagon when blood sugar levels fall too low. Glucagon causes the liver to convert stored glycogen into glucose, which is...
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
AMP-activated protein kinase
5' AMP-activated protein kinase or AMPK or 5' adenosine monophosphate-activated protein kinase is an enzyme that plays a role in cellular energy homeostasis. It consists of three proteins that together make a functional enzyme, conserved from yeast to humans. It is expressed in a number of...
, which responds to an increase in AMP
Adenosine monophosphate
Adenosine monophosphate , also known as 5'-adenylic acid, is a nucleotide that is used as a monomer in RNA. It is an ester of phosphoric acid and the nucleoside adenosine. AMP consists of a phosphate group, the sugar ribose, and the nucleobase adenine...
concentration, and also to leptin
Leptin
Leptin is a 16 kDa protein hormone that plays a key role in regulating energy intake and energy expenditure, including appetite and metabolism. It is one of the most important adipose derived hormones...
(see 4.4, Phosphorylation of reductase).
Importance
HMG-CoA reductase is a polytopic, transmembrane protein that 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 it can offer cardiovascular health benefits independent of cholesterol reduction. Statins have been shown to have anti-inflammatory properties, 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
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
, an inflammatory autoimmune disease.
HMG-CoA reductase is also an important developmental enzyme. Inhibition of its activity and the concomitant lack of isoprenoids that yields can lead to morphological defects.
Regulation
Transcription of the reductase gene
TranscriptionTranscription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
of the reductase gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
is enhanced by the sterol regulatory element binding protein
Sterol regulatory element binding protein
Sterol Regulatory Element-Binding Proteins are transcription factors that bind to the sterol regulatory element DNA sequence TCACNCCAC. Mammalian SREBPs are encoded by the genes SREBF1 and SREBF2. SREBPs belong to the basic-helix-loop-helix leucine zipper class of transcription factors...
(SREBP). This protein binds to the sterol regulatory element (SRE), located on the 5' end of the reductase gene. When SREBP
Sterol regulatory element binding protein
Sterol Regulatory Element-Binding Proteins are transcription factors that bind to the sterol regulatory element DNA sequence TCACNCCAC. Mammalian SREBPs are encoded by the genes SREBF1 and SREBF2. SREBPs belong to the basic-helix-loop-helix leucine zipper class of transcription factors...
is inactive, it is bound to the ER
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
or nuclear membrane. When cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
levels fall, SREBP is released from the membrane by proteolysis
Proteolysis
Proteolysis is the directed degradation of proteins by cellular enzymes called proteases or by intramolecular digestion.-Purposes:Proteolysis is used by the cell for several purposes...
and migrates to the nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
, 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
TranslationTranslation (genetics)
In molecular biology and genetics, translation is the third stage of protein biosynthesis . In translation, messenger RNA produced by transcription is decoded by the ribosome to produce a specific amino acid chain, or polypeptide, that will later fold into an active protein...
of mRNA is inhibited by a mevalonate derivative, which has been reported to be farnesol
Farnesol
Farnesol is a natural organic compound which is an acyclic sesquiterpene alcohol found as a colorless liquid. It is insoluble in water, but miscible with oils...
,although this role has been disputed.
Degradation of reductase
Rising levels of sterolSterol
Sterols, also known as steroid alcohols, are a subgroup of the steroids and an important class of organic molecules. They occur naturally in plants, animals, and fungi, with the most familiar type of animal sterol being cholesterol...
s increase the susceptibility of the reductase enzyme to ER-assosiated degradation (ERAD
ERAD
Endoplasmic-reticulum-associated protein degradation designates a cellular pathway which targets misfolded proteins of the endoplasmic reticulum for ubiquitination and subsequent degradation by a protein-degrading complex, called the proteasome....
) and proteolysis
Proteolysis
Proteolysis is the directed degradation of proteins by cellular enzymes called proteases or by intramolecular digestion.-Purposes:Proteolysis is used by the cell for several purposes...
. 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
AMFR
Autocrine motility factor receptor, isoform 2 is a protein that in humans is encoded by the AMFR gene.-Interactions:AMFR has been shown to interact with Valosin-containing protein.-Further reading:...
, serving as a signal for proteolytic degradation.
Phosphorylation of reductase
Short-term regulation of HMG-CoA reductase is achieved by inhibition by phosphorylationPhosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
(of Serine 872, in humans). 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
AMP-activated protein kinase
5' AMP-activated protein kinase or AMPK or 5' adenosine monophosphate-activated protein kinase is an enzyme that plays a role in cellular energy homeostasis. It consists of three proteins that together make a functional enzyme, conserved from yeast to humans. It is expressed in a number of...
, which also phosphorylates and inactivates acetyl-CoA carboxylase
Acetyl-CoA carboxylase
Acetyl-CoA carboxylase is a biotin-dependent enzyme that catalyzes the irreversible carboxylation of acetyl-CoA to produce malonyl-CoA through its two catalytic activities, biotin carboxylase and carboxyltransferase...
, the rate-limiting enzyme of fatty acid biosynthesis. Thus, both pathways utilizing acetyl-CoA for lipid synthesis are inactivated when energy charge is low in the cell, and concentrations of AMP
Adenosine monophosphate
Adenosine monophosphate , also known as 5'-adenylic acid, is a nucleotide that is used as a monomer in RNA. It is an ester of phosphoric acid and the nucleoside adenosine. AMP consists of a phosphate group, the sugar ribose, and the nucleobase adenine...
rise. There has been a great deal of research on the identity of upstream kinases that phosphorylate and activate the AMP-activated protein kinase
AMP-activated protein kinase
5' AMP-activated protein kinase or AMPK or 5' adenosine monophosphate-activated protein kinase is an enzyme that plays a role in cellular energy homeostasis. It consists of three proteins that together make a functional enzyme, conserved from yeast to humans. It is expressed in a number of...
.
Fairly recently, LKB1 has been identified as a likely AMP kinase kinase, which appears to involve calcium/calmodulin signaling. This pathway likely transduces signals from leptin
Leptin
Leptin is a 16 kDa protein hormone that plays a key role in regulating energy intake and energy expenditure, including appetite and metabolism. It is one of the most important adipose derived hormones...
, adiponectin
Adiponectin
Adiponectin is a protein which in humans is encoded by the ADIPOQ gene.- Structure :...
, and other signaling molecules.
External links
- Cholesterol Synthesis - has some good regulatory details - the HMG-CoA Reductase Structure in Interactive 3D