HMG-CoA reductase pathway
Encyclopedia
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
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...
present in all higher eukaryotes and many bacteria. It is important for the production of dimethylallyl pyrophosphate
Dimethylallyl pyrophosphate
Dimethylallyl pyrophosphate is an intermediate product of both mevalonic acid pathway and DOXP/MEP pathway. It is an isomer of isopentenyl pyrophosphate and exists in virtually all life forms...
(DMAPP) and isopentenyl pyrophosphate
Isopentenyl pyrophosphate
Isopentenyl pyrophosphate is an intermediate in the classical, HMG-CoA reductase pathway used by organisms in the biosynthesis of terpenes and terpenoids. IPP is formed from acetyl-CoA via mevalonic acid...
(IPP), which serve as the basis for the biosynthesis of molecules used in processes as diverse as terpenoid
Terpenoid
The terpenoids , sometimes called isoprenoids, are a large and diverse class of naturally occurring organic chemicals similar to terpenes, derived from five-carbon isoprene units assembled and modified in thousands of ways. Most are multicyclic structures that differ from one another not only in...
synthesis, protein prenylation
Prenylation
Prenylation, or isoprenylation, or lipidation is the addition of hydrophobic molecules to a protein. It is usually assumed that prenyl groups facilitate attachment to cell membranes, similar to lipid anchor like the GPI anchor, though direct evidence is missing...
, cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
maintenance, hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
s, protein anchoring
Lipid anchored protein
In lipid-anchored proteins, a covalently attached fatty acid such as palmitate or myristate serves to anchor them to either face of the cell membrane. Examples include G proteins and certain kinases. It is believed that the fatty acid chain inserts and assumes a place in the bilayer structure of...
, and N-glycosylation
Glycosylation
Glycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule . In biology glycosylation refers to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules...
. It is also a part of steroid biosynthesis.
Regulation and feedback
Several key enzymes can be activated through DNA transcriptional regulation on activation of SREBP (sterol regulatory element-binding protein-1 and -2). This intracellular sensor detects low 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...
levels and stimulates endogenous production by the HMG-CoA reductase pathway, as well as increasing lipoprotein uptake by up-regulating the LDL-receptor
LDL receptor
The Low-Density Lipoprotein Receptor is a mosaic protein of ~840 amino acids that mediates the endocytosis of cholesterol-rich LDL. It is a cell-surface receptor that recognizes the apoprotein B100 which is embedded in the phospholipid outer layer of LDL particles...
. Regulation of this pathway is also achieved by controlling the rate of translation of the mRNA, degradation of reductase and phosphorylation.
- For more information on regulation, see HMG-CoA reductaseHMG-CoA reductaseHMG-CoA reductase is the rate-controlling enzyme of the mevalonate pathway, the metabolic pathway that produces cholesterol and other isoprenoids...
Pharmacology
A number of drugsMedication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
target the mevalonate pathway:
- StatinStatinStatins are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver. Increased cholesterol levels have been associated with cardiovascular diseases, and statins are therefore used in the...
s (used to decrease cholesterol levelsHypercholesterolemiaHypercholesterolemia is the presence of high levels of cholesterol in the blood. It is not a disease but a metabolic derangement that can be caused by many diseases, notably cardiovascular disease...
); - BisphosphonateBisphosphonateBisphosphonates are a class of drugs that prevent the loss of bone mass, used to treat osteoporosis and similar diseases...
s (used to treat various bone-degenerative diseases)
Alternative
PlantPlant
Plants are living organisms belonging to the kingdom Plantae. Precise definitions of the kingdom vary, but as the term is used here, plants include familiar organisms such as trees, flowers, herbs, bushes, grasses, vines, ferns, mosses, and green algae. The group is also called green plants or...
s and apicomplexa
Apicomplexa
The Apicomplexa are a large group of protists, most of which possess a unique organelle called apicoplast and an apical complex structure involved in penetrating a host's cell. They are unicellular, spore-forming, and exclusively parasites of animals. Motile structures such as flagella or...
n protozoa
Protozoa
Protozoa are a diverse group of single-cells eukaryotic organisms, many of which are motile. Throughout history, protozoa have been defined as single-cell protists with animal-like behavior, e.g., movement...
such as malaria
Malaria
Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...
parasites have the ability to produce their isoprenoids (terpenoids) using an additional alternative pathway called the methylerythritol phosphate (MEP) or non-mevalonate pathway
Non-mevalonate pathway
The non-mevalonate pathway or 2-C-methyl-D-erythritol 4-phosphate/1-deoxy-D-xylulose 5-phosphate pathway of isoprenoid biosynthesis is an alternative metabolic pathway leading to the formation of isopentenyl pyrophosphate and dimethylallyl pyrophosphate that has been elucidated only...
, which takes place in their plastid
Plastid
Plastids are major organelles found in the cells of plants and algae. Plastids are the site of manufacture and storage of important chemical compounds used by the cell...
s. In addition, most bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
including important pathogens, such as Mycobacterium tuberculosis
Mycobacterium tuberculosis
Mycobacterium tuberculosis is a pathogenic bacterial species in the genus Mycobacterium and the causative agent of most cases of tuberculosis . First discovered in 1882 by Robert Koch, M...
, synthesize IPP and DMAPP via the non-mevalonate pathway
Non-mevalonate pathway
The non-mevalonate pathway or 2-C-methyl-D-erythritol 4-phosphate/1-deoxy-D-xylulose 5-phosphate pathway of isoprenoid biosynthesis is an alternative metabolic pathway leading to the formation of isopentenyl pyrophosphate and dimethylallyl pyrophosphate that has been elucidated only...
instead.
Reactions
| Reaction | Diagram | Enzyme >- | Acetyl-CoA Acetyl-CoA Acetyl coenzyme A or acetyl-CoA is an important molecule in metabolism, used in many biochemical reactions. Its main function is to convey the carbon atoms within the acetyl group to the citric acid cycle to be oxidized for energy production. In chemical structure, acetyl-CoA is the thioester... (citric acid cycle Citric acid cycle The citric acid cycle — also known as the tricarboxylic acid cycle , the Krebs cycle, or the Szent-Györgyi-Krebs cycle — is a series of chemical reactions which is used by all aerobic living organisms to generate energy through the oxidization of acetate derived from carbohydrates, fats and... ) undergoes condensation with another acetyl-CoA subunit via Acetyl-CoA Transferase to form acetoacetyl-CoA Acetoacetyl-CoA Acetoacetyl CoA is the precursor of HMG-CoA in the Mevalonate pathway, which is essential for cholesterol synthesis. It also takes a similar role in the ketone bodies synthesis pathway of the liver... |
thiolase Thiolase Thiolases also known as acetyl-Coenzyme A acetyltransferases are enzymes which converts two units of acetyl-CoA to acetoacetyl CoA in the mevalonate pathway.... >- | Acetyl-CoA condenses with acetoacetyl-CoA to form 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). |
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HMG-CoA synthase HMG-CoA synthase In molecular biology, HMG-CoA synthase is an enzyme which catalyzes the reaction in which Acetyl-CoA condenses with acetoacetyl-CoA to form 3-hydroxy-3-methylglutaryl-CoA . It is the second reaction in the mevalonate-dependent isoprenoid biosynthesis pathway. HMG-CoA is an intermediate in both... >- | HMG-CoA is reduced to mevalonate by NADPH. This reaction occurs in the cytosol. It is the rate limiting step in cholesterol synthesis, which is why the enzyme catalyzing the reaction is a target of statin Statin Statins are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver. Increased cholesterol levels have been associated with cardiovascular diseases, and statins are therefore used in the... s. |
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HMG-CoA reductase HMG-CoA reductase HMG-CoA reductase is the rate-controlling enzyme of the mevalonate pathway, the metabolic pathway that produces cholesterol and other isoprenoids... >- | Mevalonate to 5-phosphomevalonate. |
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mevalonate kinase Mevalonate kinase Mevalonate kinase is an enzyme that in humans is encoded by the MVK gene. Mevalonate kinases are found in a wide variety of organisms from bacteria to mammals... >- | 5-phosphomevalonate to 5-pyrophosphomevalonate. |
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phosphomevalonate kinase Phosphomevalonate kinase Phosphomevalonate kinase is an enzyme in the mevalonate pathway.... >- | Mevalonate-5-pyrophosphate to 3-isopentenyl pyrophosphate (IPP) (see also HIDS). |
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isopentenyl pyrophosphate isomerase |
External links
- Rensselaer Polytechnic Institute page on cholesterol synthesis (including regulation)