The mevalonate pathway, also known as the isoprenoid pathway or
HMG-CoA reductase
HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, official symbol HMGCR) is the rate-controlling enzyme (NADH-dependent, ; NADPH-dependent, ) of the mevalonate pathway, the metabolic pathway that produces cholesterol and ...
pathway is an essential
metabolic pathway
In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell. The reactants, products, and intermediates of an enzymatic reaction are known as metabolites, which are modified by a sequence of chemical ...
present in
eukaryotes
Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bact ...
,
archaea, and some
bacteria
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were am ...
.
The pathway produces two five-carbon building blocks called
isopentenyl pyrophosphate (IPP) and
dimethylallyl pyrophosphate (DMAPP), which are used to make
isoprenoids
The terpenoids, also known as isoprenoids, are a class of naturally occurring organic chemicals derived from the 5-carbon compound isoprene and its derivatives called terpenes, diterpenes, etc. While sometimes used interchangeably with "terpenes", ...
, a diverse class of over 30,000 biomolecules such as
cholesterol
Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell membr ...
,
vitamin K
Vitamin K refers to structurally similar, fat-soluble vitamers found in foods and marketed as dietary supplements. The human body requires vitamin K for post-synthesis modification of certain proteins that are required for blood coagulat ...
,
coenzyme Q10
Coenzyme Q, also known as ubiquinone and marketed as CoQ10, is a coenzyme family that is ubiquitous in animals and most bacteria (hence the name ubiquinone). In humans, the most common form is coenzyme Q10 or ubiquinone-10.
It is a 1,4-ben ...
, and all
steroid hormones.
The mevalonate pathway begins with
acetyl-CoA
Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle (Krebs cycle) to be oxidized fo ...
and ends with the production of IPP and DMAPP.
It is best known as the target of
statin
Statins, also known as HMG-CoA reductase inhibitors, are a class of lipid-lowering medications that reduce illness and mortality in those who are at high risk of cardiovascular disease. They are the most common cholesterol-lowering drugs.
L ...
s, a class of cholesterol lowering drugs. Statins inhibit
HMG-CoA reductase
HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, official symbol HMGCR) is the rate-controlling enzyme (NADH-dependent, ; NADPH-dependent, ) of the mevalonate pathway, the metabolic pathway that produces cholesterol and ...
within the mevalonate pathway.
Upper mevalonate pathway
The mevalonate pathway of eukaryotes, archaea, and eubacteria all begin the same way. The sole carbon feed stock of the pathway is acetyl-CoA. The first step condenses two
acetyl-CoA
Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle (Krebs cycle) to be oxidized fo ...
molecules to yield
acetoacetyl-CoA
Acetoacetyl CoA is the precursor of HMG-CoA in the mevalonate pathway, which is essential for cholesterol biosynthesis. It also takes a similar role in the ketone bodies synthesis ( ketogenesis) pathway of the liver. In the ketone bodies digesti ...
. This is followed by a second condensation to form
HMG-CoA (3-hydroxy-3- methyl-glutaryl-CoA). Reduction of HMG-CoA yields (R)-
mevalonate. These first 3 enzymatic steps are called the upper mevalonate pathway.
Lower mevalonate pathway
The lower mevalonate pathway which converts (R)-
mevalonate into IPP and DMAPP has 3 variants. In
eukaryotes
Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bact ...
, mevalonate is phosphorylated twice in the 5-OH position, then
decarboxylated
Decarboxylation is a chemical reaction that removes a carboxyl group and releases carbon dioxide (CO2). Usually, decarboxylation refers to a reaction of carboxylic acids, removing a carbon atom from a carbon chain. The reverse process, which is t ...
to yield IPP.
In some
archaea such as ''
Haloferax volcanii'', mevalonate is phosphorylated once in the 5-OH position, decarboxylated to yield isopentenyl phosphate (IP), and finally phosphorylated again to yield IPP (Archaeal Mevalonate Pathway I).
A third mevalonate pathway variant found in ''
Thermoplasma acidophilum'', phosphorylates mevalonate at the 3-OH position followed by phosphorylation at the 5-OH position. The resulting metabolite, mevalonate-3,5-bisphosphate, is decarboxylated to IP, and finally phosphorylated to yield IPP (Archaeal Mevalonate Pathway II).
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
cholesterol
Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell membr ...
levels and stimulates endogenous production by the HMG-CoA reductase pathway, as well as increasing
lipoprotein uptake by up-regulating the
LDL-receptor. Regulation of this pathway is also achieved by controlling the rate of translation of the mRNA, degradation of reductase and phosphorylation.
Pharmacology
A number of
drugs
A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via inhalat ...
target the ''mevalonate pathway'':
*
Statin
Statins, also known as HMG-CoA reductase inhibitors, are a class of lipid-lowering medications that reduce illness and mortality in those who are at high risk of cardiovascular disease. They are the most common cholesterol-lowering drugs.
L ...
s (used to
decrease cholesterol levels);
*
Bisphosphonate
Bisphosphonates are a class of drugs that prevent the loss of bone density, used to treat osteoporosis and similar diseases. They are the most commonly prescribed drugs used to treat osteoporosis. They are called bisphosphonates because they ...
s (used to treat various bone-degenerative diseases)
Diseases
A number of
diseases affect the ''mevalonate pathway'':
*
Mevalonate Kinase Deficiency
** Mevalonic Aciduria
** Hyperimmunoglobulinemia D Syndrome (HIDS).
Alternative pathway
Plants
Plants are predominantly photosynthetic eukaryotes of the kingdom Plantae. Historically, the plant kingdom encompassed all living things that were not animals, and included algae and fungi; however, all current definitions of Plantae exclud ...
, most
bacteria
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were am ...
, and some
protozoa
Protozoa (singular: protozoan or protozoon; alternative plural: protozoans) are a group of single-celled eukaryotes, either free-living or parasitic, that feed on organic matter such as other microorganisms or organic tissues and debris. Histor ...
such as
malaria
Malaria is a mosquito-borne infectious disease that affects humans and other animals. Malaria causes symptoms that typically include fever, tiredness, vomiting, and headaches. In severe cases, it can cause jaundice, seizures, coma, or deat ...
parasites have the ability to produce
isoprenoids
The terpenoids, also known as isoprenoids, are a class of naturally occurring organic chemicals derived from the 5-carbon compound isoprene and its derivatives called terpenes, diterpenes, etc. While sometimes used interchangeably with "terpenes", ...
using an alternative pathway called the
methylerythritol phosphate (MEP) or
non-mevalonate pathway.
The output of both the mevalonate pathway and the MEP pathway are the same, IPP and DMAPP, however the enzymatic reactions to convert acetyl-CoA into IPP are entirely different. Interaction between the two metabolic pathways can be studied by using
13C-glucose
isotopomers.
In higher plants, the MEP pathway operates in
plastids
The plastid (Greek: πλαστός; plastós: formed, molded – plural plastids) is a membrane-bound organelle found in the cells of plants, algae, and some other eukaryotic organisms. They are considered to be intracellular endosymbiotic cy ...
while the mevalonate pathway operates in the
cytosol
The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
.
Examples of bacteria that contain the MEP pathway include ''
Escherichia coli
''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus '' Esc ...
'' and pathogens such as ''
Mycobacterium tuberculosis''.
Enzymatic reactions
References
External links
Rensselaer Polytechnic Institutepage on cholesterol synthesis (including regulation)
{{MetabolismMap
Metabolic pathways