Themevalonate pathway, also known as theisoprenoid pathway orHMG-CoA reductase pathway is an essentialmetabolic pathway present ineukaryotes,archaea, and somebacteria.[1] The pathway produces two five-carbon building blocks calledisopentenyl pyrophosphate (IPP) anddimethylallyl pyrophosphate (DMAPP), which are used to makeisoprenoids, a diverse class of over 30,000 biomolecules such ascholesterol,vitamin K,coenzyme Q10, and allsteroid hormones.[2]
The mevalonate pathway begins withacetyl-CoA and ends with the production of IPP and DMAPP.[3] It is best known as the target ofstatins, a class of cholesterol lowering drugs. Statins inhibitHMG-CoA reductase within the 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 twoacetyl-CoA molecules to yieldacetoacetyl-CoA. This is followed by a second condensation to formHMG-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.[4]
The lower mevalonate pathway which converts (R)-mevalonate into IPP and DMAPP has 3 variants. Ineukaryotes, mevalonate is phosphorylated twice in the 5-OH position, thendecarboxylated to yield IPP.[4] In somearchaea such asHaloferax 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).[5] A third mevalonate pathway variant found inThermoplasma 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).[6][7]
Several keyenzymes can be activated throughDNA transcriptional regulation on activation ofSREBP (sterol regulatory element-binding protein-1 and -2). This intracellular sensor detects lowcholesterol levels and stimulates endogenous production by the HMG-CoA reductase pathway, as well as increasinglipoprotein uptake by up-regulating theLDL-receptor. Regulation of this pathway is also achieved by controlling the rate of translation of the mRNA, degradation of reductase and phosphorylation.[1]
A number ofdrugs target themevalonate pathway:
A number ofdiseases affect themevalonate pathway:
Plants, mostbacteria, and someprotozoa such asmalaria parasites have the ability to produceisoprenoids using an alternative pathway called themethylerythritol phosphate (MEP) ornon-mevalonate pathway.[9] 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 using13C-glucoseisotopomers.[10] In higher plants, the MEP pathway operates inplastids while the mevalonate pathway operates in thecytosol.[9] Examples of bacteria that contain the MEP pathway includeEscherichia coli and pathogens such asMycobacterium tuberculosis.
| Enzyme | Reaction | Description |
| Acetoacetyl-CoA thiolase |  | Acetyl-CoA (citric acid cycle) undergoes condensation with another acetyl-CoA molecule to formacetoacetyl-CoA |
| HMG-CoA synthase |  | Acetoacetyl-CoA condenses with another Acetyl-CoA molecule to form3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). |
| HMG-CoA reductase |  | HMG-CoA is reduced tomevalonate byNADPH. This is the rate limiting step in cholesterol synthesis, which is why this enzyme is a good target for pharmaceuticals (statins). |
| mevalonate-5-kinase |  | Mevalonate is phosphorylated at the 5-OH position to yieldmevalonate-5-phosphate (also calledphosphomevalonic acid). |
| mevalonate-3-kinase |  | Mevalonate is phosphorylated at the 3-OH position to yieldmevalonate-3-phosphate. 1 ATP is consumed. |
| mevalonate-3-phosphate-5-kinase |  | Mevalonate-3-phosphate is phosphorylated at the 5-OH position to yieldmevalonate-5-phosphate (also calledphosphomevalonic acid). 1 ATP is consumed. |
| phosphomevalonate kinase |  | mevalonate-5-phosphate is phosphorylated to yieldmevalonate-5-pyrophosphate. 1 ATP is consumed. |
| mevalonate-5-pyrophosphate decarboxylase |  | Mevalonate-5-pyrophosphate is decarboxylated to yieldisopentenyl pyrophosphate (IPP). 1 ATP is consumed. |
| isopentenyl pyrophosphate isomerase |  | isopentenyl pyrophosphate isisomerized todimethylallyl pyrophosphate. |
Metabolism map | ||
|---|---|---|
 Majormetabolic pathways inmetro-style map. Click any text (name of pathway or metabolites) to link to the corresponding article. Single lines: pathways common to most lifeforms. Double lines: pathways not in humans (occurs in e.g. plants, fungi, prokaryotes).  Orange nodes:carbohydrate metabolism. Violet nodes:photosynthesis. Red nodes:cellular respiration. Pink nodes:cell signaling. Blue nodes:amino acid metabolism. Grey nodes:vitamin andcofactor metabolism. Brown nodes:nucleotide andprotein metabolism. Green nodes:lipid metabolism. | ||
