Mevalonate pathway

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 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.

For more information on regulation, see HMG-CoA reductase

Pharmacology

A number of drugs target the mevalonate pathway:

• Statins (used for elevated cholesterol levels);
• Bisphosphonates (used in treatment of various bone-degenerative diseases)

Alternative

Plants and apicomplexan protozoa such as malaria parasites have the ability to produce their isoprenoids (terpenoids) using an additional alternative pathway called the methylerythritol phosphate (MEP) or non-mevalonate pathway, which takes place in their plastids. In addition, most eubacteria including important pathogens, such as Mycobacterium tuberculosis, synthesize IPP and DMAPP via the non-mevalonate pathway instead.

Reactions

Reaction

Diagram

Enzyme |- | Acetyl-CoA (citric acid cycle) is converted to acetoacetyl-CoA

thiolase |- | Acetyl-CoA condenses with acetoacetyl-CoA to form 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA).

HMG-CoA synthase |- | 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 statins.

HMG-CoA reductase |- | Mevalonate to 5-phosphomevalonate.

mevalonate kinase |- | 5-phosphomevalonate to 5-pyrophosphomevalonate.

phosphomevalonate kinase |- | Mevalonate-5-pyrophosphate to 3-isopentenyl pyrophosphate (IPP) (see also HIDS).

mevalonate-5-pyrophosphate decarboxylase |- | 3-isopentenyl pyrophosphate is isomerized to dimethylallyl pyrophosphate.

isopentenyl pyrophosphate isomerase

References

1. Berg JM, Tymoczko JL, Stryer L. Biochemistry. 5th ed. New York: W.H. Freeman. xxxviii, 974, [976] (various pagings). ISBN 0-7167-4684-0.
2. Swanson KM, Hohl RJ. Anti-cancer therapy: targeting the mevalonate pathway. Curr Cancer Drug Targets 2006;6:15-37. PMID 16475974.

External links

• Rensselaer Polytechnic Institute page on cholesterol synthesis (including regulation)

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