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mevalonate pathway

Monday 25 May 2009

The mevalonate pathway or HMG-CoA reductase pathway or mevalonate-dependent (MAD) route or isoprenoid pathway, is an important cellular metabolic pathway present in all higher eukaryotes and many bacteria.

It is important for the production of dimethylallyl pyrophosphate (DMAPP) and isopentenyl pyrophosphate (IPP), which serve as the basis for the biosynthesis of molecules used in processes as diverse as terpenoid synthesis, protein prenylation, cell membrane maintenance, hormones, protein anchoring, and N-glycosylation. It is also a part of steroid biosynthesis.

Reactions

- 1. Acetyl-CoA (from citric acid cycle) undergoes condensation with another acetyl-CoA subunit via acetyl-CoA transferase to form acetoacetyl-CoA.
- 2. Acetyl-CoA condenses with acetoacetyl-CoA to form 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA).
- 3. 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.
- 4. Mevalonate to 5-phosphomevalonate.
- 5. 5-phosphomevalonate to 5-pyrophosphomevalonate.
- 6. Mevalonate-5-pyrophosphate to 3-isopentenyl pyrophosphate (IPP) (see also HIDS).
- 7. 3-isopentenyl pyrophosphate (IPP) is isomerized to dimethylallyl pyrophosphate (DMPP).

Regulation

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.

Pharmacology

A number of drugs target the mevalonate pathway:

- statins (used for elevated cholesterol levels);
- bisphosphonates (used in treatment of various bone-degenerative diseases)

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