HMG-CoA reductase pathway
The HMG-CoA reductase pathway, also known as MVA pathway or
mevalonate-dependent (MAD) route, is an important cellular metabolic pathway present in virtually all organisms. It forms hydrophobic molecules for tasks as diverse as cell membrane maintenance, hormones, protein anchoring and N-glycosylation.
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 targets the HMG-CoA reductase pathway:- Statins (used for elevated cholesterol levels);
- Bisphosphonates (used for osteoporosis).
Alternative
Plants have two pathways to create Isoprenoids: this one and
the methylerythritol phosphate (MEP) pathway (also called MVA independent pathway)
in plastids.
Reactions - Acetyl-CoA (citric acid cycle) is converted to acetoacetyl-CoA by the enzyme thiolase:
- Acetyl-CoA condenses with acetoacetyl-CoA to form 3-hydroxy-3-methylglutaryl CoA (HMG-CoA). This reaction is catalyzed by the enzyme HMG-CoA synthase.
- HMG-CoA is reduced to mevalonate by NADPH. This reaction occurs in the cytosol. It is the committed step in cholesterol synthesis, which is why the enzyme catalyzing the reaction, HMG-CoA reductase, is a target of statins.
- Mevalonate to 5-phosphomevalonate, catalyzed by the enzyme mevalonate kinase:
- 5-phosphomevalonate to 5-pyrophosphomevalonate, catalyzed by the enzyme phosphomevalonate kinase:
- Mevalonate-5-pyrophosphate to 3-isopentenyl pyrophosphate (IPP), catalyzed by the enzyme mevalonate-5-pyrophosphate decarboxylase (see also HIDS):
- 3-Isopentenyl pyrophosphate is isomerized to dimethylallyl pyrophosphate, catalyzed by the enzyme isopentenyl pyrophosphate isomerase:
Prenyl transferase (also called farnesyl pyrophosphate synthase) catalyzes sequential condensation reactions: - Dimethylallyl pyrophosphate reacts with 3-isopentenyl pyrophosphate to form geranyl pyrophosphate:
- Geranyl pyrophosphate itself reacts with 3-isopentenyl pyrophosphate to form farnesyl pyrophosphate
The bisphosphonates inhibit the enzyme prenyl transferase (and also farnesyltranstransferase). Two molecules of farnesyl pyrophosphate condense with reduction by NADPH to form squalene - by squalene synthase;
- Squalene is reduced by NADPH to 2,3-oxidosqualene (squalene epoxide) - by squalene monooxygenase;
- 2,3-oxidosqualene is converted to a protosterol cation and finally to lanosterol, catalyzed by the enzyme lanosterol synthase:
19 further reaction steps convert lanosterol into cholesterol.
References Berg, J.M., J.L. Tymoczko, and L. Stryer, Biochemistry. 5th ed. 2002, New York: W.H. Freeman. xxxviii, 974, [976] (various pagings)
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