The HMG-CoA reductase pathway or mevalonate 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

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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

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A number of drugs target the HMG-CoA reductase pathway:

• Statins (used for elevated cholesterol levels);
• Bisphosphonates (used for osteoporosis).

Alternative

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Plants have two pathways to create Isoprenoids: this one and the methylerythritol phosphate (MEP) pathway (also called MVA independent pathway) in plastids.

Reactions

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• 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

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                      1. Berg JM, Tymoczko JL, Stryer L. Biochemistry. 5th ed. New York: W.H. Freeman. xxxviii, 974, ^* (various pagings). ISBN 0716746840.
                      2. Swanson KM, Hohl RJ. Anti-cancer therapy: targeting the mevalonate pathway. Curr Cancer Drug Targets 2006;6:15-37. PMID 16475974.

                      Metabolism