Mevalonate pathway

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The mevalonate pathway or HMG-CoA reductase pathway or mevalonate-dependent (MAD) route, 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 protein prenylation, cell membrane maintenance, hormones, protein anchoring, and N-glycosylation. It is also a part of steroid biosynthesis.

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).	Image:HMG-CoA synthase.png	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 is a target of statins.	Image:Cholesterol-Synthesis-Reaction2.png	HMG-CoA reductase
Mevalonate to 5-phosphomevalonate.	Image:Cholesterol-Synthesis-Reaction3.png	mevalonate kinase
5-phosphomevalonate to 5-pyrophosphomevalonate.	Image:Cholesterol-Synthesis-Reaction4.png	phosphomevalonate kinase
Mevalonate-5-pyrophosphate to 3-isopentenyl pyrophosphate (IPP) (see also HIDS).	Image:Cholesterol-Synthesis-Reaction5.png Image:Cholesterol-Synthesis-Reaction6.png	mevalonate-5-pyrophosphate decarboxylase
3-isopentenyl pyrophosphate is isomerized to dimethylallyl pyrophosphate.	Image:Cholesterol-Synthesis-Reaction7.png	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)

v • d • e Metabolism: Ketones/mevalonate pathway/cholesterol synthesis
To HMG-CoA	Acetyl-Coenzyme A acetyltransferase - HMG-CoA synthase (regulated step)
Ketogenesis	HMG-CoA lyase - 3-hydroxybutyrate dehydrogenase - Thiophorase
To Mevalonic acid	HMG-CoA reductase
To DMAPP	Mevalonate kinase - Phosphomevalonate kinase - Pyrophosphomevalonate decarboxylase - Isopentenyl-diphosphate delta isomerase
To Cholesterols	Dimethylallyltranstransferase - Geranyl pyrophosphate - Farnesyl-diphosphate farnesyltransferase - Squalene monooxygenase - Lanosterol synthase - CYP51A1
To Bile acids	Cholesterol 7 alpha-hydroxylase
see also intermediates

ja:メバロン酸経路

Acknowledgement and Attribution Regarding Sources of Content

Some of the initial content on this page may be incorporated in part from copyleft sources in the public domain including wikis such as Wikipedia and AskDrWiki. Drug information for patients came from the The National Library of Medicine. Infectious disease information may have come from the Centers for Disease Control (CDC). Differential Diagnoses are drawn from clinicians as well as an amalgamation of 3 sources: 1.The Disease Database; 2. Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Blackwell Publishing, 2004:3; 3. Sailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:7 .