Mevalonate pathway

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Mevalonate pathway diagram showing the conversion of acetyl-CoA into isopentenyl pyrophosphate, the essential building block of all isoprenoids. The eukaryotic variant is shown in black. Archaeal variants are shown in red and blue.

The mevalonate pathway, also known as the isoprenoid pathway or

steroid hormones.[2]

The mevalonate pathway begins with acetyl-CoA and ends with the production of IPP and DMAPP.[3] It is best known as the target of statins, a class of cholesterol lowering drugs. Statins inhibit HMG-CoA reductase within the mevalonate pathway.

Upper mevalonate pathway

The mevalonate pathway of eukaryotes, archaea, and eubacteria all begin the same way. The sole carbon feed stock of the pathway is acetyl-CoA. The first step condenses two

mevalonate. These first 3 enzymatic steps are called the upper mevalonate pathway.[4]

Lower mevalonate pathway

The lower mevalonate pathway which converts (R)-

decarboxylated to yield IPP.[4] In some archaea such as Haloferax volcanii, mevalonate is phosphorylated once in the 5-OH position, decarboxylated to yield isopentenyl phosphate (IP), and finally phosphorylated again to yield IPP (Archaeal Mevalonate Pathway I).[5] A third mevalonate pathway variant found in Thermoplasma acidophilum, phosphorylates mevalonate at the 3-OH position followed by phosphorylation at the 5-OH position. The resulting metabolite, mevalonate-3,5-bisphosphate, is decarboxylated to IP, and finally phosphorylated to yield IPP (Archaeal Mevalonate Pathway II).[6][7]

Regulation and feedback

Several key

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.[1]

Pharmacology

A number of drugs target the mevalonate pathway:

Diseases

A number of

diseases
affect the mevalonate pathway:

Alternative pathway

plastids while the mevalonate pathway operates in the cytosol.[9] Examples of bacteria that contain the MEP pathway include Escherichia coli and pathogens such as Mycobacterium tuberculosis
.

Enzymatic reactions

Enzyme Reaction Description
Acetoacetyl-CoA thiolase
Acetyl-CoA (citric acid cycle) undergoes condensation with another acetyl-CoA molecule to form acetoacetyl-CoA
HMG-CoA synthase
Acetoacetyl-CoA condenses with another Acetyl-CoA molecule to form
3-hydroxy-3-methylglutaryl-CoA
(HMG-CoA).
HMG-CoA reductase
HMG-CoA is reduced to
NADPH. This is the rate limiting step in cholesterol synthesis, which is why this enzyme is a good target for pharmaceuticals (statins
).
mevalonate-5-kinase
Mevalonate is phosphorylated at the 5-OH position to yield mevalonate-5-phosphate (also called phosphomevalonic acid).
mevalonate-3-kinase
Mevalonate is phosphorylated at the 3-OH position to yield mevalonate-3-phosphate. 1 ATP is consumed.
mevalonate-3-phosphate-5-kinase
Mevalonate-3-phosphate is phosphorylated at the 5-OH position to yield mevalonate-5-phosphate (also called phosphomevalonic acid). 1 ATP is consumed.
phosphomevalonate kinase
mevalonate-5-phosphate is phosphorylated to yield mevalonate-5-pyrophosphate. 1 ATP is consumed.
mevalonate-5-pyrophosphate decarboxylase
Mevalonate-5-pyrophosphate is decarboxylated to yield isopentenyl pyrophosphate (IPP). 1 ATP is consumed.
isopentenyl pyrophosphate isomerase
.

References

  1. ^ a b Buhaescu I, Izzedine H (2007) Mevalonate pathway: areview of clinical and therapeutical implications. ClinBiochem 40:575–584.
  2. ^ Holstein, S. A., and Hohl, R. J. (2004) Isoprenoids: Remarkable Diversity of Form and Function. Lipids 39, 293−309
  3. ^ Goldstein, J. L., and Brown, S. B. (1990) Regulation of the mevalonate pathway. Nature 343, 425−430
  4. ^ a b Miziorko H (2011) Enzymes of the mevalonate pathway of isoprenoid biosynthesis. Arch Biochem Biophys 505:131-143.
  5. ^ Dellas, N., Thomas, S. T., Manning, G., and Noel, J. P. (2013) Discovery of a metabolic alternative to the classical mevalonate pathway. eLife 2, e00672
  6. ^ Vinokur JM, Korman TP, Cao Z, Bowie JU (2014) Evidence of a novel mevalonate pathway in archaea. Biochemistry 53:4161–4168.
  7. ^ Azami Y, Hattori A, Nishimura H, Kawaide H, YoshimuraT, Hemmi H (2014) (R)-mevalonate-3-phosphate is an intermediate of the mevalonate pathway in Thermoplasma acidophilum. J Biol Chem 289:15957–15967.
  8. PMID 23251734
    .
  9. ^ a b Banerjee A, Sharkey TD. (2014) Methylerythritol 4-phosphate (MEP) pathway metabolic regulation. Nat Prod Rep 31:10431055
  10. PMID 31843486
    .

External links