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A Gene Cluster for the Mevalonate Pathway from Streptomyces sp ...
src: jb.asm.org

The mevalonate pathway, also known as the isoprenoid pathway or HMG-CoA reductase pathway is an essential metabolic pathway present in eukaryotes, archaea, and some bacteria. The pathway produces two five-carbon building blocks called isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), which are used to make isoprenoids, a diverse class of over 30,000 biomolecules such as cholesterol, heme, vitamin K, coenzyme Q10, and all steroid hormones.

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


Video 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 acetyl-CoA molecules to yield acetoacetyl-CoA. This is followed by a second condensation to form HMG-CoA (3-hydroxy-3- methyl-glutaryl-CoA). Reduction of HMG-CoA yields (R)-mevalonate. These first 3 enzymatic steps are called the upper mevalonate pathway.


Maps Mevalonate pathway



Lower mevalonate pathway

The lower mevalonate pathway which converts (R)-mevalonate into IPP and DMAPP has 3 variants. In eukaryotes, mevalonate is phosphorylated twice in the 5-OH position, then decarboxylated to yield IPP. 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). 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).


of genes encoding enzymes of the mevalonate pathway
src: www.researchgate.net


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.


Viral MicroRNAs Repress the Cholesterol Pathway, and 25 ...
src: mbio.asm.org


Pharmacology

A number of drugs target the mevalonate pathway:

  • Statins (used to decrease cholesterol levels);
  • Bisphosphonates (used to treat various bone-degenerative diseases)

Interplay of mevalonate and Hippo pathways regulates RHAMM ...
src: www.pnas.org


Diseases

A number of diseases affect the mevalonate pathway:

  • Mevalonate Kinase Deficiency
    • Mevalonic Aciduria
    • Hyperimmunoglobulinemia D Syndrome (HIDS)

Molecular Mechanisms of Action of Bisphosphonates: Current Status ...
src: clincancerres.aacrjournals.org


Alternative pathway

Plants, most bacteria, and some protozoa such as malaria parasites have the ability to produce isoprenoids using an alternative pathway called the methylerythritol phosphate (MEP) or non-mevalonate pathway. The output of both the mevalonate pathway and the MEP pathway are the same, IPP and DMAPP, however the enzymatic reactions to convert acetyl-CoA into IPP are entirely different. In higher plants, the MEP pathway operates in plastids while the mevalonate pathway operates in the cytosol. Examples of bacteria that contain the MEP pathway include Escherichia coli and pathogens such as Mycobacterium tuberculosis.


View Image
src: www.ijem.in


Enzymatic reactions


POWER POINT PUBLICATION E-ISSN: /P-ISSN: /ISBN: Promoted By ...
src: images.slideplayer.com


References


Systematic analysis and visualisation of microarray studies - ppt ...
src: slideplayer.com


External links

  • Rensselaer Polytechnic Institute page on cholesterol synthesis (including regulation)

Source of the article : Wikipedia

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