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. Wiki pathway hi def tiff.tif
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 HMG-CoA reductase pathway is an essential metabolic pathway present in eukaryotes, archaea, and some bacteria. [1] 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, vitamin K, coenzyme Q10, and all steroid hormones. [2]

Contents

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 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. [4]

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. [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 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. [1]

Pharmacology

A number of drugs target the mevalonate pathway:

Diseases

A number of diseases affect the mevalonate pathway:

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. [9] 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. Interaction between the two metabolic pathways can be studied by using 13C-glucose isotopomers. [10] In higher plants, the MEP pathway operates in 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

EnzymeReactionDescription
Acetoacetyl-CoA thiolase
Aact1.jpg
Acetyl-CoA (citric acid cycle) undergoes condensation with another acetyl-CoA molecule to form acetoacetyl-CoA
HMG-CoA synthase
HMG-CoA synthase.svg
Acetoacetyl-CoA condenses with another Acetyl-CoA molecule to form 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA).
HMG-CoA reductase
HMG-CoA reductase reaction.svg
HMG-CoA is reduced to mevalonate by 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 kinase reaction.svg
Mevalonate is phosphorylated at the 5-OH position to yield mevalonate-5-phosphate (also called phosphomevalonic acid).
mevalonate-3-kinase
M3kwiki3.jpg
Mevalonate is phosphorylated at the 3-OH position to yield mevalonate-3-phosphate. 1 ATP is consumed.
mevalonate-3-phosphate-5-kinase
M35bpK.jpg
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
Phosphomevalonate kinase reaction.svg
mevalonate-5-phosphate is phosphorylated to yield mevalonate-5-pyrophosphate. 1 ATP is consumed.
mevalonate-5-pyrophosphate decarboxylase
Mdd2.jpg
Mevalonate-5-pyrophosphate is decarboxylated to yield isopentenyl pyrophosphate (IPP). 1 ATP is consumed.
isopentenyl pyrophosphate isomerase
IPP isomerase reaction.svg
isopentenyl pyrophosphate is isomerized to dimethylallyl pyrophosphate.

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Terpenes are a class of natural products consisting of compounds with the formula (C5H8)n for n ≥ 2. Terpenes are major biosynthetic building blocks. Comprising more than 30,000 compounds, these unsaturated hydrocarbons are produced predominantly by plants, particularly conifers. In plants, terpenes and terpenoids are important mediators of ecological interactions, while some insects use some terpenes as a form of defense. Other functions of terpenoids include cell growth modulation and plant elongation, light harvesting and photoprotection, and membrane permeability and fluidity control.

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<span class="mw-page-title-main">HMG-CoA reductase</span> Mammalian protein found in Homo sapiens

HMG-CoA reductase is the rate-controlling enzyme of the mevalonate pathway, the metabolic pathway that produces cholesterol and other isoprenoids. HMGCR catalyzes the conversion of HMG-CoA to mevalonic acid, a necessary step in the biosynthesis of cholesterol. Normally in mammalian cells this enzyme is competitively suppressed so that its effect is controlled. This enzyme is the target of the widely available cholesterol-lowering drugs known collectively as the statins, which help treat dyslipidemia.

Dolichol refers to any of a group of long-chain mostly unsaturated organic compounds that are made up of varying numbers of isoprene units terminating in an α-saturated isoprenoid group, containing an alcohol functional group.

<span class="mw-page-title-main">Dimethylallyl pyrophosphate</span> Chemical compound

Dimethylallyl pyrophosphate is an isoprenoid precursor. It is a product of both the mevalonate pathway and the MEP pathway of isoprenoid precursor biosynthesis. It is an isomer of isopentenyl pyrophosphate (IPP) and exists in virtually all life forms. The enzyme isopentenyl pyrophosphate isomerase catalyzes isomerization between DMAPP and IPP.

<span class="mw-page-title-main">Mevalonic acid</span> Chemical compound

Mevalonic acid (MVA) is a key organic compound in biochemistry; the name is a contraction of dihydroxymethylvalerolactone. The carboxylate anion of mevalonic acid, which is the predominant form in biological environments, is known as mevalonate and is of major pharmaceutical importance. Drugs like statins stop the production of mevalonate by inhibiting HMG-CoA reductase.

<span class="mw-page-title-main">Isopentenyl pyrophosphate</span> Chemical compound

Isopentenyl pyrophosphate is an isoprenoid precursor. IPP is an intermediate in the classical, HMG-CoA reductase pathway and in the non-mevalonate MEP pathway of isoprenoid precursor biosynthesis. Isoprenoid precursors such as IPP, and its isomer DMAPP, are used by organisms in the biosynthesis of terpenes and terpenoids.

<span class="mw-page-title-main">HMG-CoA</span> Chemical compound

β-Hydroxy β-methylglutaryl-CoA (HMG-CoA), also known as 3-hydroxy-3-methylglutaryl coenzyme A, is an intermediate in the mevalonate and ketogenesis pathways. It is formed from acetyl CoA and acetoacetyl CoA by HMG-CoA synthase. The research of Minor J. Coon and Bimal Kumar Bachhawat in the 1950s at University of Illinois led to its discovery.

(<i>E</i>)-4-Hydroxy-3-methyl-but-2-enyl pyrophosphate Chemical compound

(E)-4-Hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP or HMB-PP) is an intermediate of the MEP pathway (non-mevalonate pathway) of isoprenoid biosynthesis. The enzyme HMB-PP synthase (GcpE, IspG) catalyzes the conversion of 2-C-methyl-D-erythritol 2,4-cyclodiphosphate (MEcPP) into HMB-PP. HMB-PP is then converted further to isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) by HMB-PP reductase (LytB, IspH).

The non-mevalonate pathway—also appearing as the mevalonate-independent pathway and the 2-C-methyl-D-erythritol 4-phosphate/1-deoxy-D-xylulose 5-phosphate (MEP/DOXP) pathway—is an alternative metabolic pathway for the biosynthesis of the isoprenoid precursors isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP). The currently preferred name for this pathway is the MEP pathway, since MEP is the first committed metabolite on the route to IPP.

<span class="mw-page-title-main">Isopentenyl-diphosphate delta isomerase</span> Class of enzymes

Isopentenyl pyrophosphate isomerase, also known as Isopentenyl-diphosphate delta isomerase, is an isomerase that catalyzes the conversion of the relatively un-reactive isopentenyl pyrophosphate (IPP) to the more-reactive electrophile dimethylallyl pyrophosphate (DMAPP). This isomerization is a key step in the biosynthesis of isoprenoids through the mevalonate pathway and the MEP pathway.

2-<i>C</i>-Methylerythritol 4-phosphate Chemical compound

2-C-Methyl-D-erythritol 4-phosphate (MEP) is an intermediate on the MEP pathway of isoprenoid precursor biosynthesis. It is the first committed metabolite on that pathway on the route to IPP and DMAPP.

<span class="mw-page-title-main">Diphosphomevalonate decarboxylase</span> InterPro Family

Diphosphomevalonate decarboxylase (EC 4.1.1.33), most commonly referred to in scientific literature as mevalonate diphosphate decarboxylase, is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Lapaquistat</span> Chemical compound

Lapaquistat (TAK-475) is a cholesterol-lowering drug candidate that was abandoned before being marketed.

<span class="mw-page-title-main">Hydroxymethylglutaryl-CoA synthase</span> Class of enzymes

In molecular biology, hydroxymethylglutaryl-CoA synthase or HMG-CoA synthase EC 2.3.3.10 is an enzyme which catalyzes the reaction in which acetyl-CoA condenses with acetoacetyl-CoA to form 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). This reaction comprises the second step in the mevalonate-dependent isoprenoid biosynthesis pathway. HMG-CoA is an intermediate in both cholesterol synthesis and ketogenesis. This reaction is overactivated in patients with diabetes mellitus type 1 if left untreated, due to prolonged insulin deficiency and the exhaustion of substrates for gluconeogenesis and the TCA cycle, notably oxaloacetate. This results in shunting of excess acetyl-CoA into the ketone synthesis pathway via HMG-CoA, leading to the development of diabetic ketoacidosis.

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4-Hydroxy-3-methylbut-2-enyl diphosphate reductase (EC 1.17.1.2, isopentenyl-diphosphate:NADP+ oxidoreductase, LytB, (E)-4-hydroxy-3-methylbut-2-en-1-yl diphosphate reductase, HMBPP reductase, IspH, LytB/IspH) is an enzyme in the non-mevalonate pathway. It acts upon (E)-4-Hydroxy-3-methyl-but-2-enyl pyrophosphate (or "HMB-PP").

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<span class="mw-page-title-main">HMG-CoA reductase family</span>

In molecular biology, the HMG-CoA reductase family is a family of enzymes which participate in the mevalonate pathway, the metabolic pathway that produces cholesterol and other isoprenoids.

Michel Rohmer, born on 31 January 1948, is a French chemist specialising in the chemistry of micro-organisms. He has particularly studied isoprenoids.

References

  1. 1 2 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. 1 2 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. ↑ Lewiecki, E. Michael (May 2010). "Bisphosphonates for the treatment of osteoporosis: insights for clinicians". Therapeutic Advances in Chronic Disease. 1 (3): 115–128. doi:10.1177/2040622310374783. ISSN   2040-6223. PMC   3513863 . PMID   23251734.
  9. 1 2 Banerjee A, Sharkey TD. (2014) Methylerythritol 4-phosphate (MEP) pathway metabolic regulation. Nat Prod Rep 31:10431055
  10. ↑ Orsi E, Beekwilder J, Peek S, Eggink G, Kengen SW, Weusthuis RA (2020). "Metabolic flux ratio analysis by parallel 13C labeling of isoprenoid biosynthesis in Rhodobacter sphaeroides". Metabolic Engineering. 57: 228–238. doi: 10.1016/j.ymben.2019.12.004 . PMID   31843486.
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