Editing Mevalonate pathway

{{Short description|Series of interconnected biochemical reactions}}
[[Image:Wiki pathway hi def tiff.tif|class=skin-invert-image|thumb|500px|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]].<ref name="GENERAL"/> 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]].<ref name="ISOPRENOIDS"/>

The mevalonate pathway begins with [[acetyl-CoA]] and ends with the production of IPP and DMAPP.<ref name="REVIEW"/> It is best known as the target of [[statin]]s, 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.<ref name="MIZIORKO"/>

==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.<ref name="MIZIORKO"/> 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).<ref name="HALOFERAX"/> 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).<ref name="THERMOPLASMA1"/><ref name="THERMOPLASMA2"/>

==Regulation and feedback==
Several key [[enzymes]] can be activated through [[DNA transcription]]al 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|LDL-receptor]]. Regulation of this pathway is also achieved by controlling the rate of translation of the mRNA, degradation of reductase and phosphorylation.<ref name="GENERAL"/>

==Pharmacology==
A number of [[medication|drugs]] target the ''mevalonate pathway'':
* [[Statin]]s (used to [[hypercholesterolemia|decrease cholesterol levels]]);
* [[Bisphosphonate]]s (used to treat various bone-degenerative diseases such as [[osteoporosis]]<ref>{{Cite journal |last=Lewiecki |first=E. Michael |date=May 2010 |title=Bisphosphonates for the treatment of osteoporosis: insights for clinicians |journal=Therapeutic Advances in Chronic Disease |volume=1 |issue=3 |pages=115–128 |doi=10.1177/2040622310374783 |issn=2040-6223 |pmc=3513863 |pmid=23251734}}</ref>)

==Diseases==
A number of [[diseases]] affect the ''mevalonate pathway'':
* [[Mevalonate kinase deficiency|Mevalonate Kinase Deficiency]] 
** Mevalonic Aciduria
** Hyperimmunoglobulinemia D Syndrome (HIDS).

==Alternative pathway ==
[[Plants]], most [[bacteria]], and some [[protozoa]] such as [[malaria]] parasites have the ability to produce [[isoprenoids]] using an alternative pathway called the [[Non-mevalonate pathway|methylerythritol phosphate (MEP)]] or [[non-mevalonate pathway]].<ref name="MEP"/> 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 <sup>13</sup>C-glucose [[isotopomers]].<ref name="13C">{{cite journal |vauthors=Orsi E, Beekwilder J, Peek S, Eggink G, Kengen SW, Weusthuis RA | title=Metabolic flux ratio analysis by parallel 13C labeling of isoprenoid biosynthesis in ''Rhodobacter sphaeroides'' | journal=Metabolic Engineering | year= 2020 | volume=57 | pages=228–238 | pmid= 31843486 | doi=10.1016/j.ymben.2019.12.004| doi-access=free }}</ref> In higher plants, the MEP pathway operates in [[plastids]] while the mevalonate pathway operates in the [[cytosol]].<ref name="MEP"/> Examples of bacteria that contain the MEP pathway include ''[[Escherichia coli]]'' and pathogens such as ''[[Mycobacterium tuberculosis]]''.

==Enzymatic reactions==

{| class="wikitable" 
|-align="center"
| '''Enzyme''' || '''Reaction''' || '''Description''' 
 |- 
 | [[Acetoacetyl-CoA thiolase]]  || style="background: light-dark(white,black)"| [[File:Aact1.jpg|class=skin-invert-image|center|400px]]  ||  [[Acetyl-CoA]] ([[citric acid cycle]]) undergoes condensation with another acetyl-CoA molecule to form [[acetoacetyl-CoA]]
 |- 
 |  [[HMG-CoA synthase]]  || style="background: light-dark(white,black)"| [[Image:HMG-CoA synthase.svg|class=skin-invert-image|center|400px]] || Acetoacetyl-CoA condenses with another Acetyl-CoA molecule to form [[3-hydroxy-3-methylglutaryl-CoA|3-'''h'''ydroxy-3-'''m'''ethyl'''g'''lutaryl-CoA]] (HMG-CoA).
 |- 
 | [[HMG-CoA reductase]] || style="background: light-dark(white,black)"| [[Image:HMG-CoA reductase reaction.svg|class=skin-invert-image|center|400px]] || 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 ([[statin]]s). 
 |- 
 | [[Mevalonate kinase|mevalonate-5-kinase]]  || style="background: light-dark(white,black)"| [[Image:Mevalonate kinase reaction.svg|class=skin-invert-image|center|400px]] || Mevalonate is phosphorylated at the 5-OH position to yield [[mevalonate-5-phosphate]] (also called ''phosphomevalonic acid''). 
|- 
 | [[mevalonate-3-kinase]]  || style="background: light-dark(white,black)"| [[Image:M3kwiki3.jpg|class=skin-invert-image|center|400px]] || Mevalonate is phosphorylated at the 3-OH position to yield [[mevalonate-3-phosphate]]. 1 ATP is consumed.
|- 
 | [[mevalonate-3-phosphate-5-kinase]]  || style="background: light-dark(white,black)"| [[File:M35bpK.jpg|class=skin-invert-image|center|400px]] || 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]] || style="background: light-dark(white,black)"| [[Image:Phosphomevalonate kinase reaction.svg|class=skin-invert-image|center|400px]] || mevalonate-5-phosphate is phosphorylated to yield [[mevalonate-5-pyrophosphate]]. 1 ATP is consumed.  
 |- 
 | [[mevalonate-5-pyrophosphate decarboxylase]] || style="background: light-dark(white,black)"| [[Image:Mdd2.jpg|class=skin-invert-image|center|400px]] || Mevalonate-5-pyrophosphate is decarboxylated to yield [[isopentenyl pyrophosphate]] (IPP). 1 ATP is consumed. 
 |- 
 | [[isopentenyl pyrophosphate isomerase]]   || style="background: light-dark(white,black)"| [[Image:IPP isomerase reaction.svg|class=skin-invert-image|center|400px]] || [[isopentenyl pyrophosphate]] is [[isomerized]] to [[dimethylallyl pyrophosphate]].
|}

==References==
{{reflist|2| refs =<ref name="GENERAL">
Buhaescu I, Izzedine H (2007) Mevalonate pathway: areview of clinical and therapeutical implications. ClinBiochem 40:575–584.
</ref>
<ref name="ISOPRENOIDS">
Holstein, S. A., and Hohl, R. J. (2004) Isoprenoids: Remarkable Diversity of Form and Function. Lipids 39, 293−309
</ref>
<ref name="REVIEW">
Goldstein, J. L., and Brown, S. B. (1990) Regulation of the mevalonate pathway. Nature 343, 425−430
</ref>
<ref name="MIZIORKO">
Miziorko H (2011) Enzymes of the mevalonate pathway of isoprenoid biosynthesis. Arch Biochem Biophys 505:131-143.
</ref>
<ref name="HALOFERAX">
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
</ref>
<ref name="THERMOPLASMA1">
Vinokur JM, Korman TP, Cao Z, Bowie JU (2014) Evidence of a novel mevalonate pathway in archaea. Biochemistry 53:4161–4168.
</ref>
<ref name="THERMOPLASMA2">
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.
</ref>
<ref name="MEP">Banerjee A, Sharkey TD. (2014) Methylerythritol 4-phosphate (MEP) pathway metabolic regulation. Nat Prod Rep 31:10431055</ref>
}}

==External links==
* [http://www.rpi.edu/dept/bcbp/molbiochem/MBWeb/mb2/part1/cholesterol.htm Rensselaer Polytechnic Institute] page on cholesterol synthesis (including regulation)

{{Mevalonate pathway}}
{{MetabolismMap}}

[[Category:Metabolic pathways]]