HMG-CoA: Difference between revisions

| verifiedrevid = 450656813

| ImageFile=HMG coenzyme A.svg

| ImageSize=300px

| IUPACName=(9R,21S)-1-[(2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-4-hydroxy-3-(phosphonooxy)tetrahydrofuran-2-yl]-3,5,9,21-tetrahydroxy-8,8,21-trimethyl-10,14,19-trioxo-2,4,6-trioxa-18-thia-11,15-diaza-3,5-diphosphatricosan-23-oic acid 3,5-dioxide

| OtherNames=3-hydroxy-3-methylglutaryl CoA; 3-hydroxy-3-methylglutaryl coenzyme A

|Section1={{Chembox Identifiers

| IUPHAR_ligand = 3040

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| CASNo_Ref = {{cascite|correct|??}}

| PubChem = 445127

| ChEBI_Ref = {{ebicite|correct|EBI}}

| MeSHName=HMG-CoA

|Section2={{Chembox Properties

| Formula=C₂₇H₄₄N₇O₂₀P₃S

| MolarMass=911.661 g/mol

| Appearance=

| Density=

| MeltingPt=

| BoilingPt=

| Solubility=

|Section3={{Chembox Hazards

| MainHazards=

| FlashPt=

| AutoignitionPt =

'''β-Hydroxy β-methylglutaryl-CoA''' ('''HMG-CoA'''), also known as '''3-hydroxy-3-methylglutaryl coenzyme A''', is an intermediate in the [[mevalonate pathway|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.<ref name="Classics in Indian Medicine">{{cite journal | url=http://www.nmji.in/archives/Volume-28/Issue-3/Classics-in-Indian-Medicine.pdf | title=Classics in Indian Medicine | first = Debi P. | last = Sarkar | name-list-style = vanc | journal=The National Medical Journal of India | year=2015 | issue=28 | pages=3 | url-status=dead | archive-url=https://web.archive.org/web/20160531082638/http://www.nmji.in/archives/Volume-28/Issue-3/Classics-in-Indian-Medicine.pdf | archive-date=2016-05-31 }}</ref><ref name="An outstanding scientist and a splendid human being">{{cite journal | title=An outstanding scientist and a splendid human being | first = Avadhesha | last = Surolia | name-list-style = vanc | author-link = Avadhesha Surolia | journal=Glycobiology | year=1997 | volume=7 | issue=4 | pages=v–ix | doi = 10.1093/glycob/7.4.453| doi-access=free }}</ref>

HMG-CoA is a [[metabolic intermediate]] in the [[metabolism]] of the [[branched-chain amino acid]]s, which include [[leucine]], [[isoleucine]], and [[valine]].<ref name="HMG biosynthesis">{{cite web|title=Valine, leucine and isoleucine degradation - Reference pathway|url=http://www.genome.jp/kegg-bin/show_pathway?map00280+C00356|website=Kyoto Encyclopedia of Genes and Genomes|publisher=Kanehisa Laboratories|date=27 January 2016|access-date=1 February 2018}}</ref> Its immediate precursors are [[β-methylglutaconyl-CoA]] (MG-CoA) and [[β-hydroxy β-methylbutyryl-CoA]] (HMB-CoA).<ref name="ISSN position stand 2013" /><ref name="HMB athletic performance-related effects 2011 review">{{cite journal | vauthors = Zanchi NE, Gerlinger-Romero F, Guimarães-Ferreira L, de Siqueira Filho MA, Felitti V, Lira FS, Seelaender M, Lancha AH | title = HMB supplementation: clinical and athletic performance-related effects and mechanisms of action | journal = Amino Acids | volume = 40 | issue = 4 | pages = 1015–1025 | date = April 2011 | pmid = 20607321 | doi = 10.1007/s00726-010-0678-0 | s2cid = 11120110 | url = https://repositorio.unal.edu.co/handle/unal/77957 | quote = HMB is a metabolite of the amino acid leucine (Van Koverin and Nissen 1992), an essential amino acid. The first step in HMB metabolism is the reversible transamination of leucine to [α-KIC] that occurs mainly extrahepatically (Block and Buse 1990). Following this enzymatic reaction, [α-KIC] may follow one of two pathways. In the first, HMB is produced from [α-KIC] by the cytosolic enzyme KIC dioxygenase (Sabourin and Bieber 1983). The cytosolic dioxygenase has been characterized extensively and differs from the mitochondrial form in that the dioxygenase enzyme is a cytosolic enzyme, whereas the dehydrogenase enzyme is found exclusively in the mitochondrion (Sabourin and Bieber 1981, 1983). Importantly, this route of HMB formation is direct and completely dependent of liver KIC dioxygenase. Following this pathway, HMB in the cytosol is first converted to cytosolic β-hydroxy-β-methylglutaryl-CoA (HMG-CoA), which can then be directed for cholesterol synthesis (Rudney 1957) (Fig. 1). In fact, numerous biochemical studies have shown that HMB is a precursor of cholesterol (Zabin and Bloch 1951; Nissen et al. 2000).<!--<br /><br /> In the second pathway, after transamination, [α-KIC] in liver generates isovaleryl-CoA through the enzymatic action of branched-chain ketoacid dehydrogenase (BCKD) and after several steps, there is production of HMG-CoA through the enzyme HMG-CoA synthase (Fig. 1). Under normal conditions the majority of KIC is converted into isovaleryl-CoA, in which approximately 5% of leucine is metabolized into HMB (Wilson et al. 2008; Van Koverin and Nissen 1992). However, Nissen and Abumrad (1997) provided evidence that the primary fate of HMB is probably conversion to HMG-CoA in the liver, for cholesterol biosynthesis.--> }}</ref><ref name="Leucine metabolism" />

[[HMG-CoA reductase]] catalyzes the conversion of HMG-CoA to [[mevalonic acid]], a necessary step in the biosynthesis of cholesterol.

== Biosynthesis ==

{{Leucine metabolism in humans|align=center}}

== Mevalonate pathway ==

{{main|Mevalonate pathway}}

[[Mevalonate]] synthesis begins with the [[beta-ketothiolase]]-catalyzed [[Claisen condensation]] of two molecules of [[acetyl-CoA]] to produce [[Acetoacetyl-CoA|acetoacetyl CoA]]. The following reaction involves the joining of [[acetyl-CoA]] and [[acetoacetyl-CoA]] to form HMG-CoA, a process catalyzed by [[HMG-CoA synthase]].<ref>{{Cite book|title=Biochemistry|last=Garrett|first=Reginald H. | name-list-style = vanc |publisher=Cengage Learning|year=2013|isbn=978-1-305-57720-6|pages=856}}</ref>

In the final step of [[mevalonate]] biosynthesis, [[HMG-CoA reductase]], an [[NADPH]]-dependent [[oxidoreductase]], catalyzes the conversion of HMG-CoA into [[mevalonate]], which is the primary regulatory point in this pathway. [[Mevalonate]] serves as the precursor to [[isoprenoid]] groups that are incorporated into a wide variety of end-products, including [[cholesterol]] in humans.<ref>{{cite journal | vauthors = Haines BE, Steussy CN, Stauffacher CV, Wiest O | title = Molecular modeling of the reaction pathway and hydride transfer reactions of HMG-CoA reductase | journal = Biochemistry | volume = 51 | issue = 40 | pages = 7983–95 | date = October 2012 | pmid = 22971202 | pmc = 3522576 | doi = 10.1021/bi3008593 }}</ref>

[[Image:Mevalonate pathway.svg|350px|thumb|left|Mevalonate pathway]]

{{Clear}}

== Ketogenesis pathway ==

[[HMG-CoA lyase]] breaks it into [[acetyl CoA]] and [[acetoacetate]].

[[Image:Ketogenesis.svg|350px|thumb|left|[[Ketogenesis]]]]

{{Clear}}

== See also ==

* [[Steroidogenic enzyme]]

== References ==

{{Reflist}}

[[Category:Thioesters of coenzyme A]]