View source for Hydroxymethylglutaryl-CoA synthase

{{Short description|Class of enzymes}}
{{infobox protein
|Name=3-hydroxy-3-methylglutaryl-Coenzyme A synthase 1 (soluble)
|caption=
|image=
|width=
|HGNCid=5007
|Symbol=HMGCS1
|AltSymbols=HMGCS
|EntrezGene=3157
|OMIM=142940
|RefSeq=NM_002130
|UniProt=Q01581
|PDB=
|ECnumber=2.3.3.10 
|Chromosome=5
|Arm=p
|Band=14
|LocusSupplementaryData=-p13
}}
{{infobox protein
|Name=3-hydroxy-3-methylglutaryl-Coenzyme A synthase 2 (mitochondrial)
|caption=
|image=
|width=
|HGNCid=5008
|Symbol=HMGCS2
|AltSymbols=
|EntrezGene=3158
|OMIM=600234
|RefSeq=NM_005518
|UniProt=P54868
|PDB=
|ECnumber=
|Chromosome=1
|Arm=p
|Band=13
|LocusSupplementaryData=-p12
}}
{{Infobox protein family
| Symbol = HMG_CoA_synt_N
| Name = Hydroxymethylglutaryl-coenzyme A synthase N terminal
| image = PDB 1txt EBI.jpg
| width = 
| caption = staphylococcus aureus 3-hydroxy-3-methylglutaryl-coa synthase
| Pfam = PF01154
| Pfam_clan = CL0046 
| InterPro = IPR013528
| SMART = 
| PROSITE = PDOC00942
| MEROPS = 
| SCOP = 
| TCDB = 
| OPM family = 
| OPM protein = 
| CAZy = 
| CDD = 
}}
{{Infobox protein family
| Symbol = HMG_CoA_synt_C
| Name = Hydroxymethylglutaryl-coenzyme A synthase C terminal
| image = PDB 1txt EBI.jpg
| width = 
| caption = staphylococcus aureus 3-hydroxy-3-methylglutaryl-coa synthase
| Pfam = PF08540
| Pfam_clan = CL0046 
| InterPro = IPR013746
| SMART = 
| PROSITE = PDOC00942
| MEROPS = 
| SCOP = 
| TCDB = 
| OPM family = 
| OPM protein = 
| CAZy = 
| CDD = 
}}
In biochemistry, '''hydroxymethylglutaryl-CoA synthase''' or '''HMG-CoA synthase''' {{EC number|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|3-'''h'''ydroxy-3-'''m'''ethyl'''g'''lutaryl-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]].

[[Image:HMG-CoA synthase.svg|650px|center|HMG-CoA synthase reaction]]

<br>

{{center|1=acetyl-CoA + H<sub>2</sub>O + acetoacetyl-CoA <math>\rightleftharpoons</math> (''S'')-3-hydroxy-3-methylglutaryl-CoA + CoA}}

The 3 [[substrate (biochemistry)|substrates]] of this enzyme are [[acetyl-CoA]], [[water|H<sub>2</sub>O]], and [[acetoacetyl-CoA]], whereas its two [[product (chemistry)|products]] are (''S'')-3-hydroxy-3-methylglutaryl-CoA and [[coenzyme A|CoA]].

In humans, the protein is encoded by the ''HMGCS1'' gene on chromosome 5.

== Classification ==

This enzyme belongs to the family of [[transferase]]s, specifically those [[acyltransferases]] that convert acyl groups into alkyl groups on transfer.

== Nomenclature ==

The [[List of enzymes|systematic name]] of this enzyme class is '''acetyl-CoA:acetoacetyl-CoA C-acetyltransferase (thioester-hydrolysing, carboxymethyl-forming)'''. Other names in common use include ''(''S'')-3-hydroxy-3-methylglutaryl-CoA acetoacetyl-CoA-lyase'', ''(CoA-acetylating)'', ''3-hydroxy-3-methylglutaryl CoA synthetase'', ''3-hydroxy-3-methylglutaryl coenzyme A synthase'', ''3-hydroxy-3-methylglutaryl coenzyme A synthetase'', ''3-hydroxy-3-methylglutaryl-CoA synthase'', ''3-hydroxy-3-methylglutaryl-coenzyme A synthase'', ''beta-hydroxy-beta-methylglutaryl-CoA synthase'', ''HMG-CoA synthase'', ''acetoacetyl coenzyme A transacetase'', ''hydroxymethylglutaryl coenzyme A synthase'', and ''hydroxymethylglutaryl coenzyme A-condensing enzyme''.

==Mechanism==

HMG-CoA synthase contains an important [[catalytic]] [[cysteine]] residue that acts as a [[nucleophile]] in the first step of the reaction: the [[acetylation]] of the [[enzyme]] by [[acetyl-CoA]] (its first [[Substrate (biochemistry)|substrate]]) to produce an acetyl-enzyme [[thioester]], releasing the [[Redox|reduced]] [[coenzyme A]]. The subsequent [[nucleophilic attack]] on [[acetoacetyl-CoA]] (its second substrate) leads to the formation of [[HMG-CoA]].<ref name="pmid15498869">{{cite journal |vauthors=Theisen MJ, Misra I, Saadat D, Campobasso N, Miziorko HM, Harrison DH | title = 3-hydroxy-3-methylglutaryl-CoA synthase intermediate complex observed in "real-time" | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 101 | issue = 47 | pages = 16442–7 |date=November 2004 | pmid = 15498869 | pmc = 534525 | doi = 10.1073/pnas.0405809101 | doi-access = free }}</ref>

== Biological role ==

This enzyme participates in 3 [[metabolism|metabolic pathways]]: [[synthesis and degradation of ketone bodies]], [[valine, leucine and isoleucine degradation]], and [[butanoate metabolism]].

==Species distribution==

HMG-CoA synthase occurs in [[eukaryotes]], [[archaea]], and certain [[bacteria]].<ref name="pmid15546978">{{cite journal | author = Bahnson BJ | title = An atomic-resolution mechanism of 3-hydroxy-3-methylglutaryl-CoA synthase | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 101 | issue = 47 | pages = 16399–400 |date=November 2004 | pmid = 15546978 | pmc = 534547 | doi = 10.1073/pnas.0407418101 | bibcode = 2004PNAS..10116399B | doi-access = free }}</ref>

===Eukaryotes===
In [[vertebrates]], there are two different [[isozymes]] of the enzyme ([[cytosolic]] and [[mitochondrial]]); in humans the cytosolic form has only 60.6% amino acid identity with the mitochondrial form of the enzyme. HMG-CoA is also found in other [[eukaryotes]] such as [[insects]], [[plants]], and [[fungus|fungi]].<ref name="pmid16640729">{{cite journal |vauthors=Bearfield JC, Keeling CI, Young S, Blomquist GJ, Tittiger C | title = Isolation, endocrine regulation and mRNA distribution of the 3-hydroxy-3-methylglutaryl coenzyme A synthase (HMG-S) gene from the pine engraver, Ips pini (Coleoptera: Scolytidae) | journal = Insect Molecular Biology | volume = 15 | issue = 2 | pages = 187–95 |date=April 2006 | pmid = 16640729 | doi = 10.1111/j.1365-2583.2006.00627.x | s2cid = 46317830 }}</ref>

====Cytosolic====
The cytosolic form is the starting point of the mevalonate pathway, which leads to [[cholesterol]] and other sterolic and isoprenoid compounds.

[[Image:Mevalonate pathway.png|350px|thumb|center|[[Mevalonate pathway]]]]

====Mitochondrial====
The mitochondrial form is responsible for the [[biosynthesis]] of [[ketone bodies]]. The [[gene]] for the mitochondrial form of the enzyme has three sterol regulatory elements in the 5' flanking region.<ref>Goldstein J.L., Brown M.S. (1990) Regulation of the mevalonate pathway. Nature 343, 425-430</ref> These elements are responsible for decreased [[Transcription (genetics)|transcription]] of the [[mRNA|message]] responsible for enzyme synthesis when [[dietary cholesterol]] is high in animals: the same is observed for [[3-hydroxy-3-methylglutaryl-CoA]] and the [[low density lipoprotein receptor]].
[[Image:Ketogenesis.svg|350px|thumb|center|[[Ketogenesis]]]]

===Bacteria===

In [[bacteria]], isoprenoid precursors are generally synthesised via an alternative, non-mevalonate pathway, however a number of [[Gram-positive]] [[pathogen]]s utilise a mevalonate pathway involving HMG-CoA synthase that is parallel to that found in [[eukaryote]]s.<ref name="pmid17128980">{{cite journal |vauthors=Steussy CN, Robison AD, Tetrick AM, Knight JT, Rodwell VW, Stauffacher CV, Sutherlin AL | title = A structural limitation on enzyme activity: the case of HMG-CoA synthase | journal = Biochemistry | volume = 45 | issue = 48 | pages = 14407–14 |date=December 2006 | pmid = 17128980 | doi = 10.1021/bi061505q }}</ref><ref name="pmid16245942">{{cite journal |vauthors=Steussy CN, Vartia AA, Burgner JW, Sutherlin A, Rodwell VW, Stauffacher CV | title = X-ray crystal structures of HMG-CoA synthase from Enterococcus faecalis and a complex with its second substrate/inhibitor acetoacetyl-CoA | journal = Biochemistry | volume = 44 | issue = 43 | pages = 14256–67 |date=November 2005 | pmid = 16245942 | doi = 10.1021/bi051487x }}</ref>

==Structural studies==

As of late 2007, 4 [[tertiary structure|structures]] have been solved for this class of enzymes, with [[Protein Data Bank|PDB]] accession codes {{PDB link|1XPK}}, {{PDB link|1XPL}}, {{PDB link|1XPM}}, and {{PDB link|2P8U}}.

==External links==
* {{MeshName|HMG-CoA+synthase}}

== References ==
{{Reflist|2}}
* {{cite journal | author = RUDNEY H | date = 1957 | title = The biosynthesis of beta-hydroxy-beta-methylglutaric acid | journal = J. Biol. Chem.  | volume = 227 | pages = 363&ndash;77  | pmid = 13449080 | issue = 1 | doi = 10.1016/S0021-9258(18)70822-3 | doi-access = free }}

{{Lipid metabolism enzymes}}
{{Mevalonate pathway}}
{{Acyltransferases}}
{{Enzymes}}
{{Portal bar|Biology|border=no}}

{{InterPro content|IPR013746}}
{{InterPro content|IPR013528}}

{{DEFAULTSORT:Hmg-Coa Synthase}}
[[Category:EC 2.3.3]]
[[Category:Protein families]]
[[Category:Human proteins]]