Hydroxymethylglutaryl-CoA synthase

<h2 id="classification">Classification</h2>
<p>This enzyme belongs to the family of <a href="/facts/Transferase/ut43BDxU">transferases</a>, specifically those <a href="/facts/Acyltransferases/vwfM9UCv">acyltransferases</a> that convert acyl groups into alkyl groups on transfer.
</p>
<h2 id="nomenclature">Nomenclature</h2>
<p>The <a href="/facts/List_of_enzymes/w2RP6EwU">systematic name</a> of this enzyme class is acetyl-CoA:acetoacetyl-CoA C-acetyltransferase (thioester-hydrolysing, carboxymethyl-forming). Other names in common use include <i>(</i>S<i>)-3-hydroxy-3-methylglutaryl-CoA acetoacetyl-CoA-lyase</i>, <i>(CoA-acetylating)</i>, <i>3-hydroxy-3-methylglutaryl CoA synthetase</i>, <i>3-hydroxy-3-methylglutaryl coenzyme A synthase</i>, <i>3-hydroxy-3-methylglutaryl coenzyme A synthetase</i>, <i>3-hydroxy-3-methylglutaryl-CoA synthase</i>, <i>3-hydroxy-3-methylglutaryl-coenzyme A synthase</i>, <i>beta-hydroxy-beta-methylglutaryl-CoA synthase</i>, <i>HMG-CoA synthase</i>, <i>acetoacetyl coenzyme A transacetase</i>, <i>hydroxymethylglutaryl coenzyme A synthase</i>, and <i>hydroxymethylglutaryl coenzyme A-condensing enzyme</i>.
</p>
<h2 id="mechanism">Mechanism</h2>
<p>HMG-CoA synthase contains an important <a href="/facts/Catalytic/LPBS7TQC">catalytic</a> <a href="/facts/Cysteine/kbqvUm6d">cysteine</a> residue that acts as a <a href="/facts/Nucleophile/xYccoaJQ">nucleophile</a> in the first step of the reaction: the <a href="/facts/Acetylation/PNMzRM4r">acetylation</a> of the <a href="/facts/Enzyme/DSI1Fh7y">enzyme</a> by <a href="/facts/Acetyl-CoA/XyxFfC84">acetyl-CoA</a> (its first <a href="/facts/Substrate_(biochemistry)/6MnaV19h">substrate</a>) to produce an acetyl-enzyme <a href="/facts/Thioester/UwfKqs1F">thioester</a>, releasing the <a href="/facts/Redox/Pyd5RVcj">reduced</a> <a href="/facts/Coenzyme_A/loAfeGpx">coenzyme A</a>. The subsequent <a href="/facts/Nucleophilic_attack/xYccoaJQ">nucleophilic attack</a> on <a href="/facts/Acetoacetyl-CoA/FGolhT4A">acetoacetyl-CoA</a> (its second substrate) leads to the formation of <a href="/facts/HMG-CoA/e8aUsAq6">HMG-CoA</a>.<a class="footnote-ref" id="fnref:1" href="#fn:1"><sup>1</sup></a>
</p>
<h2 id="biological-role">Biological role</h2>
<p>This enzyme participates in 3 <a href="/facts/Metabolism/WxDrm8k5">metabolic pathways</a>: <a href="/facts/Synthesis_and_degradation_of_ketone_bodies/BqQXpLo4">synthesis and degradation of ketone bodies</a>, <a href="/facts/Valine%2c_leucine_and_isoleucine_degradation/AuNXdA8S">valine, leucine and isoleucine degradation</a>, and <a href="/facts/Butanoate_metabolism/Sy5NrhK5">butanoate metabolism</a>.
</p>
<h2 id="species-distribution">Species distribution</h2>
<p>HMG-CoA synthase occurs in <a href="/facts/Eukaryotes/SkwyPLMA">eukaryotes</a>, <a href="/facts/Archaea/Adxh0aHw">archaea</a>, and certain <a href="/facts/Bacteria/wC8xSCsU">bacteria</a>.<a class="footnote-ref" id="fnref:2" href="#fn:2"><sup>2</sup></a>
</p>
<h3>Eukaryotes</h3>
<p>In <a href="/facts/Vertebrates/tT54FSTT">vertebrates</a>, there are two different <a href="/facts/Isozymes/WE3tbEhf">isozymes</a> of the enzyme (<a href="/facts/Cytosolic/VyXgygWm">cytosolic</a> and <a href="/facts/Mitochondrial/ErHqrdJ1">mitochondrial</a>); 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 <a href="/facts/Eukaryotes/SkwyPLMA">eukaryotes</a> such as <a href="/facts/Insects/IgDNvnUL">insects</a>, <a href="/facts/Plants/X5BMDMvS">plants</a>, and <a href="/facts/Fungus/BHo5DP59">fungi</a>.<a class="footnote-ref" id="fnref:3" href="#fn:3"><sup>3</sup></a>
</p>
<h4>Cytosolic</h4>
<p>The cytosolic form is the starting point of the mevalonate pathway, which leads to <a href="/facts/Cholesterol/TnfPlYc1">cholesterol</a> and other sterolic and isoprenoid compounds.
</p>

<h4>Mitochondrial</h4>
<p>The mitochondrial form is responsible for the <a href="/facts/Biosynthesis/aFk7Tk7f">biosynthesis</a> of <a href="/facts/Ketone_bodies/hj1EPGmS">ketone bodies</a>. The <a href="/facts/Gene/e1swwPY6">gene</a> for the mitochondrial form of the enzyme has three sterol regulatory elements in the 5' flanking region.<a class="footnote-ref" id="fnref:4" href="#fn:4"><sup>4</sup></a> These elements are responsible for decreased <a href="/facts/Transcription_(genetics)/bDgp9HDN">transcription</a> of the <a href="/facts/MRNA/oUL6qxQn">message</a> responsible for enzyme synthesis when <a href="/facts/Dietary_cholesterol/TnfPlYc1">dietary cholesterol</a> is high in animals: the same is observed for <a href="/facts/3-hydroxy-3-methylglutaryl-CoA/e8aUsAq6">3-hydroxy-3-methylglutaryl-CoA</a> and the <a href="/facts/Low_density_lipoprotein_receptor/zsSjTYyb">low density lipoprotein receptor</a>.
</p>

<h3>Bacteria</h3>
<p>In <a href="/facts/Bacteria/wC8xSCsU">bacteria</a>, isoprenoid precursors are generally synthesised via an alternative, non-mevalonate pathway, however a number of <a href="/facts/Gram-positive/H6WYQ17e">Gram-positive</a> <a href="/facts/Pathogen/axMXtV1M">pathogens</a> utilise a mevalonate pathway involving HMG-CoA synthase that is parallel to that found in <a href="/facts/Eukaryote/SkwyPLMA">eukaryotes</a>.<a class="footnote-ref" id="fnref:5" href="#fn:5"><sup>5</sup></a><a class="footnote-ref" id="fnref:6" href="#fn:6"><sup>6</sup></a>
</p>
<h2 id="structural-studies">Structural studies</h2>
<p>As of late 2007, 4 <a href="/facts/Tertiary_structure/VaN6MEYh">structures</a> have been solved for this class of enzymes, with <a href="/facts/Protein_Data_Bank/oUhq4ABD">PDB</a> accession codes <a href="https://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=1XPK">1XPK</a>, <a href="https://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=1XPL">1XPL</a>, <a href="https://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=1XPM">1XPM</a>, and <a href="https://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=2P8U">2P8U</a>.
</p>
<h2 id="external-links">External links</h2>
<ul><li><a href="https://meshb.nlm.nih.gov/record/ui?name=HMG-CoA+synthase">HMG-CoA+synthase</a> at the U.S. National Library of Medicine <a href="/facts/Medical_Subject_Headings/C57g2JuF">Medical Subject Headings</a> (MeSH)</li></ul>

<ul><li>RUDNEY H (1957). <a href="https://doi.org/10.1016%2FS0021-9258%2818%2970822-3">"The biosynthesis of beta-hydroxy-beta-methylglutaric acid"</a>. <i>J. Biol. Chem</i>. 227 (1): 363–77. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1016%2FS0021-9258%2818%2970822-3">10.1016/S0021-9258(18)70822-3</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/13449080">13449080</a>.</li></ul>

This article incorporates text from the public domain <a href="/facts/Pfam/BKJa293w">Pfam</a> and <a href="/facts/InterPro/pKwNm8t7">InterPro</a>: <a href="https://www.ebi.ac.uk/interpro/entry/IPR013746">IPR013746</a>
This article incorporates text from the public domain <a href="/facts/Pfam/BKJa293w">Pfam</a> and <a href="/facts/InterPro/pKwNm8t7">InterPro</a>: <a href="https://www.ebi.ac.uk/interpro/entry/IPR013528">IPR013528</a>

<h2 id="references">References</h2>

<ol>
<li id="fn:1"><p>Theisen MJ, Misra I, Saadat D, Campobasso N, Miziorko HM, Harrison DH (November 2004). "3-hydroxy-3-methylglutaryl-CoA synthase intermediate complex observed in "real-time"". Proc. Natl. Acad. Sci. U.S.A. 101 (47): 16442–7. doi:10.1073/pnas.0405809101. PMC 534525. PMID 15498869. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC534525" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC534525</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li>
<li id="fn:2"><p>Bahnson BJ (November 2004). "An atomic-resolution mechanism of 3-hydroxy-3-methylglutaryl-CoA synthase". Proc. Natl. Acad. Sci. U.S.A. 101 (47): 16399–400. Bibcode:2004PNAS..10116399B. doi:10.1073/pnas.0407418101. PMC 534547. PMID 15546978. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC534547" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC534547</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li>
<li id="fn:3"><p>Bearfield JC, Keeling CI, Young S, Blomquist GJ, Tittiger C (April 2006). "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)". Insect Molecular Biology. 15 (2): 187–95. doi:10.1111/j.1365-2583.2006.00627.x. PMID 16640729. S2CID 46317830. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li>
<li id="fn:4"><p>Goldstein J.L., Brown M.S. (1990) Regulation of the mevalonate pathway. Nature 343, 425-430 <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li>
<li id="fn:5"><p>Steussy CN, Robison AD, Tetrick AM, Knight JT, Rodwell VW, Stauffacher CV, Sutherlin AL (December 2006). "A structural limitation on enzyme activity: the case of HMG-CoA synthase". Biochemistry. 45 (48): 14407–14. doi:10.1021/bi061505q. PMID 17128980. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li>
<li id="fn:6"><p>Steussy CN, Vartia AA, Burgner JW, Sutherlin A, Rodwell VW, Stauffacher CV (November 2005). "X-ray crystal structures of HMG-CoA synthase from Enterococcus faecalis and a complex with its second substrate/inhibitor acetoacetyl-CoA". Biochemistry. 44 (43): 14256–67. doi:10.1021/bi051487x. PMID 16245942. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li>
</ol>

Hydroxymethylglutaryl-CoA synthase open-in-new

Hydroxymethylglutaryl-CoA synthase