Hydroxymethylglutaryl-CoA synthase

In biochemistry, hydroxymethylglutaryl-CoA synthase or HMG-CoA synthase <a href="/facts/Enzyme_Commission_number/Y5GNLRKX">EC</a> <a href="https://enzyme.expasy.org/EC/2.3.3.10">2.3.3.10</a> is an enzyme which catalyzes the reaction in which <a href="/facts/Acetyl-CoA/XyxFfC84">acetyl-CoA</a> condenses with <a href="/facts/Acetoacetyl-CoA/FGolhT4A">acetoacetyl-CoA</a> to form <a href="/facts/3-hydroxy-3-methylglutaryl-CoA/e8aUsAq6">3-hydroxy-3-methylglutaryl-CoA</a> (HMG-CoA). This reaction comprises the second step in the <a href="/facts/Mevalonate/XLRDojFU">mevalonate</a>-dependent <a href="/facts/Isoprenoid/1GvG7W7v">isoprenoid</a> <a href="/facts/Biosynthesis/aFk7Tk7f">biosynthesis</a> pathway. HMG-CoA is an intermediate in both <a href="/facts/Cholesterol_synthesis/uHea16r2">cholesterol synthesis</a> and <a href="/facts/Ketogenesis/F7uK4uxE">ketogenesis</a>. This reaction is overactivated in patients with <a href="/facts/Diabetes_mellitus_type_1/IkuQadGx">diabetes mellitus type 1</a> if left untreated, due to prolonged <a href="/facts/Insulin/oXG0myt1">insulin</a> deficiency and the exhaustion of substrates for <a href="/facts/Gluconeogenesis/Jj5THIHh">gluconeogenesis</a> and the <a href="/facts/TCA_cycle/EGJL9NXP">TCA cycle</a>, notably <a href="/facts/Oxaloacetate/ojLoQw81">oxaloacetate</a>. This results in shunting of excess acetyl-CoA into the ketone synthesis pathway via HMG-CoA, leading to the development of <a href="/facts/Diabetic_ketoacidosis/QhhbSbeM">diabetic ketoacidosis</a>.

acetyl-CoA + H2O + acetoacetyl-CoA 
 
 
 
 ⇌
 
 
 {\displaystyle \rightleftharpoons }
 
 (S)-3-hydroxy-3-methylglutaryl-CoA + CoA
The 3 <a href="/facts/Substrate_(biochemistry)/6MnaV19h">substrates</a> of this enzyme are <a href="/facts/Acetyl-CoA/XyxFfC84">acetyl-CoA</a>, <a href="/facts/Water/0lkXnJPK">H2O</a>, and <a href="/facts/Acetoacetyl-CoA/FGolhT4A">acetoacetyl-CoA</a>, whereas its two <a href="/facts/Product_(chemistry)/8uCoDUdv">products</a> are (S)-3-hydroxy-3-methylglutaryl-CoA and <a href="/facts/Coenzyme_A/loAfeGpx">CoA</a>.
In humans, the protein is encoded by the HMGCS1 gene on chromosome 5.

Hydroxymethylglutaryl-CoA synthase open-in-new

Hydroxymethylglutaryl-CoA synthase