3-hydroxy-3-methylglutaryl-CoA synthase 2 (mitochondrial) is an enzyme in humans that is encoded by the HMGCS2gene.[5]
The protein encoded by this gene belongs to the HMG-CoA synthase family. It is a mitochondrial enzyme that catalyzes the second and rate-limiting reaction of ketogenesis, a metabolic pathway that provides lipid-derived energy for various organs during times of carbohydrate deprivation, such as fasting, by addition of a third acetyl group to acetoacetyl-CoA, producing HMG-CoA.[6]
Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[5]
Clinical significance
Mutations in this gene are associated with mitochondrial HMG-CoA synthase deficiency (also known as HMGCS2D), affecting ketone body synthesis.[7] Affected patients are unable to perform ketogenesis during starvation and times of higher energy need such as fever and vigorous exercise. Commonly found is damage to heart muscles and the brain, along with hypoglycemia (not always present)[8] and elevated blood fatty acid concentration. The mortality rate is 20%.[9] Urine organic acid analysis can be used to detect likely cases, which can be further confirmed using DNA sequencing.[10]
Occurrence
HMGCS2 deficiency is a rare disorder in humans, with fewer than 20 patients reported worldwide.[11] HMGCS2 is not found in cetaceans, elephantids, or Old World fruit bats. Fruit bats are known to be very sensitive to starvation, similar to humans with HMGCS2D. The other two groups seem to have evolved other means of coping with starvation.[12]
Overview of all the structural information available in the PDB for UniProt: P54868 (Human Hydroxymethylglutaryl-CoA synthase, mitochondrial) at the PDBe-KB.
