3-hydroxy-3-methylglutaryl-CoA synthase 2 (mitochondrial) is an

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

in humans that is encoded by the ''HMGCS2''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. The protein encoded by this gene belongs to the

HMG-CoA synthase In biochemistry, hydroxymethylglutaryl-CoA synthase or HMG-CoA synthase is an enzyme which catalyzes the reaction in which acetyl-CoA condenses with acetoacetyl-CoA to form 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). This reaction comprises th ...

family. It is a mitochondrial enzyme that catalyzes the second and rate-limiting reaction of

ketogenesis Ketogenesis is the biochemical process through which organisms produce ketone bodies by breaking down fatty acids and ketogenic amino acids. The process supplies energy to certain organs, particularly the brain, heart and skeletal muscle, unde ...

, 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. Alternatively spliced

transcript variant Alternative splicing, alternative RNA splicing, or differential splicing, is an alternative RNA splicing, splicing process during gene expression that allows a single gene to produce different splice variants. For example, some exons of a gene ma ...

s encoding different isoforms have been found for this gene.

Clinical significance

Mutations in this gene are associated with mitochondrial HMG-CoA synthase deficiency (also known as HMGCS2D), affecting ketone body synthesis. 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) and elevated blood fatty acid concentration. The mortality rate is 20%. Urine organic acid analysis can be used to detect likely cases, which can be further confirmed using DNA sequencing.

Occurrence

HMGCS2 deficiency is a rare disorder in humans, with fewer than 20 patients reported worldwide HMGCS2 is not found in

cetaceans Cetacea (; , ) is an infraorder of aquatic mammals belonging to the order Artiodactyla that includes whales, dolphins and porpoises. Key characteristics are their fully aquatic lifestyle, streamlined body shape, often large size and exclusively c ...

, 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.

References

External links

* EC 2.3.3 Human proteins {{gene-1-stub