HMGCS2 explained

3-hydroxy-3-methylglutaryl-CoA synthase 2 (mitochondrial) is an enzyme in humans that is encoded by the HMGCS2 gene.^[1]

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.^[2]

Alternatively spliced transcript variants encoding different isoforms have been found for this gene.^[1]

Clinical significance

Mutations in this gene are associated with mitochondrial HMG-CoA synthase deficiency (also known as HMGCS2D), affecting ketone body synthesis.^[3] 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)^[4] and elevated blood fatty acid concentration. The mortality rate is 20%.^[5] Urine organic acid analysis can be used to detect likely cases, which can be further confirmed using DNA sequencing.^[6]

Occurrence

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.^[7]

Notes and References

1. Web site: Entrez Gene: 3-hydroxy-3-methylglutaryl-CoA synthase 2 (mitochondrial) .
2. Drabbe S, Pelzer A, Slenter D, Willighagen E . Wiki Pathways . Disorders in ketone body synthesis (Homo sapiens) . February 2023 .
3. Aledo R, Mir C, Dalton RN, Turner C, Pié J, Hegardt FG, Casals N, Champion MP . 6 . Refining the diagnosis of mitochondrial HMG-CoA synthase deficiency . Journal of Inherited Metabolic Disease . 29 . 1 . 207–211 . February 2006 . 16601895 . 10.1007/s10545-006-0214-2 . 24866271 .
4. Conlon . TA . Fitzsimons . PE . Borovickova . I . Kirby . F . Murphy . S . Knerr . I . Crushell . E . Hypoglycemia is not a defining feature of metabolic crisis in mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency: Further evidence of specific biochemical markers which may aid diagnosis. . JIMD Reports . September 2020 . 55 . 1 . 26–31 . 10.1002/jmd2.12146 . 32905056. 7463059 .
5. 丹 . 马 . 丹 . 俞 . 线粒体3-羟基3-甲基戊二酰辅酶A合成酶缺乏症1例并文献复习. Mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase deficiency: a case report and literature review . Chinese Journal of Contemporary Pediatrics . 11 November 2018 . 20 . 11 . 930–933 . 10.7499/j.issn.1008-8830.2018.11.010 . 30477625 . zh . 1008-8830 . 7389032.
6. Conlon . TA . Fitzsimons . PE . Borovickova . I . Kirby . F . Murphy . S . Knerr . I . Crushell . E . Hypoglycemia is not a defining feature of metabolic crisis in mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency: Further evidence of specific biochemical markers which may aid diagnosis. . JIMD Reports . September 2020 . 55 . 1 . 26–31 . 10.1002/jmd2.12146 . 32905056. 7463059 .
7. Jebb D, Hiller M . Recurrent loss of HMGCS2 shows that ketogenesis is not essential for the evolution of large mammalian brains . eLife . 7 . e38906 . October 2018 . 30322448 . 6191284 . 10.7554/eLife.38906 . free .