HMG-CoA explained

β-Hydroxy β-methylglutaryl-CoA (HMG-CoA), also known as 3-hydroxy-3-methylglutaryl coenzyme A, is an intermediate in the mevalonate and ketogenesis pathways. It is formed from acetyl CoA and acetoacetyl CoA by HMG-CoA synthase. The research of Minor J. Coon and Bimal Kumar Bachhawat in the 1950s at University of Illinois led to its discovery.^{[1] [2]}

HMG-CoA is a metabolic intermediate in the metabolism of the branched-chain amino acids, which include leucine, isoleucine, and valine.^[3] Its immediate precursors are β-methylglutaconyl-CoA (MG-CoA) and β-hydroxy β-methylbutyryl-CoA (HMB-CoA).^[4]

HMG-CoA reductase catalyzes the conversion of HMG-CoA to mevalonic acid, a necessary step in the biosynthesis of cholesterol.

Mevalonate pathway

See main article: Mevalonate pathway. Mevalonate synthesis begins with the beta-ketothiolase-catalyzed Claisen condensation of two molecules of acetyl-CoA to produce acetoacetyl CoA. The following reaction involves the joining of acetyl-CoA and acetoacetyl-CoA to form HMG-CoA, a process catalyzed by HMG-CoA synthase.^[5]

In the final step of mevalonate biosynthesis, HMG-CoA reductase, an NADPH-dependent oxidoreductase, catalyzes the conversion of HMG-CoA into mevalonate, which is the primary regulatory point in this pathway. Mevalonate serves as the precursor to isoprenoid groups that are incorporated into a wide variety of end-products, including cholesterol in humans.^[6]

Ketogenesis pathway

HMG-CoA lyase breaks it into acetyl CoA and acetoacetate.

See also

• Steroidogenic enzyme

Notes and References

1. Classics in Indian Medicine . Debi P. . Sarkar . vanc . The National Medical Journal of India . 2015 . 28 . 3 . dead . https://web.archive.org/web/20160531082638/http://www.nmji.in/archives/Volume-28/Issue-3/Classics-in-Indian-Medicine.pdf . 2016-05-31 .
2. An outstanding scientist and a splendid human being . Avadhesha . Surolia . vanc . Avadhesha Surolia . Glycobiology . 1997 . 7 . 4 . v–ix . 10.1093/glycob/7.4.453. free .
3. Web site: Valine, leucine and isoleucine degradation - Reference pathway. Kyoto Encyclopedia of Genes and Genomes. Kanehisa Laboratories. 27 January 2016. 1 February 2018.
4. Zanchi NE, Gerlinger-Romero F, Guimarães-Ferreira L, de Siqueira Filho MA, Felitti V, Lira FS, Seelaender M, Lancha AH . HMB supplementation: clinical and athletic performance-related effects and mechanisms of action . Amino Acids . 40 . 4 . 1015–1025 . April 2011 . 20607321 . 10.1007/s00726-010-0678-0 . 11120110 . HMB is a metabolite of the amino acid leucine (Van Koverin and Nissen 1992), an essential amino acid. The first step in HMB metabolism is the reversible transamination of leucine to [α-KIC] that occurs mainly extrahepatically (Block and Buse 1990). Following this enzymatic reaction, [α-KIC] may follow one of two pathways. In the first, HMB is produced from [α-KIC] by the cytosolic enzyme KIC dioxygenase (Sabourin and Bieber 1983). The cytosolic dioxygenase has been characterized extensively and differs from the mitochondrial form in that the dioxygenase enzyme is a cytosolic enzyme, whereas the dehydrogenase enzyme is found exclusively in the mitochondrion (Sabourin and Bieber 1981, 1983). Importantly, this route of HMB formation is direct and completely dependent of liver KIC dioxygenase. Following this pathway, HMB in the cytosol is first converted to cytosolic β-hydroxy-β-methylglutaryl-CoA (HMG-CoA), which can then be directed for cholesterol synthesis (Rudney 1957) (Fig. 1). In fact, numerous biochemical studies have shown that HMB is a precursor of cholesterol (Zabin and Bloch 1951; Nissen et al. 2000). .
5. Book: Garrett, Reginald H. . Biochemistry. vanc . Cengage Learning. 2013. 978-1-305-57720-6. 856.
6. Haines BE, Steussy CN, Stauffacher CV, Wiest O . Molecular modeling of the reaction pathway and hydride transfer reactions of HMG-CoA reductase . Biochemistry . 51 . 40 . 7983–95 . October 2012 . 22971202 . 3522576 . 10.1021/bi3008593 .