β-Hydroxy β-methylglutaryl-CoA (HMG-CoA), also known as 3-hydroxy-3-methylglutaryl coenzyme A, is an intermediate in the

mevalonate Mevalonic acid (MVA) is a key organic compound in biochemistry; the name is a contraction of dihydroxymethylvalerolactone. The carboxylate anion of mevalonic acid, which is the predominant form in biological environments, is known as ''mevalonate ...

and

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 ...

pathways. It is formed from

acetyl CoA Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle (Krebs cycle) to be oxidized fo ...

and

acetoacetyl CoA Acetoacetyl CoA is the precursor of HMG-CoA in the mevalonate pathway, which is essential for Cholesterol#Biosynthesis, cholesterol biosynthesis. It also takes a similar role in the ketone bodies synthesis (ketogenesis) pathway of the liver. In 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 ...

. The research of Minor J. Coon and Bimal Kumar Bachhawat in the 1950s at

University of Illinois The University of Illinois Urbana-Champaign (UIUC, U of I, Illinois, or University of Illinois) is a public university, public land-grant university, land-grant research university in the Champaign–Urbana metropolitan area, Illinois, United ...

led to its discovery. HMG-CoA is a

metabolic intermediate Metabolic intermediates are compounds produced during the conversion of substrates (starting molecules) into final products in biochemical reactions within cells. Although these intermediates are of relatively minor direct importance to cell ...

in the

metabolism Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

of the

branched-chain amino acid A branched-chain amino acid (BCAA) is an amino acid having an aliphatic substituent, side-chain with a branch (a central carbon atom bound to three or more carbon atoms). Among the proteinogenic amino acids, there are three BCAAs: leucine, isoleu ...

s, which include

leucine Leucine (symbol Leu or L) is an essential amino acid that is used in the biosynthesis of proteins. Leucine is an α-amino acid, meaning it contains an α-amino group (which is in the protonated −NH3+ form under biological conditions), an α-Car ...

isoleucine Isoleucine (symbol Ile or I) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid group (which is in the depro ...

, and

valine Valine (symbol Val or V) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated −NH3+ form under biological conditions), an α- carboxylic acid group (which is in the deproton ...

. Its immediate precursors are

β-methylglutaconyl-CoA 3-Methylglutaconyl-CoA (MG-CoA), also known as β-methylglutaconyl-CoA, is an intermediate in the metabolism of leucine. It is metabolized into HMG-CoA β-Hydroxy β-methylglutaryl-CoA (HMG-CoA), also known as 3-hydroxy-3-methylglutaryl coenzym ...

(MG-CoA) and β-hydroxy β-methylbutyryl-CoA (HMB-CoA).

HMG-CoA reductase HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, official symbol HMGCR) is the rate-limiting enzyme (NADH-dependent, ; NADPH-dependent, ) of the mevalonate pathway, the metabolic pathway that produces cholesterol and other ...

catalyzes the conversion of HMG-CoA to

mevalonic acid Mevalonic acid (MVA) is a key organic compound in biochemistry; the name is a contraction of dihydroxymethylvalerolactone. The carboxylate anion of mevalonic acid, which is the predominant form in biological environments, is known as ''mevalonat ...

, a necessary step in the biosynthesis of cholesterol.

Biosynthesis

Mevalonate pathway

Mevalonate Mevalonic acid (MVA) is a key organic compound in biochemistry; the name is a contraction of dihydroxymethylvalerolactone. The carboxylate anion of mevalonic acid, which is the predominant form in biological environments, is known as ''mevalonate ...

synthesis begins with the

beta-ketothiolase Trifunctional enzyme subunit beta, mitochondrial (TP-beta) also known as 3-ketoacyl-CoA thiolase, acetyl-CoA acyltransferase, or beta-ketothiolase is an enzyme that in humans is encoded by the ''HADHB'' gene. HADHB is a subunit of the mitochondr ...

-catalyzed

Claisen condensation The Claisen condensation is a carbon–carbon bond forming reaction that occurs between two esters or one ester and another carbonyl compound in the presence of a strong base. The reaction produces a β-keto ester or a β- diketone. It is named ...

of two molecules of

acetyl-CoA Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle (Krebs cycle) to be oxidation, o ...

to produce

. The following reaction involves the joining of

and

acetoacetyl-CoA Acetoacetyl CoA is the precursor of HMG-CoA in the mevalonate pathway, which is essential for cholesterol biosynthesis. It also takes a similar role in the ketone bodies synthesis ( ketogenesis) pathway of the liver. In the ketone bodies digestion ...

to form HMG-CoA, a process catalyzed by

. In the final step of

biosynthesis,

, an

NADPH Nicotinamide adenine dinucleotide phosphate, abbreviated NADP or, in older notation, TPN (triphosphopyridine nucleotide), is a cofactor used in anabolic reactions, such as the Calvin cycle and lipid and nucleic acid syntheses, which require N ...

-dependent

oxidoreductase In biochemistry, an oxidoreductase is an enzyme that catalyzes the transfer of electrons from one molecule, the reductant, also called the electron donor, to another, the oxidant, also called the electron acceptor. This group of enzymes usually ut ...

, catalyzes the conversion of HMG-CoA into

, which is the primary regulatory point in this pathway.

serves as the precursor to

isoprenoid The terpenoids, also known as isoprenoids, are a class of naturally occurring organic chemicals derived from the 5-carbon compound isoprene and its derivatives called terpenes, diterpenes, etc. While sometimes used interchangeably with "terpene ...

groups that are incorporated into a wide variety of end-products, including

cholesterol Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils. Cholesterol is biosynthesis, biosynthesized by all anima ...

in humans.

Ketogenesis pathway

HMG-CoA lyase 3-Hydroxy-3-methylglutaryl-CoA lyase (or HMG-CoA lyase) is an enzyme ( that in human is encoded by the HMGCL gene located on chromosome 1. It is a key enzyme in ketogenesis (ketone body formation). It is a ketogenic enzyme in the liver that c ...

breaks it into

and

acetoacetate Acetoacetic acid ( IUPAC name: 3-oxobutanoic acid, also known as acetonecarboxylic acid or diacetic acid) is the organic compound with the formula CHCOCHCOOH. It is the simplest beta-keto acid, and like other members of this class, it is unstable ...

References

Thioesters of coenzyme A {{Biochemistry-stub

Biosynthesis

Mevalonate pathway

Ketogenesis pathway

See also

References