Isovaleryl-CoA (also known as 3-methylbutyryl-CoA) is a metabolic intermediate formed during the catabolism of the branched-chain amino acid,

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 ...

. It is a short-chain

acyl-CoA Acyl-CoA is a group of coenzyme A, CoA-based coenzymes that metabolize carboxylic acids. Fatty acyl-CoA's are susceptible to beta oxidation, forming, ultimately, acetyl-CoA. The acetyl-CoA enters the citric acid cycle, eventually forming several e ...

thioester In organic chemistry, thioesters are organosulfur compounds with the molecular structure . They are analogous to carboxylate esters () with the sulfur in the thioester replacing oxygen in the carboxylate ester, as implied by the thio- prefix ...

that plays a key role in mitochondrial energy metabolism. The compound is converted into 3-methylcrotonyl-CoA by the enzyme isovaleryl-CoA dehydrogenase (IVD), a

flavoprotein Flavoproteins are proteins that contain a nucleic acid derivative of riboflavin. These proteins are involved in a wide array of biological processes, including removal of radicals contributing to oxidative stress, photosynthesis, and DNA repair. ...

that catalyzes the third step in the leucine degradation pathway. Deficiency of this enzyme activity results in the accumulation of isovaleryl-CoA and related metabolites, leading to a rare autosomal recessive disorder known as

isovaleric acidemia Isovaleric acidemia is a rare autosomal recessive metabolic disorder which disrupts or prevents normal metabolism of the branched-chain amino acid leucine. It is a classical type of organic acidemia. Symptoms and signs A characteristic featur ...

, characterized by metabolic crises, developmental delays, and a distinctive odor due to

isovaleric acid Isovaleric acid, also known as 3-methylbutanoic acid or β-methylbutyric acid, is a branched-chain alkyl carboxylic acid with the chemical formula (CH3)2CHCH2CO2H. It is classified as a short-chain fatty acid. Like other low-molecular-weight car ...

buildup. The metabolism of isovaleryl-CoA is vital for proper amino acid utilization and energy

homeostasis In biology, homeostasis (British English, British also homoeostasis; ) is the state of steady internal physics, physical and chemistry, chemical conditions maintained by organism, living systems. This is the condition of optimal functioning fo ...

in humans.

Catalysis of Isovaleryl-CoA dehydrogenase

The enzyme, Isovaleryl-CoA dehydrogenase (IVD), part of the family of acyl-CoA dehydogenases (ACDs), is activated through the substrate binding of Isovaleryl-CoA, within the hydrophobic pocket tailored to accommodate its branched

alkyl chain In organic chemistry, an alkyl group is an alkane missing one hydrogen. The term ''alkyl'' is intentionally unspecific to include many possible substitutions. An acyclic alkyl has the general formula of . A cycloalkyl group is derived from a cy ...

. Upon substrate binding, conformational changes position the

group for hydride transfer to the

flavin adenine dinucleotide In biochemistry, flavin adenine dinucleotide (FAD) is a redox-active coenzyme associated with various proteins, which is involved with several enzymatic reactions in metabolism. A flavoprotein is a protein that contains a flavin group, which ma ...

(FAD) cofactor. This starts the dehydrogenation process, in which two hydrogen atoms are abstracted from the β and γ carbon atoms of isovaleryl-CoA, leading to the formation of a trans-double bond. This enzymatic step results in the conversion of isovaleryl-CoA (3-methylbutyryl-CoA) into 3-methylcrotonyl-CoA, marking the third reaction in the leucine degradation pathway in the Mitochondria. IVD funcions as part of the electron transport flavoprotein (ETF) system, passing electrons from FADH₂ to ETF, which would then transport those electrons to the

electron transport chain An electron transport chain (ETC) is a series of protein complexes and other molecules which transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples th ...

. The electron transport chain establishes a

gradient In vector calculus, the gradient of a scalar-valued differentiable function f of several variables is the vector field (or vector-valued function) \nabla f whose value at a point p gives the direction and the rate of fastest increase. The g ...

by pushing protons into the

inner mitochondrial membrane The inner mitochondrial membrane (IMM) is the mitochondrial membrane which separates the mitochondrial matrix from the intermembrane space. Structure The structure of the inner mitochondrial membrane is extensively folded and compartmentalized. T ...

, contributing to ATP synthesis. The conversion of isovaleryl-CoA into 3-methylcrotonyl-CoA is thus not only central to leucine metabolism but also links amino acid catabolism to

oxidative phosphorylation Oxidative phosphorylation(UK , US : or electron transport-linked phosphorylation or terminal oxidation, is the metabolic pathway in which Cell (biology), cells use enzymes to Redox, oxidize nutrients, thereby releasing chemical energy in order ...

. Following this transformation, 3-methylcrotonyl-CoA, is

carboxylated Carboxylation is a chemical reaction in which a carboxylic acid is produced by treating a substrate with carbon dioxide. The opposite reaction is decarboxylation. In chemistry, the term carbonation is sometimes used synonymously with carboxylation ...

to form

3-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 ...

, then is hydrated and cleaved into

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 ...

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 ...

- two energy rich molecules that enter

tricarboxylic acid A tricarboxylic acid is an organic carboxylic acid that contain three carboxyl functional groups (−COOH). A well-known example is citric acid. Promient examples Some prominent substituted tricarboxylic acids Citric acid, is used in the c ...

(TCA) cycle and

ketone In organic chemistry, a ketone is an organic compound with the structure , where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group (a carbon-oxygen double bond C=O). The simplest ketone is acetone ( ...

body production

References

Thioesters of coenzyme A {{biochem-stub