Isovaleryl-CoA dehydrogenase

isovaleryl-CoA dehydrogenase

Isovaleryl-CoA dehydrogenase tetramer, Human

Identifiers

EC no.

1.3.8.4

CAS no.

37274-61-6

Databases

IntEnz

IntEnz view

BRENDA

BRENDA entry

ExPASy

NiceZyme view

KEGG

KEGG entry

MetaCyc

metabolic pathway

PRIAM

profile

PDB structures

RCSB PDB PDBe PDBsum

Gene Ontology

AmiGO / QuickGO

Search
PMC	articles
PubMed	articles
NCBI	proteins

In enzymology, an isovaleryl-CoA dehydrogenase (EC 1.3.8.4) is an enzyme that catalyzes the chemical reaction

3-methylbutanoyl-CoA + acceptor

\rightleftharpoons

3-methylbut-2-enoyl-CoA + reduced acceptor

Thus, the two substrates of this enzyme are 3-methylbutanoyl-CoA and acceptor, whereas its two products are 3-methylbut-2-enoyl-CoA and reduced acceptor.

This enzyme belongs to the family of oxidoreductases, specifically those acting on the CH-CH group of donor with other acceptors. The systematic name of this enzyme class is 3-methylbutanoyl-CoA:acceptor oxidoreductase. Other names in common use include isovaleryl-coenzyme A dehydrogenase, isovaleroyl-coenzyme A dehydrogenase, and 3-methylbutanoyl-CoA:(acceptor) oxidoreductase. This enzyme participates in valine, leucine and isoleucine degradation. It employs one cofactor, FAD.

Structural studies

As of late 2007, only one structure has been solved for this class of enzymes, with the PDB accession code 1IVH. It was created by a group containing K.A.Tiffany, D.L.Roberts, M.Wang, R.Paschke, A.-W.A.Mohsen, J.Vockley, and J.J.P.Kim. The structure was released on May 20, 1998.Doe. "PDBsum entry: 1ivh". Retrieved November 25, 2019.

Leucine metabolism

Leucine metabolism in humans

L-Leucine

Branched-chain amino
acid aminotransferase

Muscle: α-Ketoisocaproate (α-KIC)

Liver: α-Ketoisocaproate (α-KIC)

Branched-chain α-ketoacid
dehydrogenase (mitochondria)

KIC-dioxygenase
(cytosol)

Isovaleryl-CoA

β-Hydroxy
β-methylbutyrate
(HMB)

Excreted
in urine
(10–40%)

HMB-CoA

β-Hydroxy β-methylglutaryl-CoA
(HMG-CoA)

β-Methylcrotonyl-CoA
(MC-CoA)

β-Methylglutaconyl-CoA
(MG-CoA)

CO₂

O₂

CO₂

H₂O

CO₂

H₂O

(liver)
HMG-CoA
lyase

Enoyl-CoA hydratase

Isovaleryl-CoA
dehydrogenase

MC-CoA
carboxylase

MG-CoA
hydratase

HMG-CoA
reductase

HMG-CoA
synthase

β-Hydroxybutyrate
dehydrogenase

Mevalonate
pathway

Unknown
enzyme

Human metabolic pathway for HMB and isovaleryl-CoA relative to L-leucine.^[1]^[2]^[3] Of the two major pathways, L-leucine is mostly metabolized into isovaleryl-CoA, while only about 5% is metabolized into HMB.^[1]^[2]^[3]

References

^ ^a ^b Wilson JM, Fitschen PJ, Campbell B, Wilson GJ, Zanchi N, Taylor L, Wilborn C, Kalman DS, Stout JR, Hoffman JR, Ziegenfuss TN, Lopez HL, Kreider RB, Smith-Ryan AE, Antonio J (February 2013). "International Society of Sports Nutrition Position Stand: beta-hydroxy-beta-methylbutyrate (HMB)". Journal of the International Society of Sports Nutrition. 10 (1): 6. doi:10.1186/1550-2783-10-6. PMC 3568064. PMID 23374455.
^ ^a ^b Zanchi NE, Gerlinger-Romero F, Guimarães-Ferreira L, de Siqueira Filho MA, Felitti V, Lira FS, Seelaender M, Lancha AH (April 2011). "HMB supplementation: clinical and athletic performance-related effects and mechanisms of action". Amino Acids. 40 (4): 1015–1025. doi:10.1007/s00726-010-0678-0. PMID 20607321. S2CID 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).
^ ^a ^b Kohlmeier M (May 2015). "Leucine". Nutrient Metabolism: Structures, Functions, and Genes (2nd ed.). Academic Press. pp. 385–388. ISBN 978-0-12-387784-0. Retrieved 6 June 2016. Energy fuel: Eventually, most Leu is broken down, providing about 6.0kcal/g. About 60% of ingested Leu is oxidized within a few hours ... Ketogenesis: A significant proportion (40% of an ingested dose) is converted into acetyl-CoA and thereby contributes to the synthesis of ketones, steroids, fatty acids, and other compounds
Figure 8.57: Metabolism of L-leucine

BACHHAWAT BK, ROBINSON WG, COON MJ (1956). "Enzymatic carboxylation of beta-hydroxyisovaleryl coenzyme A". J. Biol. Chem. 219 (2): 539–50. doi:10.1016/S0021-9258(18)65714-X. PMID 13319276.
Ikeda Y, Tanaka K (1983). "Purification and characterization of isovaleryl coenzyme A dehydrogenase from rat liver mitochondria". J. Biol. Chem. 258 (2): 1077–85. doi:10.1016/S0021-9258(18)33161-2. PMID 6401713.
Tanaka K, Budd MA, Efron ML, Isselbacher KJ (1966). "Isovaleric acidemia: a new genetic defect of leucine metabolism". Proc. Natl. Acad. Sci. U.S.A. 56 (1): 236–42. Bibcode:1966PNAS...56..236T. doi:10.1073/pnas.56.1.236. PMC 285701. PMID 5229850.

Oxidoreductases: CH–CH oxidoreductases (EC 1.3)

1.3.1: NAD/NADP acceptor

1.3.3: Oxygen acceptor

1.3.5: Quinone

Succinate dehydrogenase
- SDHA
- SDHB
- SDHC
- SDHD

1.3.99: Other acceptors

v t e Enzymes
Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Diffusion-limited enzyme Cofactor Enzyme catalysis
Regulation	Allosteric regulation Cooperativity Enzyme inhibitor Enzyme activator
Classification	EC number Enzyme superfamily Enzyme family List of enzymes
Kinetics	Enzyme kinetics Eadie–Hofstee diagram Hanes–Woolf plot Lineweaver–Burk plot Michaelis–Menten kinetics
Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list) EC7 Translocases (list)