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Isovaleryl-CoA - Wikipedia

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Isovaleryl-CoA (also known as 3-methylbutyryl-CoA) is a metabolic intermediate formed during the catabolism of the branched-chain amino acid, Leucine. It is a short-chain acyl-CoA thioester 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 that catalyzes the third step in the leucine degradation pathway. ^[1] 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, characterized by metabolic crises, developmental delays, and a distinctive odor due to isovaleric acid buildup. ^[2]^[3] The metabolism of isovaleryl-CoA is vital for proper amino acid utilization and energy homeostasis in humans. ^[4]

Isovaleryl-CoA
Names

IUPAC name 3′-O-Phosphonoadenosine 5′-[(3R)-3-hydroxy-2,2-dimethyl-4-{[3-({2-[(3-methylbutanoyl)sulfanyl]ethyl}amino)-3-oxopropyl]amino}-4-oxobutyl dihydrogen diphosphate]
Preferred IUPAC name O¹-{[(2R,3S,4R,5R)-5-(6-Amino-9H-purin-9-yl)-4-hydroxy-3-(phosphonooxy)oxolan-2-yl]methyl} O³-[(3R)-3-hydroxy-2,2-dimethyl-4-{[3-({2-[(3-methylbutanoyl)sulfanyl]ethyl}amino)-3-oxopropyl]amino}-4-oxobutyl] dihydrogen diphosphate
Identifiers
CAS Number	6244-91-3^Y
3D model (JSmol)	Interactive image
ChEBI	CHEBI:15487
ChemSpider	145017^N
MeSH	isovaleryl-coenzyme+A
PubChem CID	165435
CompTox Dashboard (EPA)	DTXSID50978008
InChI InChI=1S/C26H44N7O17P3S/c1-14(2)9-17(35)54-8-7-28-16(34)5-6-29-24(38)21(37)26(3,4)11-47-53(44,45)50-52(42,43)46-10-15-20(49-51(39,40)41)19(36)25(48-15)33-13-32-18-22(27)30-12-31-23(18)33/h12-15,19-21,25,36-37H,5-11H2,1-4H3,(H,28,34)(H,29,38)(H,42,43)(H,44,45)(H2,27,30,31)(H2,39,40,41)/t15-,19-,20-,21+,25-/m1/s1^N Key: UYVZIWWBJMYRCD-ZMHDXICWSA-N^N InChI=1/C26H44N7O17P3S/c1-14(2)9-17(35)54-8-7-28-16(34)5-6-29-24(38)21(37)26(3,4)11-47-53(44,45)50-52(42,43)46-10-15-20(49-51(39,40)41)19(36)25(48-15)33-13-32-18-22(27)30-12-31-23(18)33/h12-15,19-21,25,36-37H,5-11H2,1-4H3,(H,28,34)(H,29,38)(H,42,43)(H,44,45)(H2,27,30,31)(H2,39,40,41)/t15-,19-,20-,21+,25-/m1/s1 Key: UYVZIWWBJMYRCD-ZMHDXICWBW
SMILES CC(C)CC(=O)SCCNC(=O)CCNC(=O)[C@@H](C(C)(C)COP(=O)(O)OP(=O)(O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)n2cnc3c2ncnc3N)O)OP(=O)(O)O)O
Properties
Chemical formula	C₂₆H₄₄N₇O₁₇P₃S
Molar mass	851.652 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). N verify (what is ^YN ?) Infobox references

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. Upon substrate binding, conformational changes position the thioester group for hydride transfer to the flavin adenine dinucleotide (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.^[1] 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.^[2]

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. The electron transport chain establishes a gradient by pushing protons into the inner mitochondrial membrane, 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.^[1]^[4]

Following this transformation, 3-methylcrotonyl-CoA, is carboxylated to form 3-methylglutaconyl-CoA, then is hydrated and cleaved into acetyl-CoA and acetoacetate - two energy rich molecules that enter tricarboxylic acid (TCA) cycle and ketone body production^[2]^[3]

References

^ ^a ^b ^c Tiffany, Karen A.; Roberts, David L.; Wang, Ming; Paschke, Rosemary; Mohsen, Al-Walid A.; Vockley, Jerry; Kim, Jung-Ja P. (1997-07-01). "Structure of Human Isovaleryl-CoA Dehydrogenase at 2.6 Å Resolution: Structural Basis for Substrate Specificity". Biochemistry. 36 (28): 8455–8464. doi:10.1021/bi970422u. ISSN 0006-2960. PMID 9214289.
^ ^a ^b ^c Mohsen, Al-Walid A.; Anderson, Bambi D.; Volchenboum, Samuel L.; Battaile, Kevin P.; Tiffany, Karen; Roberts, David; Kim, Jung-Ja P.; Vockley, Jerry (1998-07-01). "Characterization of Molecular Defects in Isovaleryl-CoA Dehydrogenase in Patients with Isovaleric Acidemia". Biochemistry. 37 (28): 10325–10335. doi:10.1021/bi973096r. ISSN 0006-2960. PMID 9665741.
^ ^a ^b Rhead, W J; Tanaka, K (January 1980). "Demonstration of a specific mitochondrial isovaleryl-CoA dehydrogenase deficiency in fibroblasts from patients with isovaleric acidemia". Proceedings of the National Academy of Sciences. 77 (1): 580–583. Bibcode:1980PNAS...77..580R. doi:10.1073/pnas.77.1.580. PMC 348317. PMID 6928646.
^ ^a ^b Battaile, Kevin P.; Nguyen, Tien V.; Vockley, Jerry; Kim, Jung-Ja P. (April 2004). "Structures of Isobutyryl-CoA Dehydrogenase and Enzyme-Product Complex". Journal of Biological Chemistry. 279 (16): 16526–16534. doi:10.1074/jbc.M400034200.

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