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TitleStructural Insights into Isovaleryl-Coenzyme A Dehydrogenase: Mechanisms of Substrate Specificity and Implications of Isovaleric Acidemia-Associated Mutations.
Journal, issue, pagesResearch (Wash D C), Vol. 8, Page 0661, Year 2025
Publish dateMay 28, 2025
AuthorsKaide Ju / Fang Bai / Youwei Xu / Qingao Li / Gengchen Su / Ye Jin / Houzao Chen / Shuyang Zhang / Xiaodong Luan /
PubMed AbstractIsovaleryl-CoA (coenzyme A) dehydrogenase (IVD) plays a pivotal role in the catabolism of leucine, converting isovaleryl-CoA to 3-methylcrotonyl-CoA. Dysfunction of IVD is linked to isovaleric ...Isovaleryl-CoA (coenzyme A) dehydrogenase (IVD) plays a pivotal role in the catabolism of leucine, converting isovaleryl-CoA to 3-methylcrotonyl-CoA. Dysfunction of IVD is linked to isovaleric acidemia (IVA), a rare metabolic disorder characterized by the accumulation of toxic metabolites. In this study, we present the cryo-electron microscopy structures of human IVD, resolved both in its apo form and in complex with its substrates, isovaleryl-CoA and butyryl-CoA. Our findings reveal a tetrameric architecture with distinct substrate-binding pockets that facilitate the enzyme's preference for short branched-chain acyl-CoAs. Key residues involved in FAD binding and substrate interaction were identified, elucidating the catalytic mechanism of IVD. Additionally, we investigated the impact of various disease-associated hotspot mutations derived from different regions, demonstrating their effects on enzyme stability and activity. Notably, mutations such as A314V, S281G/F382V, and E411K resulted in substantial loss of function, while others exhibited milder effects, which is consistent with our structural analyses. These insights enhance our understanding of IVD's enzymatic properties and provide a foundation for developing targeted therapies for IVA.
External linksResearch (Wash D C) / PubMed:40851894 / PubMed Central
MethodsEM (single particle)
Resolution2.45 - 3.35 Å
Structure data

61721

9jq3

EMDB-61721, PDB-9jq3:
Structure of human IVD in complex with FAD
Method: EM (single particle) / Resolution: 2.45 Å

61722

9jq4

EMDB-61722, PDB-9jq4:
Structure of human IVD in complex with FAD and butyryl-CoA
Method: EM (single particle) / Resolution: 2.91 Å

61723

9jq5

EMDB-61723, PDB-9jq5:
Structure of human IVD in complex with FAD and isovaleryl-CoA
Method: EM (single particle) / Resolution: 3.35 Å

Chemicals

ChemComp-FAD:
FLAVIN-ADENINE DINUCLEOTIDE / FAD*YM

ChemComp-BCO:
Butyryl Coenzyme A

ChemComp-IVC:
Isovaleryl-coenzyme A

Source
  • homo sapiens (human)
KeywordsHYDROLASE / IVD / FAD / butyryl-CoA / Isovaleryl-CoA

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