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Structural Insights into Isovaleryl-Coenzyme A Dehydrogenase: Mechanisms of Substrate Specificity and Implications of Isovaleric Acidemia-Associated Mutations

文献类型：期刊论文

作者Ju, Kaide7; Bai, Fang6; Xu, Youwei5; Li, Qingao6; Su, Gengchen7; Jin, Ye4; Chen, Houzao3; Zhang, Shuyang2,4,6,7; Luan, Xiaodong1,4
刊名RESEARCH
出版日期2025-05-28
卷号8页码:11
ISSN号2096-5168
DOI10.34133/research.0661
通讯作者Chen, Houzao(luanxiaodong@pumch.cn) ; Zhang, Shuyang(shuyangzhang103@nrdrs.org) ; Luan, Xiaodong(chenhouzao@ibms.cams.cn)
英文摘要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.
WOS关键词ACYL-COA DEHYDROGENASE ; MOLECULAR-CLONING ; TURKISH PATIENTS ; IVD GENE ; IDENTIFICATION ; SPECTRUM ; RAT
资助项目National Key Research and Development Program of China[2022YFC2703100] ; National Key Research and Development Program of China[2023YFC3605504] ; Chinese Academy of Medical Sciences Initiative for Innovative Medicine[2021-I2M-1-003] ; National High Level Hospital Clinical Research Funding[2022-PUMCH-D-002] ; National High Level Hospital Clinical Research Funding[2022-PUMCH-B-098] ; National Natural Science Foundation of China[82225007] ; National Natural Science Foundation of China[92149305] ; National Natural Science Foundation of China[82030017]
WOS研究方向Science & Technology - Other Topics
语种英语
WOS记录号WOS:001497231800001
出版者AMER ASSOC ADVANCEMENT SCIENCE
源URL[http://119.78.100.183/handle/2S10ELR8/318159]  
专题中国科学院上海药物研究所
通讯作者Chen, Houzao; Zhang, Shuyang; Luan, Xiaodong
作者单位1.Peking Union Med Coll Hosp, Inst Clin Med, Ctr Drug Res & Evaluat, Beijing 100730, Peoples R China
2.Tsinghua Univ, Tsinghua Peking Ctr Life Sci, Beijing 100084, Peoples R China
3.Chinese Acad Med Sci & Peking Union Med Coll, Inst Basic Med Sci, Dept Biochem & Mol Biol, State Key Lab Med Mol Biol, Beijing 100730, Peoples R China
4.Chinese Acad Med Sci & Peking Union Med Coll, Peking Union Med Coll Hosp, Dept Rare Dis, Beijing, Peoples R China
5.Chinese Acad Sci, CAS Key Lab Receptor Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
6.Chinese Acad Med Sci & Peking Union Med Coll, Peking Union Med Coll Hosp, Dept Cardiol, Beijing 100730, Peoples R China
7.Tsinghua Univ, Sch Basic Med Sci, Beijing 100084, Peoples R China
推荐引用方式
GB/T 7714		 Ju, Kaide,Bai, Fang,Xu, Youwei,et al. Structural Insights into Isovaleryl-Coenzyme A Dehydrogenase: Mechanisms of Substrate Specificity and Implications of Isovaleric Acidemia-Associated Mutations[J]. RESEARCH,2025,8:11.
APA Ju, Kaide.,Bai, Fang.,Xu, Youwei.,Li, Qingao.,Su, Gengchen.,...&Luan, Xiaodong.(2025).Structural Insights into Isovaleryl-Coenzyme A Dehydrogenase: Mechanisms of Substrate Specificity and Implications of Isovaleric Acidemia-Associated Mutations.RESEARCH,8,11.
MLA Ju, Kaide,et al."Structural Insights into Isovaleryl-Coenzyme A Dehydrogenase: Mechanisms of Substrate Specificity and Implications of Isovaleric Acidemia-Associated Mutations".RESEARCH 8(2025):11.

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来源：上海药物研究所

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