Structural and biochemical mechanism of short-chain enoyl-CoA hydratase (ECHS1) substrate recognition
Abstract Deficiency of short-chain enoyl-CoA hydratase (ECHS1), a crucial enzyme in fatty acid metabolism through the mitochondrial β-oxidation pathway, has been strongly linked to various diseases, especially cardiomyopathy. However, the structural and biochemical mechanisms through which ECHS1 rec...
Saved in:
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-04-01
|
| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-07924-0 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850145098147299328 |
|---|---|
| author | Gengchen Su Youwei Xu Binxian Chen Kaide Ju Ye Jin Houzao Chen Shuyang Zhang Xiaodong Luan |
| author_facet | Gengchen Su Youwei Xu Binxian Chen Kaide Ju Ye Jin Houzao Chen Shuyang Zhang Xiaodong Luan |
| author_sort | Gengchen Su |
| collection | DOAJ |
| description | Abstract Deficiency of short-chain enoyl-CoA hydratase (ECHS1), a crucial enzyme in fatty acid metabolism through the mitochondrial β-oxidation pathway, has been strongly linked to various diseases, especially cardiomyopathy. However, the structural and biochemical mechanisms through which ECHS1 recognizes acyl-CoAs remain poorly understood. Herein, cryo-EM analysis reveals the apo structure of ECHS1 and structures of the ECHS1-crotonyl-CoA, ECHS1-acetoacetyl-CoA, ECHS1-hexanoyl-CoA, and ECHS1-octanoyl-CoA complexes at high resolutions. The mechanism through which ECHS1 recognizes its substrates varies with the fatty acid chain lengths of acyl-CoAs. Furthermore, crucial point mutations in ECHS1 have a great impact on substrate recognition, resulting in significant changes in binding affinity and enzyme activity, as do disease-related point mutations in ECHS1. The functional mechanism of ECHS1 is systematically elucidated from structural and biochemical perspectives. These findings provide a theoretical basis for subsequent work focused on determining the role of ECHS1 deficiency (ECHS1D) in the occurrence of diseases such as cardiomyopathy. |
| format | Article |
| id | doaj-art-32c11adbed86445c9e0efae6b7fdbbcc |
| institution | OA Journals |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-32c11adbed86445c9e0efae6b7fdbbcc2025-08-20T02:28:10ZengNature PortfolioCommunications Biology2399-36422025-04-018111210.1038/s42003-025-07924-0Structural and biochemical mechanism of short-chain enoyl-CoA hydratase (ECHS1) substrate recognitionGengchen Su0Youwei Xu1Binxian Chen2Kaide Ju3Ye Jin4Houzao Chen5Shuyang Zhang6Xiaodong Luan7Department of Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical ScienceThe CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesSchool of Medicine, Tsinghua UniversitySchool of Medicine, Tsinghua UniversityDepartment of Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical ScienceDepartment of Biochemistry and Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical CollegeDepartment of Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical ScienceDepartment of Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical ScienceAbstract Deficiency of short-chain enoyl-CoA hydratase (ECHS1), a crucial enzyme in fatty acid metabolism through the mitochondrial β-oxidation pathway, has been strongly linked to various diseases, especially cardiomyopathy. However, the structural and biochemical mechanisms through which ECHS1 recognizes acyl-CoAs remain poorly understood. Herein, cryo-EM analysis reveals the apo structure of ECHS1 and structures of the ECHS1-crotonyl-CoA, ECHS1-acetoacetyl-CoA, ECHS1-hexanoyl-CoA, and ECHS1-octanoyl-CoA complexes at high resolutions. The mechanism through which ECHS1 recognizes its substrates varies with the fatty acid chain lengths of acyl-CoAs. Furthermore, crucial point mutations in ECHS1 have a great impact on substrate recognition, resulting in significant changes in binding affinity and enzyme activity, as do disease-related point mutations in ECHS1. The functional mechanism of ECHS1 is systematically elucidated from structural and biochemical perspectives. These findings provide a theoretical basis for subsequent work focused on determining the role of ECHS1 deficiency (ECHS1D) in the occurrence of diseases such as cardiomyopathy.https://doi.org/10.1038/s42003-025-07924-0 |
| spellingShingle | Gengchen Su Youwei Xu Binxian Chen Kaide Ju Ye Jin Houzao Chen Shuyang Zhang Xiaodong Luan Structural and biochemical mechanism of short-chain enoyl-CoA hydratase (ECHS1) substrate recognition Communications Biology |
| title | Structural and biochemical mechanism of short-chain enoyl-CoA hydratase (ECHS1) substrate recognition |
| title_full | Structural and biochemical mechanism of short-chain enoyl-CoA hydratase (ECHS1) substrate recognition |
| title_fullStr | Structural and biochemical mechanism of short-chain enoyl-CoA hydratase (ECHS1) substrate recognition |
| title_full_unstemmed | Structural and biochemical mechanism of short-chain enoyl-CoA hydratase (ECHS1) substrate recognition |
| title_short | Structural and biochemical mechanism of short-chain enoyl-CoA hydratase (ECHS1) substrate recognition |
| title_sort | structural and biochemical mechanism of short chain enoyl coa hydratase echs1 substrate recognition |
| url | https://doi.org/10.1038/s42003-025-07924-0 |
| work_keys_str_mv | AT gengchensu structuralandbiochemicalmechanismofshortchainenoylcoahydrataseechs1substraterecognition AT youweixu structuralandbiochemicalmechanismofshortchainenoylcoahydrataseechs1substraterecognition AT binxianchen structuralandbiochemicalmechanismofshortchainenoylcoahydrataseechs1substraterecognition AT kaideju structuralandbiochemicalmechanismofshortchainenoylcoahydrataseechs1substraterecognition AT yejin structuralandbiochemicalmechanismofshortchainenoylcoahydrataseechs1substraterecognition AT houzaochen structuralandbiochemicalmechanismofshortchainenoylcoahydrataseechs1substraterecognition AT shuyangzhang structuralandbiochemicalmechanismofshortchainenoylcoahydrataseechs1substraterecognition AT xiaodongluan structuralandbiochemicalmechanismofshortchainenoylcoahydrataseechs1substraterecognition |