Download MendeleyStructural and biochemical mechanism of short-chain enoyl-CoA hydratase (ECHS1) substrate recognition.
Su, G., Xu, Y., Chen, B., Ju, K., Jin, Y., Chen, H., Zhang, S., Luan, X.(2025) Commun Biol 8: 619-619
- PubMed: 40240482
- DOI: https://doi.org/10.1038/s42003-025-07924-0
- Primary Citation of Related Structures:
8ZRU, 8ZRV, 8ZRW, 8ZRX, 8ZRY - PubMed 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.
Organizational Affiliation:
Department of Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, 100730, Beijing, China.
