Structural and biochemical mechanism of short-chain enoyl-CoA hydratase (ECHS1) substrate recognition
Year: 2025
Type: article
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.
Source: Communications Biology
Authors: Gengchen Su, Youwei Xu, Binxian Chen, Kaide Ju, Ye Jin, Houzao Chen, Shuyang Zhang, Xiaodong Luan
Institutions: Chinese Academy of Medical Sciences & Peking Union Medical College, Peking Union Medical College Hospital, Tsinghua University, Chinese Academy of Sciences, Shanghai Institute of Materia Medica, Institute of Basic Medical Sciences of the Chinese Academy of Medical Sciences, State Key Laboratory of Medical Molecular Biology, Center for Life Sciences
Language: English
Subfield: Materials Chemistry
Field: Materials Science
Domain: Physical Sciences
Open Access status: gold
Estimated APC paid: $4,190
OpenAlex ID: W4409495344