Journal Article

Structural and biochemical mechanism of short-chain enoyl-CoA hydratase (ECHS1) substrate recognition

Zhang, Shuyang, Jin, Ye, Chen, Binxian, Su, Gengchen, Ju, Kaide, Xu, Youwei, Chen, Houzao, Luan, Xiaodong

2025

Overview

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. The study of ECHS1 functional mechanism provides a theoretical basis for subsequent work focused on determining the role of ECHS1 deficiency (ECHS1D) in the occurrence of diseases such as cardiomyopathy.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 101/28 / 38/77 / 631/45/173 / 631/45/535/1258/1259 / 631/535/1258/1259 / 631/57/2272/2273 / 82/103 / 82/16 / 82/47 / 82/80 / 82/83 / Acyl Coenzyme A - chemistry / Acyl Coenzyme A - metabolism / Biomedical and Life Sciences / Cardiomyopathy / Cryoelectron Microscopy / Enoyl-CoA hydratase / Enoyl-CoA Hydratase - chemistry / Enoyl-CoA Hydratase - genetics / Enoyl-CoA Hydratase - metabolism / Enzymatic activity / Enzymes / Fatty acids / Humans / Life Sciences / Models, Molecular / Mutation / Point mutation / Protein Binding / Protein Conformation / Substrate Specificity