Affiliation:
1. Department of Pharmacology and Chemical Biology State Key Laboratory of Systems Medicine for Cancer School of Medicine Shanghai Jiao Tong University Shanghai 200025 China
2. Department of Chemical Biology School of Chemistry and Chemical Engineering Shanghai Jiao Tong University Shanghai 200240 China
Abstract
AbstractThe human fatty acid synthase (hFASN) produces fatty acids for cellar membrane construction, energy storage, biomolecule modifications and signal transduction. Abnormal expression and functions of hFASN highly associate with numerous human diseases such as obesity, diabetes, and cancers, and thereby it has been considered as a valuable potential drug target. So far, the structural and catalytic mechanisms of most of the hFASN enzymatic modules have been extensively studied, except the key dehydratase module (hDH). Here we presented the enzymatic characterization and the high‐resolution crystal structure of hDH. We demonstrated that the hDH preferentially catalyzes the acyl substrates with short lengths between 4 to 8‐carbons, and exhibits much lower enzymatic activity on longer substrates. Subsequent structural study showed that hDH displays a pseudo‐dimeric organization with a single L‐shaped composite hydrophobic catalytic tunnel as well as an atypical ACP binding site nearby, indicating that hDH achieves distinct substrate recognition and dehydration mechanisms compared to the conventional bacterial fatty acid dehydratases identified. Our findings laid the foundation for understanding the biological and pathogenic functions of hFASN, and may facilitate therapeutical drug development against diseases with abnormal functionality of hFASN.
Funder
National Natural Science Foundation of China
Science and Technology Commission of Shanghai Municipality
Innovative Research Team of High-level Local University in Shanghai