8ZEV

Crystal structure of the dehydratase domain of human fatty acid synthase

Summary for 8ZEV

• Entry DOI: 10.2210/pdb8zev/pdb
• Descriptor: Fatty acid synthase, IODIDE ION (3 entities in total)
• Functional Keywords: human; fatty acid synthase; fasn; dehydratase domain; dh, biosynthetic protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 113275.16

Authors

Zhang, L.,Zhang, L. (deposition date: 2024-05-07, release date: 2025-03-19)

Primary citation

Cai, C.,Huang, Y.,Zhang, L.,Zhang, L.
Structural Basis of the Dehydratase Module (hDH) of Human Fatty Acid Synthase.
Chembiochem, 25:e202400466-e202400466, 2024

PubMed Abstract: The 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.

PubMed: 38955950
DOI: 10.1002/cbic.202400466

Experimental method

X-RAY DIFFRACTION (1.8 Å)