8HSY

Acyl-ACP Synthetase structure

Summary for 8HSY

• Entry DOI: 10.2210/pdb8hsy/pdb
• EMDB information: 35008
• Descriptor: Acyl-acyl carrier protein synthetase (1 entity in total)
• Functional Keywords: acyl-acp synthetase, tool enzyme, cytosolic protein
• Biological source: Vibrio harveyi
• Total number of polymer chains: 6
• Total formula weight: 362977.55

Authors

Huang, H.,Wang, C.,Chang, S.,Cui, T.,Xu, Y.,Zhang, H.,Zhou, C.,Zhang, X.,Feng, Y. (deposition date: 2022-12-20, release date: 2023-12-27, Last modification date: 2025-01-15)

Primary citation

Huang, H.,Chang, S.,Cui, T.,Huang, M.,Qu, J.,Zhang, H.,Lu, T.,Zhang, X.,Zhou, C.,Feng, Y.
An inhibitory mechanism of AasS, an exogenous fatty acid scavenger: Implications for re-sensitization of FAS II antimicrobials.
Plos Pathog., 20:e1012376-e1012376, 2024

PubMed Abstract: Antimicrobial resistance is an ongoing "one health" challenge of global concern. The acyl-ACP synthetase (termed AasS) of the zoonotic pathogen Vibrio harveyi recycles exogenous fatty acid (eFA), bypassing the requirement of type II fatty acid synthesis (FAS II), a druggable pathway. A growing body of bacterial AasS-type isoenzymes compromises the clinical efficacy of FAS II-directed antimicrobials, like cerulenin. Very recently, an acyl adenylate mimic, C10-AMS, was proposed as a lead compound against AasS activity. However, the underlying mechanism remains poorly understood. Here we present two high-resolution cryo-EM structures of AasS liganded with C10-AMS inhibitor (2.33 Å) and C10-AMP intermediate (2.19 Å) in addition to its apo form (2.53 Å). Apart from our measurements for C10-AMS' Ki value of around 0.6 μM, structural and functional analyses explained how this inhibitor interacts with AasS enzyme. Unlike an open state of AasS, ready for C10-AMP formation, a closed conformation is trapped by the C10-AMS inhibitor. Tight binding of C10-AMS blocks fatty acyl substrate entry, and therefore inhibits AasS action. Additionally, this intermediate analog C10-AMS appears to be a mixed-type AasS inhibitor. In summary, our results provide the proof of principle that inhibiting salvage of eFA by AasS reverses the FAS II bypass. This facilitates the development of next-generation anti-bacterial therapeutics, esp. the dual therapy consisting of C10-AMS scaffold derivatives combined with certain FAS II inhibitors.

PubMed: 39008531
DOI: 10.1371/journal.ppat.1012376

Experimental method

ELECTRON MICROSCOPY (2.53 Å)