Common Dynamic Determinants Govern Quorum Quenching Activity in N-Terminal Serine Hydrolases

0558665 - MBÚ 2023 RIV US eng J - Journal Article
Surpeta, B. - Grulich, Michal - Palyzová, Andrea - Marešová, Helena - Brezovský, J.
Common Dynamic Determinants Govern Quorum Quenching Activity in N-Terminal Serine Hydrolases.
ACS Catalysis. Roč. 12, č. 11 (2022), s. 6359-6374. ISSN 2155-5435. E-ISSN 2155-5435
Institutional support: RVO:61388971
Keywords : penicillin-g acylase * homoserine-lactone-acylase * antibiotic-resistance * molecular-dynamics * substrate-binding * qm/mm calculations * specificity * health * site * perspectives * quorum quenching * N-terminal serine hydrolase * acyl-homoserine lactone acylase * penicillin G acylase * qm * mm * molecular dynamics * reaction mechanism
OECD category: Microbiology
Impact factor: 12.9, year: 2022
Method of publishing: Limited access
https://pubs.acs.org/doi/10.1021/acscatal.2c00569

Growing concerns about microbial antibiotic resistance havemotivated extensive research into ways of overcoming antibiotic resistance.Quorum quenching (QQ) processes disrupt bacterial communication via quorumsensing, which enables bacteria to sense the surrounding bacterial cell density andmarkedly affects their virulence. Due to its indirect mode of action, QQ is believedto exert limited pressure on essential bacterial functions and may thus avoidinducing resistance. Although many enzymes display QQ activity against variousbacterial signaling molecules, their mechanisms of action are poorly understood,limiting their potential optimization as QQ agents. Here, we evaluate the capacityof three N-terminal serine hydrolases to degrade N-acyl-homoserine lactones(HSLs) that serve as signaling compounds for Gram-negative bacteria. Using molecular dynamics (MD) simulations of the freeenzymes and their complexes with two signaling molecules of different lengths, followed by quantum mechanics/molecularmechanics MD simulations of two catalytic steps, we clarify the molecular processes underpinning their QQ activity. We concludethat all three enzymes degrade HSLs via similar reaction mechanisms. Moreover, we experimentally confirmed the activity of twopenicillin G acylases fromEscherichia coli(ecPGA) andAchromobacterspp. (aPGA), adding these industrially optimized enzymes tothe QQ toolbox. We also observed substrate-dependent differences in the catalytic actions of these enzymes, arising primarily fromthe distinct structures of their acyl-binding cavities and the dynamics of their molecular gates. As a consequence, thefirst reactionstep catalyzed by ecPGA with a longer substrate had an elevated energy barrier compared to its complex with a shorter substratebecause its shallow acyl-binding site could not accommodate a productive substrate-binding configuration of the former one.
Permanent Link: https://hdl.handle.net/11104/0332427