Catalytic specificity and crystal structure of cystathionine γ-lyase from Pseudomonas aeruginosa

The escalating drug resistance among microorganisms underscores the urgent need for innovative therapeutic strategies and a comprehensive understanding of bacteria's defense mechanisms against oxidative stress and antibiotics. Among the recently discovered barriers, the endogenous production of hydrogen sulfide (H2S), via the reverse transsulfuration pathway, emerges as a noteworthy factor. In this study, we have explored the catalytic capabilities and crystal structure of cystathionine γ-lyase from Pseudomonas aeruginosa (PaCGL). In addition to a canonical L-cystathionine hydrolysis, purified PaCGL can catalyze the production of H2S using L-cysteine and/or L-homocysteine as alternative substrates. Comparative analysis with counterparts in other pathogens and humans revealed distinct structural features within the primary enzyme cavities, including a differently folded entrance loop to the catalytic site, potentially influencing substrate and/or inhibitor access. These findings offer opportunities for developing specific inhibitors to limit or eliminate bacterial H2S synthesis, weakening a defense barrier against the host immune system.