Cystathionine γ-Lyase and its Potential as a Therapeutic Target: From H2S Production to Oxidative Stress

Cystathionine γ-lyase (CSE) has become a target of interest in recent years via its ability to synthesize hydrogen sulfide. However, lack of suitable inhibitors has prevented scientists from properly delineating the role of CSE in disease and disease state, therefore hindering the progress of this field. This study aimed to revise commonly known CSE inhibitors, such as L-PAG, by using three distinct enzymatic assays as well as several CSE substrates. Moreover clavulanic acid was identified as a novel inhibitor for CSE for the first time. Although L-PAG remains as the best CSE inhibitor, this study has been able to clarify discrepancies of CSE inhibition found within the literature, as well as providing a better mechanistic view of this enzyme. By focusing on the mechanism of CSE (via γ and β-elimination) as well as substrate preference, the work shown here has provided a basis that could aid in the future discovery of more selective potent inhibitors. In addition, this study has shown the beneficial effects that CSE can have under oxidative stress. By using oxidative stress models such as excess of 4-hydroxynonenal (HNE) and 4-oxononenal (ONE), two known biomarkers of oxidative stress, this work has shown that CSE is able to create powerful antioxidants from several substrates, which can scavenge HNE and ONE therefore preventing protein crosslinking. Overall, this work shows the therapeutic potential of CSE, from its inhibition, to its ability to create powerful antioxidants under oxidative stress.