Inhibitory Activity and Proposed Binding Model of γ-Glutamyl Cysteine, the Precursor of Glutathione, on Angiotensin Converting Enzyme

Owing to their various physiological activities, thiol compounds, such as l-cysteine with UV-protection properties and captopril that inhibits the catalytic activity of angiotensin converting enzyme (ACE), are currently used as supplements and pharmaceuticals. Glutathione (GSH) plays an important role in intracellular protective effects and is currently used for the treatment of cataract and detoxification from metal poisoning. In contrast to GSH, the GSH precursor γ-glutamyl cysteine ​​(γ-EC) has been reported to exhibit neuroprotective effects, thus making it an attractive key biological protective molecule. However, its characteristics are largely unknown. Here, we evaluated the ACE inhibitory function of γ-EC and its mechanism by comparing it with that of GSH in vitro. ACE inhibitory analysis showed that the IC50 of GSH and γ-EC against ACE were 8.3 μM and 3.9 × 102 μM, respectively. These data suggested that γ-EC exerted ACE inhibitory activity, but it was weaker than that of GSH. Docking simulation showed that the ACE inhibitory activity of both compounds was due to the interaction of their carboxyl groups of Glu with Zn2+ in the active center of ACE. Moreover, GSH could fit more compactly in the pocket of ACE, forming more hydrogen bonds with the enzyme than γ-EC. By analyzing its kinetics and in vivo efficacy, we hope that γ-EC could be used as a promising compound for lowering blood pressure in applications with moderate activity, such as functional foods.