Fig. 16.

CO inhibition of CBS leads to decreased concentration of sulfur species such as H₂S, cysteine persulfides, and glutathione, resulting in impairment of cancer cells’ ability to neutralize ROS. CBS synthesizes cystathionine from homocysteine and serine to generate H₂S. Cystathionine is further converted to cysteine by cystathionine gamma-lyase (CSE). Cystine can be converted to cysteine persulfide by CBS and CSE. Cysteine persulfide induces Keap1 persulfidation and dissociation of the Keap1-Nrf2 complex. Nrf2 translocates to the nucleus and binds to ARE to express antioxidative proteins such as glutamate cysteine ligase (GCL), glutathione synthetase (GS), glutathione reductase (GR), and glucose-6-phosphate dehydrogenase (G6PD). GCL and GS use the cysteine produced by CBS/CSE to synthesize GSH, which acts as the major antioxidative resolution in the cell. GR reduces oxidized glutathione with NADPH, which can be regenerated from NADP+ by G6PD.