Hydrogen sulfide functions as a micro-modulator bound at the copper active site of Cu/Zn-SOD to regulate the catalytic activity of the enzyme
Dongdong Wu, Sheng Jin, Ruo-Xiao Cheng, Wenjie Cai, Wenlong Xue, Qingqing Zhang, Lejie Yang, Qi Zhu, Mengyao Li, Lin Ge, Yizhen Wang, Xue-Pan Mu, Yu Wang, Igor Ying Zhang, Qi Zhang, Ying Chen, Shengyang Cai, Bo Tan, Ye Li, Y.L. Chen, Pu-Juan Zhang, Chen Sun, Yue Yin, Ming-Jie Wang, Yi Zhun Zhu, Yi Zhun Zhu, Bei‐Bei Tao, Jiahai Zhou, Weixue Huang, Yi‐Chun Zhu, Yi‐Chun Zhu
Abstract
The present study examines whether there is a mechanism beyond the current concept of post-translational modifications to regulate the function of a protein. A small gas molecule, hydrogen sulfide (H 2 S), was found to bind at active-site copper of Cu/Zn-SOD using a series of methods including radiolabeled binding assay, X-ray absorption near-edge structure (XANES), and crystallography. Such an H 2 S binding enhanced the electrostatic forces to guide the negatively charged substrate superoxide radicals to the catalytic copper ion, changed the geometry and energy of the frontier molecular orbitals of the active site, and subsequently facilitated the transfer of an electron from the superoxide radical to the catalytic copper ion and the breakage of the copper-His61 bridge. The physiological relevance of such an H 2 S effect was also examined in both in vitro and in vivo models where the cardioprotective effects of H 2 S were dependent on Cu/Zn-SOD.