题目：Hydrogen Sulfide: Detoxification Mechanisms in Health and Disease
报告人: Dr. Changyuan Lu 美国康奈尔医学院药学系
地点: 博彩平台
907-1445
时间: 7月15日上午9:30-10:30
Hydrogen sulfide (H2S) is a gaseous transmitter, known to regulate diverse physiological and pathophysiological processes. Sulfhydration of Cys-sulfur, protein sulfhydration, can determine the structure and function of proteins, thereby plays a fundamental role in the cell signaling actions of endogenously produced H2S as well as the toxic actions of excess inhaled H2S. An understanding of mechanisms that regulate protein sulfhydration is expected to improve our understanding of tissue function/dysfunction and to provide unanticipated new therapeutic insights. This presentation will be focused on defining the function, regulation and biological relevance of a three-enzyme pathway of H2S detoxification in the mitochondrial: sulfide quinone oxidoreductase (SQR) converts H2S to a persulfide (RSSH). Subsequently, sulfur dioxygenase (ETHE1) oxidizes the highly reactive intermediate RSSH to sulfite. The final reaction is catalyzed by thiosulfate sulfotransferase (TST), which converts sulfite to thiosulfate, for safe excreted in urine. Since small molecule persulfides are predicted to be in equilibrium with protein persulfides, the SQR/ETHE1/TST pathway is hypothesized to indirectly determine the extent of protein sulfhydration , hence, it modulates diverse protein activities.
To advance this research, we have cloned, over-expressed and purified human ETHE1. Glutathione persulfide was identified as the sole physiological substrate of ETHE1 among all known thiol-containing species. Using a novel affinity-capture MS-based approach, we are able to quantify the physiological concentrations of small molecule persulfides in murine tissue samples. Further studies showed that genetic knockdown of ETHE1 results in increased levels of glutathione persulfide in cells, confirming that ETHE1 catalyzed metabolism broadly governs cellular persulfide levels. To test whether this action of ETHE1 extends to the control of protein persulfide levels, we developed a proteomic approach for unbiased identification of sulfhydration sites on peptides and proteins. Application of this approach identified 12 endogenous protein persulfides in mouse liver and many more produced as a consequence of exposure to chemical donors of H2S, including enzymes of the tricarboxylic acid (TCA) cycle and of glycolysis that can impact cell bioenergetics.
