The Incomplete Glutathione Puzzle: Just Guessing at Numbers and Figures?

被引:114
作者
Deponte, Marcel [1 ]
机构
[1] Ruprecht Karls Univ Heidelberg, Dept Parasitol, Neuenheimer Feld 324, D-69120 Heidelberg, Germany
关键词
glutathione; concentration; compartmentalization; kinetics; rate constant; function; DISULFIDE BOND FORMATION; MITOCHONDRIAL INTERMEMBRANE SPACE; ELECTRON-PARAMAGNETIC-RESONANCE; FALCIPARUM ANTIOXIDANT PROTEIN; OXIDATIVE STRESS-RESPONSE; S-D-LACTOYLGLUTATHIONE; SACCHAROMYCES-CEREVISIAE; PLASMODIUM-FALCIPARUM; MONOTHIOL GLUTAREDOXINS; HYDROGEN-PEROXIDE;
D O I
10.1089/ars.2017.7123
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Significance: Glutathione metabolism is comparable to a jigsaw puzzle with too many pieces. It is supposed to comprise (i) the reduction of disulfides, hydroperoxides, sulfenic acids, and nitrosothiols, (ii) the detoxification of aldehydes, xenobiotics, and heavy metals, and (iii) the synthesis of eicosanoids, steroids, and iron-sulfur clusters. In addition, glutathione affects oxidative protein folding and redox signaling. Here, I try to provide an overview on the relevance of glutathione-dependent pathways with an emphasis on quantitative data. Recent Advances: Intracellular redox measurements reveal that the cytosol, the nucleus, and mitochondria contain very little glutathione disulfide and that oxidative challenges are rapidly counterbalanced. Genetic approaches suggest that iron metabolism is the centerpiece of the glutathione puzzle in yeast. Furthermore, recent biochemical studies provide novel insights on glutathione transport processes and uncoupling mechanisms. Critical Issues: Which parts of the glutathione puzzle are most relevant? Does this explain the high intracellular concentrations of reduced glutathione? How can iron-sulfur cluster biogenesis, oxidative protein folding, or redox signaling occur at high glutathione concentrations? Answers to these questions not only seem to depend on the organism, cell type, and subcellular compartment but also on different ideologies among researchers. Future Directions: A rational approach to compare the relevance of glutathione-dependent pathways is to combine genetic and quantitative kinetic data. However, there are still many missing pieces and too little is known about the compartment-specific repertoire and concentration of numerous metabolites, substrates, enzymes, and transporters as well as rate constants and enzyme kinetic patterns. Gathering this information might require the development of novel tools but is crucial to address potential kinetic competitions and to decipher uncoupling mechanisms to solve the glutathione puzzle.
引用
收藏
页码:1130 / 1161
页数:32
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