Disulfide Reductase Systems In Liver


Colin G. Miller, Edward E. Schmidt


British Journal of Pharmacology


Intermediary metabolism and detoxification place high demands on the disulfide reductase systems in most hepatocytesubcellular compartments. Biosynthetic, metabolic, cytoprotective and signalling activities in the cytosol; regulation oftranscription in nuclei; respiration in mitochondria; and protein folding in endoplasmic reticulum all require resident disulfidereductase activities. In the cytosol, two NADPH-dependent enzymes, glutathione reductase and thioredoxin reductase, as well asa recently identified NADPH-independent system that uses catabolism of methionine to maintain pools of reduced glutathione,supply disulfide reducing power. However the necessary discontinuity between the cytosol and the interior of organelles restrictsthe ability of the cytosolic systems to support needs in other compartments. Maintenance of molecular- and charge-gradientsacross the inner-mitochondrial membrane, which is needed for oxidative phosphorylation, mandates that the matrix maintain anautonomous set of NADPH-dependent disulfide reductase systems. Elsewhere, complex mechanisms mediate the transfer of cy-tosolic reducing power into specific compartments. The redox needs in each compartment also differ, with the lumen of theendoplasmic reticulum, the mitochondrial inter-membrane space and some signalling proteins in the cytosol each requiringdifferent levels of protein oxidation. Here, we present an overview of the current understanding of the disulfide reductase systemsin major subcellular compartments of hepatocytes, integrating knowledge obtained from direct analyses on liver with inferencesfrom other model systems. Additionally, we discuss relevant advances in the expandingfield of redox signalling.



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