Disulfide reductase systems in liver

Abstract

Intermediary metabolism and detoxification place high demands on the disulfide reductase systems in most hepatocyte subcellular compartments. Biosynthetic, metabolic, cytoprotective and signalling activities in the cytosol; regulation of transcription in nuclei; respiration in mitochondria; and protein folding in endoplasmic reticulum all require resident disulfide reductase activities. In the cytosol, two NADPH-dependent enzymes, glutathione reductase and thioredoxin reductase, as well as a 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 restricts the ability of the cytosolic systems to support needs in other compartments. Maintenance of molecular- and charge-gradients across the inner-mitochondrial membrane, which is needed for oxidative phosphorylation, mandates that the matrix maintain an autonomous set of NADPH-dependent disulfide reductase systems. Elsewhere, complex mechanisms mediate the transfer of cytosolic reducing power into specific compartments. The redox needs in each compartment also differ, with the lumen of the endoplasmic reticulum, the mitochondrial inter-membrane space and some signalling proteins in the cytosol each requiring different levels of protein oxidation. Here, we present an overview of the current understanding of the disulfide reductase systems in major subcellular compartments of hepatocytes, integrating knowledge obtained from direct analyses on liver with inferences from other model systems. Additionally, we discuss relevant advances in the expanding field of redox signalling. LINKED ARTICLES: This article is part of a themed section on Chemical Biology of Reactive Sulfur Species. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.4/issuetoc.

Figure 1

Oxidative modifications of S amino acids. For simplicity, only the species discussed in this review are included. Protein thiols (dark blue S) undergo two electron oxidation to a disulfide (light blue S) or are oxidized to the S‐glutathionylated (light blue S), S‐nitrosothiol (green S), S‐persulfide (green S) or sulfenic acid (green S), which can be further oxidized to the sulfinic acid (red S) and sulfonic acid (purple S) by subsequent reactions with H₂O₂. Thioethers, like in Met, have the same S‐redox state as thiols (dark blue S) and can be oxidized to the S‐sulfoxide (Met‐O).

Figure 2

Disulfide reductases of the eukaryotic cell. The various disulfide reductase systems are shown in each major organelle. Also represented is the trafficking of cytosolic GSH to all compartments and the GSH : GSSG ratios for each compartment. The NADPH‐independent disulfide reductase pathway is shown in the lower left of the panel, demonstrating the conversion of Met to Cys and subsequently GSH. Green and red arrows represent reductive and oxidative processes, respectively; black arrows depict molecular trafficking. See text for more details.

Figure 3

Prxs in catalysis, over‐oxidation and signalling. Peroxidase activity, over‐oxidation (loss of peroxidase activity) and signalling are each likely to be initiated by the rapid reaction between H₂O₂ and a reduced Prx (blue circle) to form a sulfenic acid. In the catalytic cycle (top, blue panel), the reaction of the SOH with a ‘resolving’ Cys on a second reduced Prx yields an intermolecular disulfide and H₂O, and the disulfide is subsequently reduced by Trx or Grx. In severe oxidative stress (middle, red panel), it is proposed that the sulfenic acid can be over‐oxidized by H₂O₂, yielding sulfinic or sulfonic forms respectively. The sulfinic form can be repaired by sulfiredoxin to a thiol, whereas the sulfonic form is considered irreparable (Biteau et al., 2003). The over‐oxidized forms, however, might have other functions in cells (Chae et al., 2012). In signalling (bottom, yellow panel), Prx‐SOH is proposed to induce a disulfide on a redox‐regulated target protein (green pentagon), such as STAT3.

Figure 4

Hepatic transsulfuration and H₂S generation. Upper panel (blue) depicts transsulfuration in which homocysteine and serine are converted into Cys and pyruvate. In the lower panel (yellow), transsulfuration of Cys or cystine yields cystathionine and H₂S or α‐ketobutyrate and Cys persulfide, respectively, which is converted to Cys and H₂S. Each carbon backbone and reactive S is colour coded, so the fate of each amino acid and each S can be followed.