Figure 5. Alternative pathways can maintain redox homeostasis in hepatocytes.
(a) In normal hepatocytes, glucose utilization by the pentose phosphate pathway (blue) yields NADPH, which feeds the GSH and Trx1 systems (yellow). These systems maintain cytosolic redox homeostasis, drive RNR, and reduce L-cystine into cysteine. MTS (red) supplies SAM for methylation reactions and provides an alternative source of cytosolic cysteine, which is used for protein- (green) and GSH-synthesis. (b) Concomitant genetic ablation of GR and TrxR1 (red “Ø”) in TR/GR-null livers uncouples glucose oxidation and NADPH from the major disulfide reduction systems. In this case, MTS uses dietary methionine to provide an alternative source of cytosolic cysteine. This cysteine is sufficient to support protein synthesis and to serve as the sole source of cytosolic disulfide reduction power in TR/GR-null livers without the use of NADPH. (c) Balanced reaction for utilization of two electrons of reducing power in TR/GR-null hepatocytes. Gcl, glutamate-cysteine ligase; Gss, GSH-synthase; PPPi, inorganic triphosphate; X, any methyl- (Me-) acceptor for SAM-dependent methyl transferase activity.