Figure 3
Figure 3. Alterations in erythrocyte glutathione (GSH) metabolism in SCD. Normal GSH metabolism: GSH is a potent antioxidant responsible for maintaining cellular redox balance. GSH is synthesized from the amino acids glutamate, cysteine (the rate-limiting substrate), and glycine. Metabolism is catalyzed sequentially by 2 cytosolic enzymes, γ-glutamylcysteine synthetase (γ-GSC) and glutathione synthetase (GS). This pathway occurs in virtually all cells, including erythrocytes, although hepatocytes are the major producer and exporter of GSH. Glutamate and cysteine are catalyzed by γ-GSC to γ-glutamyl-cysteine, which is metabolized to GSH through the actions of GS. GSH is directly oxidized to GSSG during scavenging of free radicals. It is also enzymatically oxidized by glutathione peroxidase (GPx) during the reduction of hydrogen peroxide and other peroxides. GSSG is then reduced and recycled back to GSH by the NADPH-dependent glutathione reductase (GR). During NADH and NADPH biosynthesis, glutamine is converted to glutamate. Although this is a process independent of GSH synthesis, the byproduct of this reaction is used as a substrate for GSH synthesis, while providing the essential co-enzyme for the recycling of GSH from GSSG by NADPH-dependent glutathione reductase.1,9,10 Alterations in GSH metabolism in SCD: Arrows indicate increased substrate and decreased GSH concentrations within the erythrocyte of patients with SCD. Despite more than adequate substrate, including cysteine, the rate-limiting amino acid for GSH production, GSH levels are very low in sickle erythrocytes. Further aberrations in GSH metabolism occur in patients with PH. Most notable is the erythrocyte glutamine depletion that occurs in patients with PH, compared with healthy volunteers and SCD patients without PH, while glutamate levels (significantly higher in SCD patients without PH compared with controls) begin to trend down in SCD patients with PH. Erythrocyte glutamine concentration and the glutamine:glutamate ratio inversely correlate with Doppler echocardiography tricuspid regurgitant jet velocity, a clinical marker of early mortality in SCD.26

Alterations in erythrocyte glutathione (GSH) metabolism in SCD. Normal GSH metabolism: GSH is a potent antioxidant responsible for maintaining cellular redox balance. GSH is synthesized from the amino acids glutamate, cysteine (the rate-limiting substrate), and glycine. Metabolism is catalyzed sequentially by 2 cytosolic enzymes, γ-glutamylcysteine synthetase (γ-GSC) and glutathione synthetase (GS). This pathway occurs in virtually all cells, including erythrocytes, although hepatocytes are the major producer and exporter of GSH. Glutamate and cysteine are catalyzed by γ-GSC to γ-glutamyl-cysteine, which is metabolized to GSH through the actions of GS. GSH is directly oxidized to GSSG during scavenging of free radicals. It is also enzymatically oxidized by glutathione peroxidase (GPx) during the reduction of hydrogen peroxide and other peroxides. GSSG is then reduced and recycled back to GSH by the NADPH-dependent glutathione reductase (GR). During NADH and NADPH biosynthesis, glutamine is converted to glutamate. Although this is a process independent of GSH synthesis, the byproduct of this reaction is used as a substrate for GSH synthesis, while providing the essential co-enzyme for the recycling of GSH from GSSG by NADPH-dependent glutathione reductase.1,9,10  Alterations in GSH metabolism in SCD: Arrows indicate increased substrate and decreased GSH concentrations within the erythrocyte of patients with SCD. Despite more than adequate substrate, including cysteine, the rate-limiting amino acid for GSH production, GSH levels are very low in sickle erythrocytes. Further aberrations in GSH metabolism occur in patients with PH. Most notable is the erythrocyte glutamine depletion that occurs in patients with PH, compared with healthy volunteers and SCD patients without PH, while glutamate levels (significantly higher in SCD patients without PH compared with controls) begin to trend down in SCD patients with PH. Erythrocyte glutamine concentration and the glutamine:glutamate ratio inversely correlate with Doppler echocardiography tricuspid regurgitant jet velocity, a clinical marker of early mortality in SCD.26 

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