Point Mutations That Reduce Erythrocyte Resistance to Oxidative Stress

Oxygen transport is a primary goal of erythrocytes. The high maintenance of oxygen in erythrocytes defines high speed of formation of active forms of oxygen – superoxide (O2⎯), a hydrogen peroxide (H2O2) and a hydroxyl radical (·OH). A constant source of active forms of oxygen in erythrocytes is hemoglobin oxidation in a methemoglobin with formation of superoxide (O2⎯). Therefore erythrocytes should have a powerful antioxidant system, which prevents the toxic action of active forms of oxygen on hemoglobin and erythrocyte membrane. Mature erythrocytes have neither cytoplasmic organelles nor a nucleus and consequently are not capable to synthesize proteins and lipids, to carry out oxidative phosphorylation or to maintain tricarboxylic acid cycle reactions. The energy of erythrocytes comes for the most part from anaerobic glycolysis – via the Embden-Meyerhof-Parnas pathway (EMP pathway). Thus, glucose catabolism provides preservation of structure and function of hemoglobin, integrity of an erythrocyte membrane and formation of energy for the work of ionic pumps. Anaerobic glycolysis in itself is a power-consuming process. Glucose arrives in erythrocytes by the facilitated diffusion by glucose transporter type 1. Hexokinase is the first enzyme of EMP pathway, it provides glucose phosphorylation. Further during consecutive reactions with participation of glucose-6-phosphate isomerase, phosphofructokinase, aldolase, glyceraldehydes 3-phosphate dehydrogenase, phosphoglycerate kinase, phosphoglycerate mutase, enolase, pyruvate kinase one molecule of glucose gives 4 molecules of adenosine triphosphate (ATP) and 2 molecules of restored nicotinamide adenine dinucleotide (NADH), and at the same time, 2 ATP molecules are spent at the initial stage of EMP pathway. A certain quantity of glucose with formation of restored compounds – glutathione (GSH) and nicotinamide adenine dinucleotide phosphate (NADPH) is taken away through pentose phosphate pathway (aerobic glycolysis). Glucose6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase provide the stages of pentose phosphate pathway. The hydroxyl radical, the most active component of oxidative stress, is neutralized by GSH. Methemoglobin reductase restores a methemoglobin into hemoglobin, NADPH being the donor of hydrogen, which is formed in EMP pathway and NADPH is in its turn formed in pentose phosphate pathway. Superoxide dismutase 1 enzyme contributes superoxide (O2⎯) to turn into hydrogen peroxide. The hydrogen peroxide is destroyed by catalase and glutathione peroxidase, GSH being the donor of hydrogen. Peroxiredoxin 2 is an antioxidant enzyme that uses cystein residues to