Red Cells Metabolism and Glycolysis PDF

RED CELLS METABOLISM AND GLYCOLYSIS The mature red cell does not possess a nucleus nor cytoplasmic subcellular structure as microsomes or mitochondria. This renders the red cell devoid of certain cycle characteristics of the other cells such as Krebs cycle, respiratory chain,… etc....

RED CELLS METABOLISM AND GLYCOLYSIS The mature red cell does not possess a nucleus nor cytoplasmic subcellular structure as microsomes or mitochondria. This renders the red cell devoid of certain cycle characteristics of the other cells such as Krebs cycle, respiratory chain,… etc. In fact the red cells nearly depends on glycolysis for covering all of its metabolic activities. However a number of hydrolytic enzymes e.g. some peptidases, ATPase and cholinesterase are present, in a rather inactive form in the intact cell, as they are bound to lipoprotein matrix of red cell stroma. Rapaport-leubering (R-L cycle) of red cells: This is a characteristic cycle present in red cell of man and some other mammals It is supplementary to glycolysis and starts as a side pathway from it at the triose phosphate level. The importance of the cycle can be shown from the fact that the red cell produce energy in high amounts which far exceeds its need (due to absence of metabolic cycles that need energy in red cells). The Rapaport-luebering cycle therefor serves as a mechanism for dissipation (or wasting) the excess energy not needed fir red cells. The cycle is actually a 2-step system that originates from 1,3 diphosphoglyceric of glycolysis as follows: 1) 1,3diphosphoglyceric mutase 2,3diphosphoglyceric. 2) 2,3diphosphoglyceric phosphatase 3-phosphoglyceric. p Dr. Somaia Negm 1  3-phosphoglyceric can then proceed in the cycle as in ordinary glycolysis. By this cycle the high energy phosphate in position 1 of 1,3diphosphoglyceric is lost by conversion to 2,3diphosphoglyceric (the phosphate group at carbon 2 of 2,3diphosphoglyceric is low energy phosphate). Importance of 2,3 diphosphoglyceric (2,3 DPG) to red cell: 1) 2,3diphosphoglyceric produced by R-L in the red cells plays an important role in dissociation of oxygen from oxyhemoglobin. This is because when organic phosphates (as 2,3diphosphoglyceric) bind to hemoglobin, it results in a decrease of affinity of hemoglobin molecule to oxygen i.e. increase oxygen dissociation and delivery to tissues. 2) Tissue hypoxia has an important effect on the level of red cell 2,3diphosphoglyceric. So in case of hypoxic, stagnant hypoxia, and anemia hypoxia there is as an increase in red cell organic phosphate of oxygen from hemoglobin to tissues. 3) In person suffering from pyruvate kinase deficiency (a congenital disease) there is accumulation of 2,3diphosphoglyceric and so affinity of hemoglobin to oxygen is less than normal in such conditions. 4) In the rare disease, hexokinase deficiency there is a decrease of 2,3diphosphoglyceric to two third of normal, so affinity of hemoglobin to oxygen is greater than normal. Dr. Somaia Negm 2 Pyruvate kinase deficiency: This is a hereditary disease characterized by the presence of hemolytic anemia that result from congenital deficiency of pyruvate kinase enzyme in red cell. Pyruvate kinase step is one of few sources of red cell energy by glycolysis. So there be shortage of the energy supply to red cell resulting in failure to maintain ell wall integrity with ionic imbalance leading to cell hemolysis. The disorder is transmitted as an autosomal recessive trait and is found predominantly in people of northern European stock. Red cells become rigid and deformed and peripheral blood shows features or hemolysis with relatively marked reticulocytotsis and many piokilocytosis and distorted cells (spherocytes are not common). Late gall bladder-stone and hemosiderosis from multiple blood transfusion will occur. Treatment is by repeated blood transfusion and splenectomy if the transfusion requirements increase. Control and regulation of glycolysis: In metabolic pathways, enzymes catalyzing essentially irreversible reactions are actually the potential sites for regulation. In fact glycolysis can be considered as an amphibolic cycle i.e. serves an anabolic as well as catabolic cycle. By the catabolic route glucose is degraded and ATP is generated. On the other hand by its anabolic pathway pyruvic acid is converted to active acetate, and this later compound is used for synthesis (anabolism) of fatty acid. Dr. Somaia Negm 3  In glycolysis, the three irreversible reactions catalyzed by hexokinase, phosphofructokinase and pyruvate kinase, are the most important regulatory sites for glycolysis: A. Phosphofructokinase reaction: This the most important control site in glycolysis. The inhibitory factors for phosphofructokinase (and so glycolysis will be inhibited include): 1. ATP excess (because there is no need for more energy production. Citrate excess: citric acid is formed by combination between active acetate (produced from pyruvic) and oxaloacetic acid (Krebs cycle). So the presence of high citrate level means that there is excess active acetate (produced from pyruvic) and so there is no need for more pyruvic acid production through glycolysis. The stimulatory factors include: - High level of AMP (or lowered ATP\AMP ratio). This means that glycolysis is stimulated when the energy of cell (ATP) is low (as indicated by high AMP level). - High level of fructose 2,6diphosphate. This is the most important regulatory factor. This compound was recently discovered and was found to be a potent stimulant for phosphofructokinase enzyme. It acts like AMP in an allosteric manner - Low level of citrate: meaning that there is an increased need for active acetate (the building block for citrate and fatty acid synthesis, again note that active acetate is produced from pyruvic acid, that is produced by glycolysis) Dr. Somaia Negm 4 B. Hexokinase reaction: This reaction is allosterically inhibited by glucose-6-phosphate. When phosphofructokinase is blocked, the level of fructose-6- phosphate will be increased resulting in accumulation of glucose-6- phosphte and the later will produce allosteric inhibition of hexokinase. So inhibition of phosphofructokinase by high level of ATP or by excess citrate, will further result in inhibition of hexokinase (by the accumulated by glucose-6-phosphate). C. Pyruvate kinase reaction: This also inhibited by excess ATP in the cell. Also it was recently found that it is regulated by phohosohorylation- dephosphorylation reactions where the phosphorylated form is inactive, and the dephosphorylated form is the active form. N.B: 1. Phosphofructokinase is considered as the pace-maker of glycolysis. 2. The reason why phosphokinase is much more important regulatory site for glycolysis rather than the hexokinase reaction is that: glucose- 6-phosphate is an intermediate for other cycles (e.g. pentose shunt, glycogenesis,….etc.) beside glycolysis, and so inhibition of hexokinase will result in inhibition of many other cycles. On the other hand the first irreversible reaction unique (characteristic) for glycolysis is the phosphofructokinase reaction. So alteration of phosphofructokinase activity will result in alteration of activity only cycle, that is glycolysis. Dr. Somaia Negm 5