RBC Metabolism - Pentose Phosphate Pathway - Glucose Transporters - PDF

HMIM224 Block SEM 242 Metabolism of RBCs  Objectives 1- Understanding the general structural & functional features of red blood cells (RBCs). 2- Recognizing the main metabolic pathways occurring in RBCs with reference to their relations to functions of RBCs. 3- Ide...

HMIM224 Block SEM 242 Metabolism of RBCs  Objectives 1- Understanding the general structural & functional features of red blood cells (RBCs). 2- Recognizing the main metabolic pathways occurring in RBCs with reference to their relations to functions of RBCs. 3- Identifying some of the main & common diseases of RBCs as implication of defects of RBCs metabolism. https://next.amboss.com/us/article/WS0PA2?q=erythrocytes %20metabolism#Zd72e24d3a032aab08560121f9540cc82  Metabolism of RBCs RBCs contain NO Nucleus (No nucleic acids, DNA & RNA) RBCs can NOT Reproduce, RBCs contain NO Cell Organelles ( mitochondria, Golgi, ER, Ribosomes & Lysosomes) NO Synthetic Activities: NO Protein Synthesis, NO Lipid Synthesis, NO Carbohydrate Synthesis A In adults, cells are produced in the bone marrow and circulate for ~ 120 days. Disorders of red blood cells include anemia, polycythemia, and hemolysis.  Metabolism of RBCs cont. RBCs contain NO Mitochondria so there is NO Oxidation of Fatty acids or Ketone Bodies or NO Citric Acid Cycle, CAC (Tricarboxylic Acid Cycle, TCA) NO Respiratory Chain (electron transport chain) Energy in the form of ATP is obtained ONLY from the glycolytic breakdown of glucose with the production of lactate (2 ATP) (Anaerobic Glycolysis) ATP produced being used for : 1. keeping the biconcave shape of RBCs 2. Regulation of transport of ions & water in and out of RBCs  Glucose Transport Through RBC Membrane Glucose is transported through RBC membrane glucose by facilitated diffusion using glucose transporters-1 (GLUT-1) Glucose Transporters-1 (GLUT-1) are independent on insulin i.e. insulin does not promote glucose transport to RBCS  1- Anaerobic Glycolysis in RBCs  Glucose is metabolized in RBCs through Anaerobic Glycolysis (that requires no mitochondria and no oxygen)  One Molecule of Glucose yields 2 ATP Molecules by one anaerobic glycolytic pathway  In addition to production of 2 Molecules of Lactate.  Lactate is transported to blood & in the liver it is converted to glucose (Cori Cycle) Anaerobic Glycolysis Importance of glycolysis in red cells:  ATP Energy production: It is the only pathway that supplies the red cells with ATP.  NADH for Reduction of methemoglobin: Glycolysis provides NADH for reduction of metHb by cytochrome b5 reductase )Cytochrome b5 reductase(  In red cells 2,3 bisphosphoglycerate (2,3 BPG) binds to Hb, decreasing its affinity for O2, and helps its availability to tissues.  Synthesis of 2,3 BisphosPhoGlycerate (2, 3 BPG) In RBCs, some of glycolysis pathways are modified so that 2, 3 Bisphosphoglycerate is formed (by Bisphosphoglycerate Mutase). (2, 3 BPG) binds to DeoxyHb stabilize the tense state (T state) of Hb , decrease affinity of hemoglobin for oxygen and favors release of O2 to the peripheral tissues. So, it helps oxyhemoglobin to unload oxygen. This is required in cases of hypoxia & high altitudes. )2,3BPG(  Genetic Defects in Enzymes of Glycolysis Genetic defects of one of the enzymes of glycolysis in RBCs results in a reduced rate of glycolysis in RBCs & by this way will deprive RBCs of the only means for producing energy (ATP). As a result, congenital chronic hemolytic anemia will be a consequence as RBCs will not be able to keep the biconcave flexible shape which allows it to squeeze through narrow capillaries with an end result of hemolysis (destruction of RBCs). Blood film shows dysmorphic RBCs called ecchinocytes 95% of genetic defects in glycolytic enzymes is caused by pyruvate kinase deficiency  RBCs membrane structure RBCs must be able to squeeze through some tight spots in microcirculation (capillaries). For that RBCs must be easily & reversibly deformable. Its membrane must be both fluid & flexible. RBCs membrane comprises a lipid bilayer (which determine the membrane fluidity), proteins (which is responsible for flexibility) that are either peripheral or integral penetrating the lipid bilayer & carbohydrates that occur only on the external surface. The membrane skeleton is four structural proteins that include  &  spectrin, ankyrin, protein 4.1 & actin. Defects of proteins leads to abnormalities of shape of RBCs membrane as hereditary spherocytosis & elliptocytosis.  2- Pentose Phosphate Pathway (PPP) or Hexose Monophosphate Pathway (HMP) An alternative oxidative pathway for glucose Occurs in the cytosol of many cells of the body including RBCs Importance in RBCs: No ATP production. NADPH production (PPP is the only source for NADPH in RBCs). Ribose-5-phosphate production for adenine nucleotide synthesis.  Uses of NADPH in Normal Cellular Metabolism 1. Lipids Synthesis : fatty acid, cholesterol, steroids & sphingolipids 2. Methemoglobin Reduction to hemoglobin NADPH methemoglobin reductase (minor pathway) 3. Nitric oxide Synthesis 4. Phagocytosis by oxygen-dependent by WBCs (macrophages) 5. Antioxidant Mechanisms (part of Glutathione system ) NADPH reduces oxidized glutathione and in RBCS, Glutathione is needed in reduced form for: Glucose 6- phosphate dehydrogenase deficiency (G6PD Deficiency): G6PD is the first enzyme of pentose phosphate pathway (PPP). Its deficiency leads to reduced production of NADPH ending in Acute