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Hematology 425, RBC Metabolism, Hgb and Iron

Hematology 425, RBC Metabolism, Hgb and Iron. Russ Morrison October 3, 2006. RBC Metabolism, Hgb and Iron. The RBC survives for approximately 120 days through the process of glycolysis

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Hematology 425, RBC Metabolism, Hgb and Iron

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  1. Hematology 425, RBC Metabolism, Hgb and Iron Russ Morrison October 3, 2006

  2. RBC Metabolism, Hgb and Iron • The RBC survives for approximately 120 days through the process of glycolysis • The main function of the RBC is transport of oxygen and CO2 to and from the tissues – this function does not require consumption of energy (ATP) • RBCs lack a nucleus and other organelles and can not utilize proteins and lipids for energy – they obtain energy only from carbohydrates through the EM pathway

  3. RBC Metabolism, Hgb and Iron • RBC Process which Require Energy • Maintenance of intracellular cationic electrochemical gradients (Na+, K+, Ca+ pump and equilibrium) • Maintenance of membrane phospholipid • Maintenance of skeletal protein plasticity • Maintenance of ferrous hemoglobin • Protection of cell proteins from oxidative denaturation

  4. RBC Metabolism, Hgb and Iron • RBC Process which Require Energy • Initiation and maintenance of glycolysis • Synthesis of glutathione • Mediation of nucleotide salvage reactions

  5. RBC Metabolism, Hgb and Iron • RBC energy is stored and available as ATP, ADP and AMP – review structure & calorie “bank” • Glycolysis generates ATP from ADP and ATP is the greatest reservoir of energy in the RBC • 15% of ATP production is consumed through membrane exchange pathways that allow maintenance of Na+, K+, Ca+ levels • High K+ and low Na+ and Ca+ intracellularly and low K+ and high Na +and Ca+ extracellularly. • If deprived of ATP energy, cation balance goes awry, the RBC swells and is destroyed

  6. RBC Metabolism, Hgb and Iron • Plasma glucose enters the RBC glucose catabolic process through facilitated membrane transport. • 90-95% of glucose consumption is anaerobic through the EM pathway. • Through the EM pathway, glucose is metabolized to lactic acid using 2 ATP and generating 4 ATP molecules per molecule of glucose for a net gain of 2 ATP.

  7. RBC Metabolism, Hgb and Iron • A diversion shunt off the EMP (Luebering-Rapaport pathway) provides 2,3-BPG. • 2,3-BPG regulates O2 delivery to tissues • The methemoglobin reductase pathway, another EMP bypass, produces NADH • NADH helps maintain hemoglobin in the functionally reduced state.

  8. RBC Metabolism, Hgb and Iron • 5-10% of glucose consumption occurs through aerobic glycolysis through another diversion pathway – hexose monophosphate pathway. • The hexose monophosphate pathway provides a pool of reduced glutathione to combat potential oxidant injury to the RBC

  9. RBC Metabolism, Hgb and Iron • The enzyme deficiency in the EMP responsible for most cases of hereditary nonspherocytic hemolytic anemia is pyruvate kinase • The enzyme within the hexose monophosphate pathway that is most likely to give rise to deficient HMP function is G-6-PD

  10. RBC Metabolism, Hgb and Iron Hemoglobin • The Hgb molecule consists of four heme groups and two pairs of UNLIKE polypeptide chains • Hgb is the main component of the red blood cells, its concentration within the red blood cells is around 34 g/dL • Hgb is a red pigment with mw of 68,000 daltons • The vehicle for O2 transport in the body

  11. RBC Metabolism, Hgb and Iron • See figure 9-2 of text • Heme consists of a ring of carbon, hydrogen and nitrogen (protoporphyrin IX) with an atom of ferrous (Fe2+) iron attached, entire structure is called ferroprotoporphyrin. • Each heme group is positioned in a pocket of the polypeptide chain near the surface of the Hgb molecule. • Heme combines reversibly with one O2 molecule • Heme gives blood its red pigment

  12. RBC Metabolism, Hgb and Iron • The globin of the hemoglobin molecule is made up of two pairs of polypeptide chains • Chains are 141-146 amino acids each • Variations in the amino acid sequence give rise to different types of polypeptide chains • Each type of polypeptide chain is designated by a Greek letter

  13. RBC Metabolism, Hgb and Iron

  14. RBC Metabolism, Hgb and Iron • See figure 9-3each polypeptide chain is divided into eight helices and 7 nonhelical segments • Helices are designated A to H and are rigid and linear • Nonhelical segments are more flexible and lie between the helical segments, designated NA, CD, etc. through HC

  15. RBC Metabolism, Hgb and Iron • Globin chains are looped to form a cleft pocket for heme • Heme is suspended between the E and F helices • The Fe at the center of the protoporphyrin IX ring forms a bond with F8 and through the linked oxygen with E7 • Amino acids in this cleft are hydrophobic and each chain contains a heme group with iron positioned between two histidine radicals

  16. RBC Metabolism, Hgb and Iron • Amino acids on the outside of the cleft are hydrophilic, making the molecule water-soluble • The arrangement of amino acids also helps iron stay in the ferrous form • The complete hgb molecule is spherical, has 4 heme groups attached to 4 polypeptide chains and may carry up to 4 oxygen molecules

  17. RBC Metabolism, Hgb and Iron • The biosynthesis of heme takes place in the mitochondria and cytoplasm of the RBC precursors from pronormoblast to reticulocyte in the bone marrow. • Mature RBCs can not make hgb because they have no mitochondria and lose the capability of using the tricarboxylic acid cycle necessary for hgb synthesis

  18. RBC Metabolism, Hgb and Iron • Assembly of heme occurs at the mitochondria where protoporphyrin IX is built. • Transferrin carries iron in the ferric (Fe3+) form to developing RBCs • Fe goes through the RBC membrane to the mitochondria and is united with protoporphyrin IX to make heme • Heme leaves the mitochondria and is joined to globin chains in the cytoplasm.

  19. RBC Metabolism, Hgb and Iron • 6 genes control synthesis of 6 globin chains • Alpha and zeta genes are on C16 • Gamma, beta, delta and epsilon genes are on C11 • Each set of single chains is synthesized in equal amounts at the ribosomes • Globin chains are released from the ribosomes into the cytoplasm

  20. RBC Metabolism, Hgb and Iron • In the cytoplasm, globin chains bind hemes and then pair off • An alpha chain and non-alpha chain combine to form dimers • 2 dimers combine to form tetramers, completing the hemoglobin molecule • 2 alpha and 2 beta chains in a Hgb molecule is called HgbA • 2 alpha and 2 delta is Hgb A2, while 2 alpha and 2 gamma is HgbF. • Globin chains exhibit different charge and may be separated electrophoretically

  21. RBC Metabolism, Hgb and Iron • Progression of Hgb Production – see figure 9-6 and table 9-2 • Hemoglobin F, predominant in-utero, has a higher affinity for oxygen and is able to “extract” oxygen across the placenta from the mother to the fetus

  22. RBC Metabolism, Hgb and Iron • A modified form of hemoglobin A is formed by postsynthetic, nonenzymatic reactions of sugars with amino groups of the globin chains, Hgb A1. • The most common form of modified Hgb A1 is Hgb A1c in which glucose is added to the N terminus of the beta chain. • Hgb A1c is normally 4-6% of Hgb A and is an important marker in management of diabetes (A1c becomes increased and reflects management during span of RBC life cycle)

  23. RBC Metabolism, Hgb and Iron • Regulation of hemoglobin production • Regulation of heme takes place in the heme production pathway • Rate limiting step is thought to be the initial formation of aminolevulinic acid (ALA) • ALA synthesis is inhibited by heme leading to decreased heme production (negative feedback) • Other feedback mechanisms may play a role

  24. RBC Metabolism, Hgb and Iron • Regulation of hemoglobin production • Globin production is regulated by the rate at which the DNA code is transcribed to mRNA • The amount of globin produced is proportional to the amount of mRNA • Heme (hemin) controls the rate of globin synthesis in intact reticulocytes and in its absence, globin production decreases • Normal mature RBCs contain complete Hgb molecules and pools of free heme or free globin chains are minute.

  25. RBC Metabolism, Hgb and Iron • Hgb synthesis is stimulated by tissue hypoxia • Hypoxia causes the kidneys to produce increased EPO which in turn stimulates production of Hgb and RBCs • Hgb Reference ranges adult male 14.0-18.0 g/dL adult female 12.0-15.0 g/dL newborn 16.5-21.5 g/dL

  26. RBC Metabolism, Hgb and Iron • The function of Hgb is to bind oxygen readily in the lung, transport oxygen, and unload oxygen in the tissues • The affinity of Hgb for oxygen depends on pH, 2,3 BPG, pCO2, temperature, Hgb variants. • Review oxygen dissociation curve, figure 9-7 • Shifts in the oxygen dissociation curve due to pH is known as the Bohr effect.

  27. RBC Metabolism, Hgb and Iron • Iron • Iron is essential for sustained life in all living organisms except Lactobacillus and Bacillus species. • Most functional iron in humans is in hemoglobin or myoglobin,, which carry oxygen • About one fourth of iron is in a storage form

  28. RBC Metabolism, Hgb and Iron • Functions of iron • Carrier of electrons used to bind with cofactors essential to basic metabolic oxidative and reductive reactions • Catalyst for oxygenation, hydroxylation and other metabolic processes • Ability to cycle between ferrous and ferric forms makes iron useful in many biochemical reactions

  29. RBC Metabolism, Hgb and Iron • Iron must be carefully regulated due to its potential toxicity • Regulation is complex to preserve iron needed, while not allowing toxicity • Too little iron causes cellular functions to be suboptimal • Too much iron may produce organ damage and death

  30. RBC Metabolism, Hgb and Iron • Iron status is dependent on iron intake, iron bioavailability and iron losses • We have mechanisms for absorbing dietary iron efficiently, but not for eliminating excess iron effectively • Understanding of molecular mechanisms involved in iron metabolism are just beginning to be understood

  31. RBC Metabolism, Hgb and Iron • Iron is obtained through dietary means via heme (Fe2+), organic and nonheme (Fe3+), inorganic iron. • More iron is absorbed from the heme form of iron (meats) than from the nonheme form (legumes and leafy vegetables). • 5-35% of heme iron is absorbed from a meal, while 2-20% of nonhem iron will be absorbed.

  32. RBC Metabolism, Hgb and Iron • Maximal absorption of iron takes place in the duodenum and the jejunum. • Iron from food must be in the ferrous form to be bound to the enterocytes of the mucosal epithelium where it is internalized. • Review figure 10-1

  33. RBC Metabolism, Hgb and Iron • Once absorbed, iron is transported in plasma bound to a carrier protein, transferrin. • Transferrin receptors located on all cells in the body (except mature RBCs), aid in providing transferrin-bound iron access into cells and also play a critical role in the release of iron from transferrin within the cell. • IRE-BP regulates the amoount of transferrin, transferrin receptor and ferritin in the body. • The transferrin gene is on C3

  34. RBC Metabolism, Hgb and Iron • Ferritin and hemosiderin are storage forms of iron. • Most storage of iron is in the ferritin form, a water-soluble complex. • Hemosiderin is water-insoluble, made up of ferritin aggregates and found in macrophages in the bone marrow and liver.

  35. Laboratory Assessment of Iron

  36. Additional Laboratory Tests • Bone Marrow or liver biopsy with specific staining and qualitative/semi-quantitative assessment of available/stored iron. • In BM, the type of iron in macrophages is hemosiderin, the degenerative product of ferritin molecules that have been incorporated into lysosomes of the macrophagees. • Reticulocytes in the bone marrow that contain iron are termed siderocytes. • Serum transferrin receptor analysis • Red cell protoporphyrin test

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