The Hemoglobin molecule Major oxygen-carrying pigment of the body, 90% of the dry weight of the red cell

The primary globin chains in the adult, alpha, beta Haemoglobin tetramer- aplha2beta2 Each chain is non-covalently bound to a single heme group in its hydrophobic pocket Haemoglobin has 4 heme groups, can bind to 4 oxygen The globin polypeptides are synthetised in erythropoietic cells. Selective expression of genes on chromosomes 16 and 11- result of sequential activation and inactivation Alpha gene family on chromosome 16-3 genes- one zeta(), 2 alpha(1 and 2(identical)) Beta gene family on chromosome 11- 5 genes-epsilon(, expressed in the embryo) , two gamma(), delta () gene; and the beta () gene Heme also controls globin synthesis- iron deficiency, redued hem synthesis, reduced globin chain production(microcytic red cells) The earliest embryonic hemoglobins synthesized by the erythroblasts in the yolk sac and liver are 22(Gower 1), 22 (Portland), followed by 22(Gower 2) 12 week embryo- 22 (HbF), synthetized in the yolk sac and liver(in the erythroblasts) Adult beta chain is synthetized in the spleen and bone marrow (in the erythroblast) At birth 25%is HbA, rest is HbF In adult- HbF and HbA2(22)- 4% Hb interacts with 3 diffusible ligands- o2, Co2, and NO, delivery of O2, elimination of CO2, control of vascular tone by NO pre-mRNA is cut, intervening sequences are excised contiguous sequence of mRNA addition of a CAP and poly A tail mRNA is translated in cytoplasm, globin acquires heme, alpha and beta dimers are formed the tetramer is assembled

Hemoglobin and Oxygen Prototype of an allosteric protein, its structure and function is influenced by other molecules 2,3-BPG major intracellular modulator, decreases Hbs affinity to oxygen, but binds poorly to oxygenated Hb 2 forms- T(taut) and R(relaxed), 2,3-BPG stabilizes the T structure After first oxygen is taken up, the uptake of the next oxygen is facilitated and so on- sigmoid shape of the dissociation curve Hemoglobin and Carbon Dioxide

10% of diffused CO2 binds directly to the amino acid terminus of the globin chain- Carbamino haemoglobin(non enzymatic process) Most of CO2 H2CO3, hydratedHCO3-, H+ H+ is accepted by haemoglobin, reinforcing its T configuration, enhanced O2 release- Bohr effect The anion exchanger protein (AE1),band 3 allows HCO3- to cross the cell membrane for Cl As a result increased CO2 that the blood can deliver to the lungs 80& of CO2 as bicarbonate ion, 10% as carbaminohemoglobin, and 10% in solution Hemoglobin and nitric oxide (NO) Synthesized from arginine by nitric oxide synthases, it is a tent vasodilator In hypoxic venous blood, NO is taken up by the T Hb converted to nitrate In lung Hb takes up oxygen, small fraction of heme bound NO is shifted to the 93beta cysteine residue(highly reactive site), NO binds to a thiol(SH) group on this reside forming S-nitrohemoglobin(SNO-Hb) Oxygen release in tisues RT SNO-Hb is transferred ot of the cell and delivered to the vessel wall, inducing vasodilation and increased blood flow Coordination with O2 maximum tissue oxygenation No- endothelial-derived relaxing factor (EDRF) In hemolysis arginase is released which destroys arhinine NO synthase cant synthesize NOpulmonary hypertension, leg ulcers, priapism, risk of stroke (lactic dehydrogenase is a marker of these complicatuions Oxygen affinity Percentage saturation of haemoglobin at different oxygen tensions is described by the oxygen dissociation curve Heme-heme cooperation- sigmoid curve 100% saturation in the lung , 95Hgmm 75% saturation in the peripheral tissues, 40Hgmm(vebous blood) O2 affintiy- partial pressure at which Hb is half saturated, the p50 (normally 28Hgmm) Myoglobin is a monomer with similar globin, same heme, but lacks of heme-heme interaction and 2,3-BPG participation Very low p50- 1-2mmHg, high O2 affinty, - takes O2 away from Hb and passes it along to the mitochondria O2 dissociation curve is moved to the right as 2,3-BPG binds and pH drops and vica versa HbF binds 2,3-BPG less avidly than does HbA- the curve lies to the left Increased O2 affinity helps moving O2 from the mother to the fetus