Structure of hemoglobin molecule:
Hemoglobin is synthesized in adults in the bone marrow, but during fetal life, it is synthesized in the liver and spleen . The mammalian hemoglobin has a molecular weight of approximately 65,000. The normal adult hemoglobin is of type A , which contains two α- and two β- globin chains. The α- chain contains 141 amino acids and β- chain contains 146 amino acids . Fetal hemoglobin ( HbF ) contains two α- and two γ- globin chains. The γ- chains contain approximately the same number of amino acids as β- chain. HbA2 contains two α and two γ, δ chains and it is present in normal adult blood in a ratio of 1.3 – 3 % of total normal hemoglobin.The capacity of Hb to bind O2 depends on the presence of a bound prosthetic group called heme. The heme is the red color of blood. The heme group consists of an organic component ( protoporphyrin ) and a central iron atom. The protoporphyrin is made of four pyrrole rings. Four methyl groups , two vinyl groups and two propionate side chains are attached .
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Pyrrole
The iron atom lies in the center bounded to the four nitrogen atoms. Normally Fe+2 has six coordination sites. The fifth site is occupied by the imidazole ring of histidine residue from the prot. In deoxy Hb, the 6th site remains unoccupiedHemoglobin molecule is spherical and there is interaction between α- and β- chains. The four chains are arranged in a helical A-H structure ( or form ) besides the interhelical regions. The globin chains are arranged in such a way that polar amino acids are on the external surface of the molecule and the non polar are to the inside , e.g. for non polar amino acids : leucine, valine, methionine and phenylalanine , but amino acids having both polar and nonpolar ( tyrosine, tryptophan, and thrionine ) are arranged so that the polar groups are on the outside and the nonpolar group on the inside with the exception of the histidine, which is polar and present in the interior part ( 2 histidines: the proximal F8 is above the plane of heme, and the distal histidine E7 is below the plane ).
The distal histidine surrounds and protects the six coordination positions from oxidation . So, it is vital for maintaining life (iron remains in the ferrous state ) . Distal histidine also decreases the binding of CO to hemoglobin about hundred time.
Binding affinity of hemoglobin to oxygen is also affected by the presence of organic phosphate as 2,3 – diphosphoglycerate ( 2,3 DPG ) .It stabilizes the T or deoxygenated form of Hb by crosslinking the β chains and forming additional salt bridges that must be broken prior to formation of R form. 2,3 DPG presence causes reduced affinity of hemoglobin to oxygen and more delivery of oxygen to the tissues. 2,3 DPG is also known as 2,3 – bisphosphoglycerate ( 2,3 BPG ). It is a highly ionic compound. It is present in the RBC at approximately the same concentration as that of Hb . without 2,3 – BPG , Hb would be extremely inefficient O2 transporter , releasing only 8% of its O2 in the tissues. 2,3 – DPG binding to Hb has another important physiological role in transport of O2 from mothers ( maternal adult HbA ) to fetus blood ( fetal Hb ) HbA 2α 2β HbF 2α 2 γ
Oxy & deoxyhaemoglobin
T-conformation: lower affinity to O2 (deoxy Hb)R-conformation: higher affinity to O2 (oxyHb) T RHb + O2 HbO2
DPG binds more weakly to HbF than to adult HbA . In HbF ,γ globin chain is about 72% identical to β globin chain of HbA . One important difference is the substitution of serine for histidine 21 in the β chain ( this is the binding site of 2,3, DPG ) . This change removes 2 positive charges from the 2,3, DPG binding site ( one from each chain ) and reduces affinity of 2,3 – DPG for fetal Hb, thereby increasing the oxygen binding affinity of HbF relative to that of maternal ( HbA ) . This difference in affinity allows O2 to be transferred from mother to fetus.
Abnormal hemglobins: Hemoglobinopathies:
Since α,β,γ and δ chains of the globin moiety of the hemoglobin are synthesized from amino acids under genetic control as are other body proteins, occasional errors in their formation are to be expected. However, the occurance of such errors results in abnormal hemoglobins in humans. Structural changes in the globin chains of hemoglobin may result in alteration in one or more of the following properties:Solubility, as in case of HbS. HbS contains two α- and two β- chains but at position 6, valine replaces glutamine. In HbC , also in the β- chain at position 6, lysine replaces glutamine. So , the change in composition of globin chains will lead to inherited disorders called hemoglobinopathies.
The common symptoms are anemia and muscular fatigue due to failure of proper oxygenation. Abnormal hemoglobins may be classified into two general types as follows… Those where there is altered combination and absence of complete chain, e.g. α and β- thalassemia. Those where there is altered sequence of amino acids e.g. HbS and HbC .
Hemoglobinopathies Examples: 1- Sickle cell disease "HbS": Normally there is 2-α and 2-β globin chains in HbA, but glutamine is replaced by valine at position 6 of β chain, causing decrease in solubility of Hb and increase affinity of Hb to oxygen causing tissue hypoxia and sickling RBCs leading to hemolytic anemia. RBCs survival time is 30 days instead of 120 days .
2- α- Thalassemia : ": also called " thalassemia minor " In this condition HbH which contains 4 β- chains caused by defective synthesis of α- chains production of insoluble Hb 3- β- Thalassemia : or : thalassemia major ": It is common in our country " Iraq" HbF present which contains 2α and 2γ chains. It's caused by failure to switch from synthesis of γ chain to β- chain at birth, resulting in production of HbF which has abnormal affinity to O2 resulting in anemia and if not treated severe anemia will develop, jaundice as well as liver and spleen enlargement.
4- Methemoglobinemia: When HbM is present , proximal or distal histidine is replaced by tyrosine in this case. So protection of iron in hemoglobin in ferrous state will be lost leading to oxidation of iron to ferric state. So, Hb will lose ability to transport O2 and the condition is called methemoglobinemia. 5- Riverdale hemoglobinemia : There is altered tertiary structure of helical folding of globin around the heme leading to unstable hemoglobin. F - helix over B- helix will be lost in globin molecules causing early breakdown of hemoglobin and hemolysis then anemia will occur. 6- Gunhill hemoglobinemia: There is deletion of 5 amino acids, the last amino acid in F-helix and the 1st four amino acids in the FG-interhelix causing abnormal folding and abnormal Hb. Hemolysis and anemia will occur.
Various forms of hemoglobin:1- Oxyhemoglobin : (HbO2 ) or fully oxygenated hemoglobin:Iron will be in ferrous state ( Fe+2 ).2- Deoxy hemoglobin: or " reduced hemoglobin “It is Hb not combined with O2 . Also iron in reduced form ( Fe+2 ) . 3- Methemoglobin :Iron is in ferric state " Fe+3 " . It is either congenital abnormal Hb or due to presence of oxidizing agent like potassium ferricyanide, or potassium cyanide .4- Carboxy hemoglobin :The iron is in ferrous state , it is Hb combined with CO2.5- Cyanmethemoglobin :It is a compound produced in the determination of Hb in blood due to using drabkin's solution.
BLOOD CELLS
LIVERBilirubin diglucuronide (water-soluble)
2 UDP-glucuronic acid
via bile duct to intestines
Stercobilin excreted in feces
Urobilinogen formed by bacteria
KIDNEY
Urobilin excreted in urineCO
Biliverdin IX Heme oxygenase
O2
Bilirubin (water-insoluble)
NADP+
NADPH
Biliverdin reductase
Heme
Globin
Hemoglobin
reabsorbed into blood
Bilirubin (water-insoluble)
via blood to the liver
INTESTINE
Figure 2. Catabolism of hemoglobin