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STRUCTURE OF HUMAN OXYHAEMOGLOBIN AT 2.1 ANGSTROMS RESOLUTIONSTRUCTURE OF HUMAN OXYHAEMOGLOBIN AT 2.1 ANGSTROMS RESOLUTION
Structural highlights
Disease[HBA_HUMAN] Defects in HBA1 may be a cause of Heinz body anemias (HEIBAN) [MIM:140700]. This is a form of non-spherocytic hemolytic anemia of Dacie type 1. After splenectomy, which has little benefit, basophilic inclusions called Heinz bodies are demonstrable in the erythrocytes. Before splenectomy, diffuse or punctate basophilia may be evident. Most of these cases are probably instances of hemoglobinopathy. The hemoglobin demonstrates heat lability. Heinz bodies are observed also with the Ivemark syndrome (asplenia with cardiovascular anomalies) and with glutathione peroxidase deficiency.[1] Defects in HBA1 are the cause of alpha-thalassemia (A-THAL) [MIM:604131]. The thalassemias are the most common monogenic diseases and occur mostly in Mediterranean and Southeast Asian populations. The hallmark of alpha-thalassemia is an imbalance in globin-chain production in the adult HbA molecule. The level of alpha chain production can range from none to very nearly normal levels. Deletion of both copies of each of the two alpha-globin genes causes alpha(0)-thalassemia, also known as homozygous alpha thalassemia. Due to the complete absence of alpha chains, the predominant fetal hemoglobin is a tetramer of gamma-chains (Bart hemoglobin) that has essentially no oxygen carrying capacity. This causes oxygen starvation in the fetal tissues leading to prenatal lethality or early neonatal death. The loss of three alpha genes results in high levels of a tetramer of four beta chains (hemoglobin H), causing a severe and life-threatening anemia known as hemoglobin H disease. Untreated, most patients die in childhood or early adolescence. The loss of two alpha genes results in mild alpha-thalassemia, also known as heterozygous alpha-thalassemia. Affected individuals have small red cells and a mild anemia (microcytosis). If three of the four alpha-globin genes are functional, individuals are completely asymptomatic. Some rare forms of alpha-thalassemia are due to point mutations (non-deletional alpha-thalassemia). The thalassemic phenotype is due to unstable globin alpha chains that are rapidly catabolized prior to formation of the alpha-beta heterotetramers. Note=Alpha(0)-thalassemia is associated with non-immune hydrops fetalis, a generalized edema of the fetus with fluid accumulation in the body cavities due to non-immune causes. Non-immune hydrops fetalis is not a diagnosis in itself but a symptom, a feature of many genetic disorders, and the end-stage of a wide variety of disorders. Defects in HBA1 are the cause of hemoglobin H disease (HBH) [MIM:613978]. HBH is a form of alpha-thalassemia due to the loss of three alpha genes. This results in high levels of a tetramer of four beta chains (hemoglobin H), causing a severe and life-threatening anemia. Untreated, most patients die in childhood or early adolescence.[2] [HBB_HUMAN] Defects in HBB may be a cause of Heinz body anemias (HEIBAN) [MIM:140700]. This is a form of non-spherocytic hemolytic anemia of Dacie type 1. After splenectomy, which has little benefit, basophilic inclusions called Heinz bodies are demonstrable in the erythrocytes. Before splenectomy, diffuse or punctate basophilia may be evident. Most of these cases are probably instances of hemoglobinopathy. The hemoglobin demonstrates heat lability. Heinz bodies are observed also with the Ivemark syndrome (asplenia with cardiovascular anomalies) and with glutathione peroxidase deficiency.[3] [4] [5] [6] Defects in HBB are the cause of beta-thalassemia (B-THAL) [MIM:613985]. A form of thalassemia. Thalassemias are common monogenic diseases occurring mostly in Mediterranean and Southeast Asian populations. The hallmark of beta-thalassemia is an imbalance in globin-chain production in the adult HbA molecule. Absence of beta chain causes beta(0)-thalassemia, while reduced amounts of detectable beta globin causes beta(+)-thalassemia. In the severe forms of beta-thalassemia, the excess alpha globin chains accumulate in the developing erythroid precursors in the marrow. Their deposition leads to a vast increase in erythroid apoptosis that in turn causes ineffective erythropoiesis and severe microcytic hypochromic anemia. Clinically, beta-thalassemia is divided into thalassemia major which is transfusion dependent, thalassemia intermedia (of intermediate severity), and thalassemia minor that is asymptomatic.[7] Defects in HBB are the cause of sickle cell anemia (SKCA) [MIM:603903]; also known as sickle cell disease. Sickle cell anemia is characterized by abnormally shaped red cells resulting in chronic anemia and periodic episodes of pain, serious infections and damage to vital organs. Normal red blood cells are round and flexible and flow easily through blood vessels, but in sickle cell anemia, the abnormal hemoglobin (called Hb S) causes red blood cells to become stiff. They are C-shaped and resembles a sickle. These stiffer red blood cells can led to microvascular occlusion thus cutting off the blood supply to nearby tissues. Defects in HBB are the cause of beta-thalassemia dominant inclusion body type (B-THALIB) [MIM:603902]. An autosomal dominant form of beta thalassemia characterized by moderate anemia, lifelong jaundice, cholelithiasis and splenomegaly, marked morphologic changes in the red cells, erythroid hyperplasia of the bone marrow with increased numbers of multinucleate red cell precursors, and the presence of large inclusion bodies in the normoblasts, both in the marrow and in the peripheral blood after splenectomy.[8] Function[HBA_HUMAN] Involved in oxygen transport from the lung to the various peripheral tissues. [HBB_HUMAN] Involved in oxygen transport from the lung to the various peripheral tissues.[9] LVV-hemorphin-7 potentiates the activity of bradykinin, causing a decrease in blood pressure.[10] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedThe structure of human oxyhaemoglobin was determined by single crystal X-ray analysis at 2.1 A resolution. Data were collected on an Arndt-Wonacott camera at -2 degrees C. The structure was refined to an R factor of 0.223 by the Jack-Levitt method, starting from Baldwin's model of human carbon monoxide haemoglobin. The active sites in the alpha and beta subunit are distinct. The iron atoms are 0.16(8) A and 0.00(8) A from the mean plane of the porphyrin carbons and nitrogens (0.12(8) A and -0.11(8) A from the mean plane of the porphyrin nitrogens) in the alpha and beta subunit, respectively, in correlation with the orientation of HisF8 relative to the porphyrin nitrogens. The haem group appears to be nearly planar in the alpha subunit but ruffled in the beta subunit. The Fe-O(1)-O(2) angles are 153(7) degrees and 159(12) degrees in the alpha and beta subunit, respectively. The oxygen molecule forms a hydrogen bond to N epsilon of HisE7 in the alpha, but either none or a weak one in the beta subunit. The following bond lengths were found: Fe-N epsilon (HisF8) = 1.94(9) A (alpha) and 2.07(9) A (beta); Fe-O(1) = 1.66(8) A (alpha) and 1.87(13) A (beta); Fe-Nporph (mean = 1.99(5) A (alpha) and 1.96(6) A (beta). These dimensions agree with the values obtained in oxymyoglobin and model compounds. The C-terminal residues, ArgHC3(141 alpha) and HisHC3(146 beta), are relatively delocalized, and their positions do not enable them to form the intersubunit salt bridges in which they are involved in deoxyhaemoglobin. The penultimate tyrosine residues, TyrHC2 140 alpha and 145 beta, are relatively localized and maintain the hydrogen bonds to the carbonyl oxygens of ValFG5 (93 alpha and 98 beta), with only minor variations compared to their geometry in deoxyhaemoglobin. TyrHC2(145 beta), however, alternates between a major and a minor site, in conjunction with CysF9(93 beta), both sharing the internal pocket between the F and H helices while in the major conformation. This suggests that the role of the penultimate tyrosines in the allosteric mechanism may differ from that previously proposed by Perutz. The overall quaternary structure of oxyhaemoglobin is identical, within experimental error, to that of carbon monoxide haemoglobin, and thus confirms the applicability of the allosteric mechanisms proposed by Perutz and Baldwin & Chothia to the process of oxygen binding. Structure of human oxyhaemoglobin at 2.1 A resolution.,Shaanan B J Mol Biol. 1983 Nov 25;171(1):31-59. PMID:6644819[11] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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