3p5q
Ferric R-state human aquomethemoglobin
Structural highlights
DiseaseHBA_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] FunctionHBA_HUMAN Involved in oxygen transport from the lung to the various peripheral tissues. Publication Abstract from PubMedThe crystal structure of tetrameric (alphabeta)(2) R-state human adult aquomethemoglobin is reported at 2.0 A resolution. The asymmetric unit contained one alphabeta subunit pair. The R-state crystal belonged to space group P4(1)2(1)2, with unit-cell parameters a = b = 53.6, c = 192.8 A. An Fe-bound water molecule was modeled into the heme distal pockets of each of the alpha and beta subunits. In the alpha subunit, a highly ordered liganded water was modeled with an Fe-O(water) distance of 2.2 A and appears to be protected against escape from the distal pocket by the conformation of the heme propionate groups, which point upwards towards the distal His58 residue aided by a hydrogen-bonding network involving the solvent. In the beta subunit, the liganded water exhibited greater motion and was modeled with a longer Fe-O(water) distance of 2.5 A; in this subunit both propionate groups point downwards away from the distal His63 residue, presumably allowing greater motion of the liganded water in and out of the distal pocket. Structure of human R-state aquomethemoglobin at 2.0 A resolution.,Yi J, Thomas LM, Richter-Addo GB Acta Crystallogr Sect F Struct Biol Cryst Commun. 2011 Jun 1;67(Pt, 6):647-51. Epub 2011 May 24. PMID:21636902[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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