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The crystal structure of recombinant human adult hemoglobinThe crystal structure of recombinant human adult hemoglobin
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 PubMedWe describe the synthesis and O2 affinity of genetically engineered human adult haemoglobin (rHbA) wrapped covalently with recombinant human serum albumins (rHSAs) as an artificial O2 carrier used for a completely synthetic red blood cell (RBC) substitute. Wild-type rHbA [rHbA(wt)] expressed in yeast species Pichia pastoris shows an identical amino acid sequence and three-dimensional structure to those of native HbA. It is particularly interesting that two orientations of the prosthetic haem group in rHbA(wt) were aligned by gentle heating in the natural form. Covalent wrapping of rHbA(wt) with three rHSAs conferred a core-shell structured haemoglobin-albumin cluster: rHbA(wt)-rHSA3. Three variant clusters containing an rHbA mutant core were also created: Leu-beta28 --> Phe, Leu-beta28 --> Trp, and Leu-beta28 --> Tyr/His-beta63 --> Gln. Replacement of Leu-beta28 with Trp decreased the distal space in the haem pocket, thereby yielding a cluster with moderately low O2 affinity which is nearly the same as that of human RBC. Genetically engineered haemoglobin wrapped covalently with human serum albumins as an artificial O2 carrier.,Funaki R, Okamoto W, Endo C, Morita Y, Kihira K, Komatsu T J Mater Chem B. 2019 Dec 16. doi: 10.1039/c9tb02184a. PMID:31840728[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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