6hk2 | pdb_00006hk2
Crystal structure of ferric R-state human methemoglobin bound to maleimide-deferoxamine bifunctional chelator (DFO)
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 PubMedProteins, as a major component of organisms, are considered the preferred biomaterials for drug delivery vehicles. Hemoglobin (Hb) has been recently rediscovered as a potential drug carrier, but its use for biomedical applications still lacks extensive investigation. To further explore the possibility of utilizing Hb as a potential tumor targeting drug carrier, we examined and compared the biodistribution of Hb in healthy and lung tumor-bearing mice, using for the first time (89)Zr labelled Hb in a positron emission tomography (PET) measurement. Hb displays a very high conjugation yield in its fast and selective reaction with the maleimide-deferoxamine (DFO) bifunctional chelator. The high-resolution X-ray structure of the Hb-DFO complex demonstrated that cysteine beta93 is the sole attachment moiety to the alphabeta-protomer of Hb. The Hb-DFO complex shows quantitative uptake of (89)Zr in solution as determined by radiochromatography. Injection of 0.03 mg of Hb-DFO-(89)Zr complex in healthy mice indicates very high radioactivity in liver, followed by spleen and lungs, whereas a threefold increased dosage results in intensification of PET signal in kidneys and decreased signal in liver and spleen. No difference in biodistribution pattern is observed between naive and tumor-bearing mice. Interestingly, the liver Hb uptake did not decrease upon clodronate-mediated macrophage depletion, indicating that other immune cells contribute to Hb clearance. This finding is of particular interest for rapidly developing clinical immunology and projects aiming to target, label or specifically deliver agents to immune cells. Biodistribution PET/CT Study of Hemoglobin-DFO-(89)Zr Complex in Healthy and Lung Tumor-Bearing Mice.,Kiraga L, Cerutti G, Braniewska A, Strzemecki D, Sas Z, Boffi A, Savino C, Montemiglio LC, Turnham D, Seaton G, Bonamore A, Clarkson R, Dabkowski AM, Paisey SJ, Taciak B, Kucharzewska P, Rygiel TP, Krol M Int J Mol Sci. 2020 Jul 15;21(14):4991. doi: 10.3390/ijms21144991. PMID:32679799[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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