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]
Function
HBA_HUMAN Involved in oxygen transport from the lung to the various peripheral tissues.
Publication Abstract from PubMed
Phenylhydroxylamine (PhNHOH) and nitrosobenzene (PhNO) interact with human tetrameric hemoglobin (Hb) to form the nitrosobenzene adduct Hb(PhNO). These interactions also frequently lead to methemoglobin formation in red blood cells. We utilize UV-vis spectroscopy and X-ray crystallography to identify the primary and secondary products that form when PhNHOH and related alkylhydroxylamines (RNHOH; R = Me, t-Bu) react with human ferric Hb. We show that with MeNHOH, the primary product is Hb[alpha-Fe(III)(H(2)O)][beta-Fe(II)(MeNO)], in which nitrosomethane is bound to the beta subunit but not the alpha subunit. Attempts to isolate a nitrosochloramphenicol (CAMNO) adduct resulted in our isolation of a Hb[alpha-Fe(II)][beta-Fe(II)-cySOx](CAMNO) product (cySOx = oxidized cysteine) in which CAMNO was located outside of the protein in the solvent region between the beta2 and alpha2 subunits of the same tetramer. We also observed that the betacys93 residue had been oxidized. In the case of t-BuNHOH, we demonstrate that the isolated product is the beta-hemichrome Hb[alpha-Fe(III)(H(2)O)][beta-Fe(III)(His)(2)](t-BuNHOH), in which the beta heme has slipped approximately 4.4 A towards the solvent exterior to accommodate the bis-His heme coordination. When PhNHOH is used, a similar beta-hemichrome Hb[alpha-Fe(III)(H(2)O)][beta-Fe(III)(His)(2)-cySOx](PhNHOH) was obtained. Our results reveal, for the first time, the X-ray structural determination of a beta-hemichrome in a human Hb derivative. Our UV-vis and X-ray crystal structural result reveal that although Hb(PhNO) and Hb(RNO) complexes may form as primary products, attempted isolation of these products by crystallization may result in the structural determination of their secondary products which may contain beta-hemichromes en route to further protein degradation.
Crystal structural investigations of heme protein derivatives resulting from reactions of aryl- and alkylhydroxylamines with human hemoglobin.,Powell SM, Wang B, Herrera VE, Prather KY, Nguyen NT, Abucayon EG, Thomas LM, Safo MK, Richter-Addo GB J Inorg Biochem. 2023 Sep;246:112304. doi: 10.1016/j.jinorgbio.2023.112304. Epub , 2023 Jun 25. PMID:37406385[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Ohba Y, Yamamoto K, Hattori Y, Kawata R, Miyaji T. Hyperunstable hemoglobin Toyama [alpha 2 136(H19)Leu----Arg beta 2]: detection and identification by in vitro biosynthesis with radioactive amino acids. Hemoglobin. 1987;11(6):539-56. PMID:2833478
- ↑ Traeger-Synodinos J, Harteveld CL, Kanavakis E, Giordano PC, Kattamis C, Bernini LF. Hb Aghia Sophia [alpha62(E11)Val-->0 (alpha1)], an "in-frame" deletion causing alpha-thalassemia. Hemoglobin. 1999 Nov;23(4):317-24. PMID:10569720
- ↑ Powell SM, Wang B, Herrera VE, Prather KY, Nguyen NT, Abucayon EG, Thomas LM, Safo MK, Richter-Addo GB. Crystal structural investigations of heme protein derivatives resulting from J Inorg Biochem. 2023 Sep;246:112304. PMID:37406385 doi:10.1016/j.jinorgbio.2023.112304
