8fdn
Human Hemoglobin with N-tertbutylhydroxylamine
Structural highlights
DiseaseHBB_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.[1] [2] [3] [4] 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.[5] 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.[6] FunctionHBB_HUMAN Involved in oxygen transport from the lung to the various peripheral tissues.[7] LVV-hemorphin-7 potentiates the activity of bradykinin, causing a decrease in blood pressure.[8] Publication Abstract from PubMedPhenylhydroxylamine (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[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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