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From Proteopedia
Structural Basis for the Potent Antisickling Effect of a Novel Class of 5-Membered Heterocyclic Aldehydic Compounds
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. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedNaturally occurring five-membered heterocyclic aldehydes, including 5-hydroxymethyl-2-furfural, increase the oxygen affinity of hemoglobin (Hb) and strongly inhibit the sickling of homozygous sickle red blood (SS) cells. X-ray studies of Hb complexed with these compounds indicate that they form Schiff base adducts in a symmetrical fashion with the N-terminal alphaVal1 nitrogens of Hb. Interestingly, two cocrystal types were isolated during crystallization experiments with deoxygenated Hb (deoxyHb): one crystal type was composed of the low-affinity or tense (T) state Hb quaternary structure; the other crystal type was composed of high-affinity or relaxed state Hb (with a R2 quaternary structure). The R2 crystal appears to be formed as a result of the aldehydes binding to fully or partially ligated Hb in the deoxyHb solution. Repeated attempts to crystallize the compounds with liganded Hb failed, except on rare occasions when very few R state crystals were obtained. Oxygen equilibrium, high performance liquid chromatography (HPLC), antisickling, and X-ray studies suggest that the examined heterocyclic aldehydes may be acting to prevent polymerization of sickle hemoglobin (HbS) by binding to and stabilizing liganded Hb in the form of R2 and/or various relaxed state Hbs, as well as binding to and destabilizing unliganded T state Hb. The proposed mechanism may provide a general model for the antisickling effects of aldehyde containing small molecules that bind to N-terminal alphaVal1 nitrogens of Hb. The examined compounds also represent a new class of potentially therapeutic agents for treating sickle cell disease (SCD). Structural basis for the potent antisickling effect of a novel class of five-membered heterocyclic aldehydic compounds.,Safo MK, Abdulmalik O, Danso-Danquah R, Burnett JC, Nokuri S, Joshi GS, Musayev FN, Asakura T, Abraham DJ J Med Chem. 2004 Sep 9;47(19):4665-76. PMID:15341482[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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