Altered sulfhydryl reactivity of hemoglobins and red blood cell membranes in congenital Heinz body hemolytic anemia.
Altered sulfhydryl reactivity of hemoglobins and red blood cell membranes in congenital Heinz body hemolytic anemia.
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先天性亨氏体溶血性贫血中血红蛋白和红细胞膜的巯基反应性改变。
DOI：
10.1172/jci105950
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发表时间：
1968
期刊：
影响因子：
--
通讯作者：
J. Dacie
中科院分区：
文献类型：
--
作者：
H. Jacob;M. Brain;J. Dacie
在血红蛋白不稳定的 Köln（β-98 缬氨酸 --> 蛋氨酸）和 Hammersmith（β-42 苯丙氨酸 --> 丝氨酸）患者中研究了血红蛋白沉淀到 Heinz 小体和溶血性贫血的机制，这是先天性 Heinz 小体溶血性贫血 (CHBHA) 的特征。 CHBHA 血红蛋白 β 链第 93 位的半胱氨酸以混合二硫键过度结合谷胱甘肽。由此产生的细胞内“游离”GSH 的减少加速了己糖单磷酸分流代谢。通过用对汞苯甲酸酯 (PMB) 人为封闭正常血红蛋白 A 的巯基，可以在 50°C 加热时诱导 CHBHA 血红蛋白的独特沉淀性。由于先前报道的科隆血红蛋白中血红素流量过多，该血红蛋白中的预期血红素/珠蛋白比率降低了 30%。加热（50 摄氏度）时血红素损失进一步增加，这是 CHBHA 血红蛋白独特的热沉淀性的基础；如果氰化物或一氧化碳抑制血红素的脱离，则其会被延迟。海因茨小体可能通过混合二硫键连接到红细胞膜硫醇基团上，并由巯基乙醇释放。血红蛋白 Köln-(59)Fe 与红细胞血影的结合在 50°C 下生成亨氏小体时显着增强，但如果膜硫醇被 PMB 预封闭，则血红蛋白 Köln-(59)Fe 与红细胞血影的结合会受到抑制。膜硫醇通过与亨氏小体的反应而被耗尽，使得 CHBHA 红细胞对膜巯基抑制剂高度敏感，表现为过度的阳离子渗漏、渗透脆性和自溶血。我们得出结论，细胞和膜硫醇均以混合二硫化物形式与 CHBHA 血红蛋白的 β-93 巯基结合。与此同时，血红素对 β-92 的亲和力减弱，表明由此产生的过度游离血红素的降解可能会产生该综合征的色素性双吡咯尿症。亨氏小体反映了血红素缺乏的球蛋白的高度可沉淀性，它附着在膜上的巯基上，从而耗尽了膜上的巯基。如前所述，这可能是该综合征溶血性贫血的基础，导致膜渗透性过高、脾脏过早受压，并最终导致红细胞渗透性破坏。
The mechanisms of hemoglobin precipitation into Heinz bodies and hemolytic anemia that characterize congenital Heinz body hemolytic anemia (CHBHA) were studied in patients with the unstable hemoglobins, Köln (beta-98 valine --> methionine) and Hammersmith (beta-42 phenylalanine --> serine). The cysteines in the 93rd position of the beta-chains of CHBHA hemoglobins bound glutathione excessively in mixed disulfide linkage. The resulting diminished "free" GSH within the cell accelerated hexose monophosphate shunt metabolism. The unique precipitability of CHBHA hemoglobins when heated at 50 degrees C could be induced in normal hemoglobin A by artificially blockading its sulfhydryl groups with paramercuribenzoate (PMB). Reflecting the previously reported excessive flux of hemes from hemoglobin Köln, the expected heme/globin ratio in this hemoglobin was reduced by 30%. The further increment in heme loss that occurs with heat (50 degrees C) underlies the unique heat precipitability of CHBHA hemoglobins; it was retarded if detachment of heme was inhibited by cyanide or carbon monoxide.Heinz bodies were attached to red cell membrane thiol groups presumably through mixed disulfide bonds, being released by mercaptoethanol. Binding of hemoglobin Köln-(59)Fe to red cell ghosts, which was markedly enhanced when Heinz bodies were generated at 50 degrees C, was inhibited if membrane thiols were preblockaded by PMB. The depletion of membrane thiols by their reaction with Heinz bodies rendered CHBHA red cells hypersusceptible to membrane sulfhydryl inhibitors, as manifested by inordinate cation leakage, osmotic fragility, and autohemolysis. We conclude that both cellular and membrane thiols bind beta-93 sulfhydryls of CHBHA hemoglobins as mixed disulfides. Concomitantly, heme avidity to beta-92 lessens, suggesting that degradation of the resulting excessively freed heme may produce the pigmented dipyrroluria of this syndrome. Heinz bodies, reflecting the heightend precipitability of heme-deficient globin, attach to, thereby depleting, membrane sulfhydryl groups. This, as shown previously, could underlie the hemolytic anemia of this syndrome by causing membrane hyperpermeability, premature splenic entrapment, and ultimately osmotic destruction of red blood cells.