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Research Article Free access | 10.1172/JCI106421

The role of hemoglobin heme loss in Heinz body formation: studies with a partially heme-deficient hemoglobin and with genetically unstable hemoglobins

Harry S. Jacob and Kaspar H. Winterhalter

Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota 55455

Laboratorium für Molekularbiologie der Eidgenössischen Technischen Hochschule, Zürich, Switzerland

Find articles by Jacob, H. in: JCI | PubMed | Google Scholar

Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota 55455

Laboratorium für Molekularbiologie der Eidgenössischen Technischen Hochschule, Zürich, Switzerland

Find articles by Winterhalter, K. in: JCI | PubMed | Google Scholar

Published November 1, 1970 - More info

Published in Volume 49, Issue 11 on November 1, 1970
J Clin Invest. 1970;49(11):2008–2016. https://doi.org/10.1172/JCI106421.
© 1970 The American Society for Clinical Investigation
Published November 1, 1970 - Version history
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Abstract

A number of mutant hemoglobins are inordinately unstable, denaturing in circulating red cells into Heinz bodies, resulting in congenital Heinz body hemolytic anemia (CHBHA). We have emphasized that most such hemoglobins involve amino acid substitutions at sites neighboring the heme group of the β-polypeptide chain, and have shown that heme binding to globin is diminished thereby. Thus, hemes were progressively lost from four unstable hemoglobins (Köln, Hammersmith, San Francisco, and Zürich) as they precipitated into Heinz bodies at 50°C.

The role of heme loss, especially from beta chains, in Heinz body formation was supported by studies with a hemoglobin synthesized to contain hemes only on its alpha chains (α2hemeβ20). The behavior of this compound, postulated to be an intermediary in the formation of Heinz bodies, mimicked that of the genetically unstable hemoglobins in several ways: (a) it precipitated at 50°C into typical coccoid Heinz bodies; (b) as also observed with CHBHA hemoglobins this denaturation was virtually prevented by the heme ligands, cyanide or carbon monoxide, which inhibit further heme loss; it was potentiated by oxidation of hemes to the ferri- state, which accentuates heme loss; (c) the thiol groups of α2hemeβ20 were hyperreactive, forming mixed disulfides with glutathione and membrane sulfhydryls at rates similar to those of CHBHA hemoglobins and 10 or more times that of normal hemoglobin A; (d) heme repletion of the protein molecules by the addition of crystalline hemin to either α2hemeβ20 or to the genetically unstable hemoglobins, prevented their precipitation into Heinz bodies and normalized their aberrant electrophoretic behaviors; and (e) during Heinz body formation at 50°C both α2hemeβ20 and the genetically unstable hemoglobins released free αheme-chains into solution, suggesting that the bulk of the whitish, Heinz body precipitate is naked β8-chains.

We conclude that heme loss from mutant beta chains is an early step in Heinz body formation in several of the unstable hemoglobinopathies. The resulting hemedepleted compounds, of which synthetic α2hemeβ20 is a prototype, are unstable, cleaving into β0-chain precipitates (the bulk of the Heinz body material) and soluble, free αheme-chains (demonstrated previously in hemolysates from many patients with CHBHA).

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