Heme stability in the human embryonic hemoglobins

Robson, N. C.; Brittain, Thomas

doi:10.1016/0162-0134(96)00030-x

Cited by 15 publications

(5 citation statements)

References 24 publications

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“…This interaction between the lysine side-chain and the propionate group has also been observed in structures containing the embryonic (41) and fetal γ (45) chains. This interaction in ζ, , and γ chains helps explain the higher heme affinities found in their respective embryonic methemoglobins relative to the adult methemoglobin (46).…”

Section: Resultsmentioning

confidence: 90%

The Role of β Chains in the Control of the Hemoglobin Oxygen Binding Function: Chimeric Human/Mouse Proteins, Structure, and Function

et al. 2001

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By using transgenic methodologies, we have produced a number of mouse/human chimeric hemoglobins containing adult mouse and human embryonic globin chains. A detailed analysis of the oxygen binding properties of these proteins identifies the dominant role played by the specific beta-type globin chains in the control of the oxygen binding characteristics. Further analysis traces the origins of these effects to alterations in the properties of the T states of these proteins. The human zeta/mouse beta chimeric protein has been crystallized, and its structure has been determined by X-ray diffraction to a resolution of 2.1 A with R (R(free)) values of 21.6% (24.9%). Close examination of the structure indicates that the subunit interfaces contain contacts which, although different from those present in either the parent human or the parent mouse proteins, retain the overall stabilizing interactions seen in other R state hemoglobins.

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Section: Resultsmentioning

confidence: 90%

The Role of β Chains in the Control of the Hemoglobin Oxygen Binding Function: Chimeric Human/Mouse Proteins, Structure, and Function

et al. 2001

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“…This observation is consistent with the report of Macdonald and Charache (23), wherein they observed a slow rate of Hb F oxidation in the presence of menadione. The high in vitro stability of Hb F to oxidant stress has been ascribed to the tightly bound globin protein character in Hb F as compared to other Hb's studied (24). An alternative explanation of Hb F relative stability to HU-induced effect as compared to Hb AA is the presence of cysteine at β112 (which is one likely reaction site of oxidants attack due to the presence of the -SH group), whereas in the γ chain of Hb F, this position is replaced by threonine (23).…”

Section: Discussionmentioning

confidence: 99%

Hydroxyurea-induced oxidative damage of normal and sickle cell hemoglobins in vitro: Amelioration by radical scavengers

Iyamu

Fasold

Roa

et al. 2001

J. Clin. Lab. Anal.

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Hydroxyurea (HU) induces fetal hemoglobin (Hb F) production in patients with sickle cell anemia. The therapeutic dosage of HU used for Hb F induction often elicits myelosuppression, which becomes its major associated complication. We examined the effect of HU on hemoglobin modulation and the role of radical scavengers on these induced changes. In vitro exposure of human blood to various concentrations of HU at predetermined time intervals induced a progressive dose‐dependent oxidation (MetHb formation) of both adult (Hb AA) and sickle (Hb SS) hemoglobins. The oxidative effect of HU on Hb SS was 3 times greater than its effect on Hb AA. Similar but less profound changes were observed in H2O2‐treated samples. Hb F was, however, observed to be relatively resistant to HU‐induced oxidative damage. A substantial protective effect of Hb by α‐tocopherol, ascorbic acid, and D‐mannitol was observed during pretreatment of Hb AA and Hb SS blood samples. Analyses of the hemoglobins and their globin chain components by high‐performance liquid chromatography revealed a considerable protective effect by these free radical scavengers. These results indicate that the HU‐induced damage of hemoglobin and their component globin chains can be reduced by radical scavengers. J. Clin. Lab. Anal. 15:1–7, 2001. © 2001 Wiley‐Liss, Inc.

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“…Thus we can only speculate as to whether the corresponding semiHbs are responsible for the observed stereoselectivity in the haem insertion reactions, or whether this is intrinsic to the isolated globins. However, we do note that the embryonic Hbs exhibit much stronger binding of haem in their β-type subunits [45], and this phenomenon could well influence the selection of haem orientation in any semiHb intermediates. Further support for the primacy of β-type subunits in determining overall haem disorder levels comes from the observation of a decrease in recombinant α-subunit haem disorder when the partner subunit is changed from β to ε. Haem disorder thus appears to preserve a record of the ensemble of apoglobin tertiary and quaternary structures present at the time of haem insertion.…”

Section: Nature Of Haem Insertion In Hb Biosynthesismentioning

confidence: 78%

Haem disorder in recombinant- and reticulocyte-derived haemoglobins: evidence for stereoselective haem insertion in eukaryotes

Mathews

Brittain

2001

Biochemical Journal

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We have used NMR spectroscopy to measure haem disorder in adult human haemoglobin (HbA) obtained from mature erythrocyte cells and from yeast expressing recombinant HbA. Reticulocyte-derived HbA contained much higher levels of haem disorder (11 % α-and 28 % β-subunit disorder) than observed for HbA from mature erythrocytes (1.5 % α-and 8 % β-subunit disorder). Thus, unlike in itro combination of haem and apoHb, biosynthetic haem insertion is not random with respect to orientation, but appears to show stereoselectivity. Recombinant HbA isolated from yeast showed 32 % α-and 45 % β-subunit

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Heme stability in the human embryonic hemoglobins

Cited by 15 publications

References 24 publications

The Role of β Chains in the Control of the Hemoglobin Oxygen Binding Function: Chimeric Human/Mouse Proteins, Structure, and Function

The Role of β Chains in the Control of the Hemoglobin Oxygen Binding Function: Chimeric Human/Mouse Proteins, Structure, and Function

Hydroxyurea-induced oxidative damage of normal and sickle cell hemoglobins in vitro: Amelioration by radical scavengers

Haem disorder in recombinant- and reticulocyte-derived haemoglobins: evidence for stereoselective haem insertion in eukaryotes

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