HB hope, β136(H14)Gly→Asp, in a Diabetic Japanese Female and its Functional Characterization

Abstract

A beta-variant hemoglobin, first misjudged as a marked elevation of Hb A1, was found in a 68-year-old Japanese female with diabetes mellitus. This hemoglobin was isolated by Bio-Rex 70 chromatography combined with chromatofocusing, and was found to be Hb Hope, beta 136(H14)Gly----Asp, by classical and high performance liquid chromatographic peptide mapping techniques. Intrinsic oxygen affinity of this hemoglobin was approximately one-third as compared with that of Hb A0. This property was still observed in the constituent beta subunits isolated. Effects of such allosteric effectors as H+ (at a fixed concentration of Cl-), anion (Cl-), 2,3-diphosphoglycerate and carbon dioxide were more or less depressed. Among others, a marked reduction in the carbamate effect should be noted in a structural interpretation of the functional modifications. Subunit cooperativity, on the contrary, was not different from that in Hb A0 (n = 2.8-2.9). Explanation of these altered functions were attempted on the basis of the altered structure. The reduced stability of Hb Hope is also described.

Molecular basis of a novel adaptation to hypoxic-hypercapnia in a strictly fossorial mole

“…Hb Hope also exhibits a markedly lowered Cl - effect relative to Hb A [21], providing additional support for the view that this characteristic arises from the loss of two anion binding sites in the eastern mole protein (i.e., between δ1Val and δ82Lys of each dimer; see Figure 6A). However, it is of note that the P 50 of coast mole Hb I exposed to saturating DPG in 0.1 M Cl - media was higher than values obtained when either of these anions were present alone (Figure 3).…”

“…However, a rare Hb mutant in humans, Hb Hope, is characterized by a comparable charge altering replacement (β136Gly→Asp) and, interestingly, exhibits functional properties similar to that of eastern mole Hb [20,21]. It has been proposed that the altered behaviour of Hb Hope arises from the formation of an intra-chain salt bridge between the carboxyl (COO - ) group of β136Asp and the charged α-amino group (NH 2 + ) of β1Val [22], thus deleting a pair of DPG binding sites and stabilizing the T-state molecule via the newly established ionic linkage [21,23,24]. However, the electrophoretic properties of Hb Hope remain unchanged at pH 8.6 [25], where the N-terminius is expected to be deprotonated (its pKa is ~6.4-6.8; [26,27]) and the β1Val-β136Asp salt-bridge thus destabilized.…”

“…Conversely, the δ136Gly→Glu replacement in eastern mole Hb (through its neutralization of the cationic charge of δ82Lys) should disallow this δ1Val-δ82Lys interaction. Indeed, in the absence of DPG, the CO 2 effect (ΔP 50 /Δ[CO 2 ]) of the Hb Hope variant is 70% lower at a PCO 2 of 40 mm Hg [23] than in human Hb A, and nearly 90% lower at a PCO 2 of 80 mm Hg [21]. …”

ASSOCIATION OF Hb HOPE [β136(H14)Gly → Asp] AND Hb H DISEASE

“…Associations of Hb Hope with Hb S, Hb E, b-thal and athal-2 have been reported in several Blacks, Japanese, Thais, Laotians, and Cubans (3)(4)(5)(6)(7). Associations of Hb Hope with Hb S, Hb E, b-thal and athal-2 have been reported in several Blacks, Japanese, Thais, Laotians, and Cubans (3)(4)(5)(6)(7).…”

Haemoglobin Hope: A Rare Hb Variant Causing Spuriously Elevated HbA1c Values on HPLC Assay

“…Since, at pH 8.6 no charge difference can be detected between Hb Hope and Hb A. So in HPLC method both elute in same window leading to probable overestimation [12]. As capillary electrophoresis was done at pH 9.4, Hb Hope and Hb A can be differentiated from each other.…”