Functional aspects of hemoglobin evolution in the mammals

Scott, Alan F.; Bunn, H. Franklin; Brush, Alan H.

doi:10.1007/bf01739256

Cited by 12 publications

(3 citation statements)

References 19 publications

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“…While in utero, mice do not have a high-oxygen affinity hemoglobin such as HbF, but instead have low production of 2,3-DPG that reaches adult levels at about 3 weeks of age. 30 We speculate that low 2,3-DPG (an antisickling condition) results in reduced destruction of non-F cells during the first 2 to 3 weeks of life, both in marrow before release and as reticulocytes in peripheral blood, which may partially account for low neonatal levels of HbF.…”

Section: Age Dependence Of Hbf and F Cellsmentioning

confidence: 89%

Second generation knockout sickle mice: the effect of HbF

Fabry

Suzuka

Weinberg

et al. 2001

Blood

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Sickle transgenic mice expressing exclusively human globins are desirable for studying pathophysiology and testing gene therapy strategies, but they must have significant pathology and show evidence of amelioration by antisickling hemoglobins. Mice were generated that expressed exclusively human sickle hemoglobin with 3 levels of HbF using their previously described sickle constructs (cointegrated human miniLCR␣2 and miniLCR␤ S [PNAS 89:12150, 1992]), mouse ␣-and ␤-globin-knockouts, and 3 different human ␥-transgenes. It was found that, at all 3 levels of HbF expression, these mice have balanced chain synthesis, nearly normal mean corpuscular hemoglobin, and, in some cases, F cells. Mice with the least adult HbF expression were the most severe. Progressive increase in HbF from less than 3% to 20% to 40% correlated with progressive increase in hematocrit (22% to 34% to 40%) and progressive decrease in reticulocyte count (from 60% to 30% to 13%). Urine concentrating ability was normalized at high HbF, and tissue damage detected by histopathology and organ weight were ameliorated by increased HbF. The ␥-transgene that produces intermediate levels of HbF was introduced into knockout sickle mice described by Pàszty and coworkers that express the miniLCR␣1 G

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Section: Age Dependence Of Hbf and F Cellsmentioning

confidence: 89%

Second generation knockout sickle mice: the effect of HbF

Fabry

Suzuka

Weinberg

et al. 2001

Blood

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“…Moreover, previous studies indicate that the adult Hbs of both groups have independently evolved dramatically reduced O 2 affinities and suppressed sensitivities to DPG (Bunn et al, 1974;Bunn, 1980Bunn, , 1971Scott et al, 1976Scott et al, , 1977Taketa, 1973), features that may limit the capacity to regulate Hb-O 2 affinity. In mammals with DPG-insensitive Hbs, the reduced plasticity in blood-O 2 affinity may limit physiological niche breadth (Bunn, 1980;Kay, 1977;Scott et al, 1976Scott et al, , 1977. Those taxa that have secondarily lost the capacity to regulate Hb-O 2 affinity through changes in erythrocytic DPG concentration '…are restricted to a much narrower range of possible habitats and/or life-styles', according to Kay (1977).…”

Section: Introductionmentioning

confidence: 99%

Genetically based low oxygen affinities of felid hemoglobins: lack of biochemical adaptation to high-altitude hypoxia in the snow leopard

Janečka

Nielsen

Andersen

et al. 2015

Journal of Experimental Biology

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Genetically based modifications of hemoglobin (Hb) function that increase blood-O 2 affinity are hallmarks of hypoxia adaptation in vertebrates. Among mammals, felid Hbs are unusual in that they have low intrinsic O 2 affinities and reduced sensitivities to the allosteric cofactor 2,3-diphosphoglycerate (DPG). This combination of features compromises the acclimatization capacity of blood-O 2 affinity and has led to the hypothesis that felids have a restricted physiological niche breadth relative to other mammals. In seeming defiance of this conjecture, the snow leopard (Panthera uncia) has an extraordinarily broad elevational distribution and occurs at elevations above 6000 m in the Himalayas. Here, we characterized structural and functional variation of big cat Hbs and investigated molecular mechanisms of Hb adaptation and allosteric regulation that may contribute to the extreme hypoxia tolerance of the snow leopard. Experiments revealed that purified Hbs from snow leopard and African lion exhibited equally low O 2 affinities and DPG sensitivities. Both properties are primarily attributable to a single amino acid substitution, β2His→Phe, which occurred in the common ancestor of Felidae. Given the low O 2 affinity and reduced regulatory capacity of feline Hbs, the extreme hypoxia tolerance of snow leopards must be attributable to compensatory modifications of other steps in the O 2 -transport pathway.

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“…2004). As with ruminants, the Hbs of felines exhibit low intrinsic O 2 affinities and low sensitivities to DPG; moreover in both taxons the phosphate insensitivity correlates with the presence of low (<1 m m L −1 red cells) DPG concentrations (Taketa 1974, Scott et al. 1976, 1977, Herrmann & Haskins 2005) indicating that Cl − ions are the major effectors of blood‐O 2 affinity.…”

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confidence: 99%

Temperature dependence of haemoglobin–oxygen affinity in heterothermic vertebrates: mechanisms and biological significance

Weber¹,

Campbell²

2010

Acta Physiologica

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As demonstrated by August Krogh et al. a century ago, the oxygen-binding reaction of vertebrate haemoglobin is cooperative (described by sigmoid O(2) equilibrium curves) and modulated by CO(2) and protons (lowered pH) that - in conjunction with later discovered allosteric effectors (chloride, lactate and organic phosphate anions) - enhance O(2) unloading from blood in relatively acidic and oxygen-poor tissues. Based on the exothermic nature of the oxygenation of the haem groups, haemoglobin-O(2) affinity also decreases with rising temperature. This thermal sensitivity favours oxygen unloading in warm working muscles, but may become detrimental in regionally heterothermic animals, for example in cold-tolerant birds and mammals and warm-bodied fish, where it may perturb the balance between O(2) unloading and O(2) requirement in organs with substantially different temperatures than at the respiratory organs and thus commonly is reduced or obliterated. Given that the oxygenation of haemoglobin is linked with the endothermic release of allosteric effectors, increased effector interaction is an effective strategy that is widely exploited to achieve adaptive reductions in the temperature dependence of blood-O(2) affinity. The molecular mechanisms implicated in heterothermic vertebrates from different taxonomic groups reveal remarkable variability, both as regards the effectors implicated (protons in tunas, organic phosphates in sharks and billfish, chloride ions in ruminants and chloride and phosphate anions in the extinct woolly mammoth, etc.) and binding sites for the same effectors, indicating multiple evolutionary origins, but convergent physiological functionality (reductions in temperature dependence of O(2) -binding affinity that safeguard tissue O(2) supply).

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Functional aspects of hemoglobin evolution in the mammals

Cited by 12 publications

References 19 publications

Second generation knockout sickle mice: the effect of HbF

Second generation knockout sickle mice: the effect of HbF

Genetically based low oxygen affinities of felid hemoglobins: lack of biochemical adaptation to high-altitude hypoxia in the snow leopard

Temperature dependence of haemoglobin–oxygen affinity in heterothermic vertebrates: mechanisms and biological significance

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