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

Abstract

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).

Origin and mechanism of thermal insensitivity in mole hemoglobins: a test of the ‘additional’ chloride binding site hypothesis

“…Although heterotropic ligands are known to be important modulators of Hb-O 2 affinity in vivo, the molecular mechanisms underlying the effect of temperature on Hb-O 2 affinity are much less understood (Weber and Campbell, 2011). This is surprising given that the temperature dependence of blood-O 2 affinity (whereby Hb-O 2 affinity tends to increase with decreasing temperature) was first observed more than 100years ago (Barcroft and King, 1909).…”

“…This is surprising given that the temperature dependence of blood-O 2 affinity (whereby Hb-O 2 affinity tends to increase with decreasing temperature) was first observed more than 100years ago (Barcroft and King, 1909). As with blood-O 2 affinity, temperature sensitivity varies substantially among species, with the magnitude of this effect resulting from a symphony of oxygenation-linked chemical processes that together determine the overall enthalpy of oxygenation (⌬HЈ) (Weber and Campbell, 2011). Because ⌬H O2 and ⌬H H2O are virtually invariant, variations in HЈ appear to be primarily driven by changes in endothermic contributions from oxygenation-linked effector release and/or possibly by changes in ⌬H TrR (Weber and Campbell, 2011).…”

“…As with blood-O 2 affinity, temperature sensitivity varies substantially among species, with the magnitude of this effect resulting from a symphony of oxygenation-linked chemical processes that together determine the overall enthalpy of oxygenation (⌬HЈ) (Weber and Campbell, 2011). Because ⌬H O2 and ⌬H H2O are virtually invariant, variations in HЈ appear to be primarily driven by changes in endothermic contributions from oxygenation-linked effector release and/or possibly by changes in ⌬H TrR (Weber and Campbell, 2011). Notably, numerical reductions in HЈ -whereby Hb-O 2 affinity is less affected by changes in temperature -may have had important evolutionary consequences for a number of mammalian lineages (Campbell et al, 2010a;Weber and Campbell, 2011).…”

Bovine hemoglobin polymorphism: a novel alpha-globin variant identified in the Agerolese breed from southern Italy

“…A visual inspection of the 3D structure of bovine hemoglobin (PDB code 2QSS) revealed that the side chain of the amino acid at position 27 is located at the protein surface pointing out toward the solvent, in a region that is far from the heme groups, and is not involved in intra-and/or inter-dimer contacts, or in binding to allosteric effectors (data not shown). On this basis, no functional consequences of the p.Ala27Thr substitution can be predicted according to known site mutation determinants (Storz and Moriyama 2008;Weber and Campbell 2011). The same amino acid replacement at the same position has already been detected in α-chain globin variants from goat breeds present in southern Italy (Puglia and Sardegna) (Pieragostini et al 2005;Pirastru et al 2009) and from human families in Caserta (Campania) (Lacerra et al 2004).…”

“…Studying genetic variants is also important because of the impact that single amino acid substitutions can have on protein function. A prototype example is hemoglobin, where different globin genes contribute to a protein phenotype in which amino acid replacements can affect development of a pathological state or, more generally, organism adaptation to environmental conditions, which are peculiar for the breed and/or related to the uniqueness of its products (Haenlein et al 1987;Storz and Moriyama 2008;Pieragostini et al 2010;Weber and Campbell 2011). In bovine, hemoglobin polymorphism was originally described for alleles Hb A and Hb B (Bangham and Blumberg 1958).…”