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Structure determines function- how is haemoglobin regulated to deliver…

- - - - They probably evolved from enzymes that protected the organism against the toxic oxygen molecule. As single-celled organisms developed the capacity to use oxygen.
        When multicellular organisms increased in size and complexity, their surface to volume ratios diminished, and simple diffusion of oxygen across the body wall was inadequate to reach all of the cells. The development of vascular and coelomic circulatory systems that could move oxygen away from the inner body wall enhanced the oxygen diffusion rate, but the low solubility of oxygen in body fluids was still limiting. The evolution of simple oxygen-binding proteins into multisubunit, circulating proteins, in combination with the advent of circulatory systems, made possible the transport of oxygen on a significant scale from the periphery of the organism to metabolizing cells in its interior.
        FUNCTIONAL ADAPTATIONS OF OXYGEN-TRANSPORT PROTEINS
      - changes in atmospheric composition (oxygen has gradually increased due to increasing plant photosynthesis) driving factor in Hb protein structure (THE BIOSPHERE)
        
        theory: Hb radiation in response to selection pressures by matching the supply of oxygen from the environment with the demands of the organism. (EVOL OF HAEMO RUFUS)
        The ancestral gene for haemoglobin (Hb) is ancient and has evolved from bacteria to humans
        
        variation between species
  - - - key stimulus to increase the rate of production of haemoglobin and thereby to increase the oxygen-carrying capacity of the blood.
        (Functional adaptations of oxygen-transport proteins)
        
        The primitive crustaceans Artemia salina (Heip et al. 1978b) and Daphnia magna (Kobayashi et al. 1988) both respond to hypoxia with an increase in hemoglobin synthesis. Kobayashi and Gonoi (1985) showed that the swimming ability of Daphnia magna in hypoxic water was directly proportional to the animal’s hemoglobin content. Red Daphnia raised under conditions of low oxygen level swam faster and for longer than pale Daphnia. Larvae of the phantom midge Chironomus thummi thummi, an insect, also produce more hemoglobin under hypoxic conditions (Weber et al. 1985) . (functional...)
        
        regulation appears to be mediated by oxygen sensors. (functional...)
        
        In fishes, the haemoglobin concentration
        varies according to environmental conditions
        
        Several arthropods respond to environmental oxygen levels by increasing or decreasing the rate of synthesis of an extracellular hemoglobin,
    - - attributable to allelic differences in sensitivity to 2,3-diphosphoglycerate (DPG), an allosteric cofactor that stabilizes the low-affinity, (Evolutionary and functional..)
      - Differences in O2-binding affinity of the alternative β-chain hemoglobin isoforms were entirely attributable to allelic differences in sensitivity to 2,3-diphosphoglycerate (DPG), an allosteric cofactor that stabilizes the low-affinity, deoxygenated conformation of the hemoglobin tetramer. The two-locus β-globin haplotype that predominates at high altitude is associated with suppressed DPG-sensitivity
      - In fish: allosteric modulation of Hb–oxygen affinity by organic phosphates ensures adequate oxygenation in the gills under reduced environmental oxygen. (EVOLUT OF HAEMO)
      - degeneration of binding site for allosteric effector
        
        The hemoglobin of new world camelids such as llama, guanaco and vicuña, which live in altitudes up to 5000 m, has a partly degenerated binding site for the allosteric effector 2,3-bisphosphoglycerate caused by a His2→Asn mutation on the β-subunit, which removes two of the seven contacts between the hemoglobin molecule and its allosteric effector 2,3-bisphosphoglycerate thereby increasing oxygen affinity
        
        high oxygen affinity= adapted to high altitude environment**
    - - increased blood oxygen affinity has been proven to be advantageous for animals living at high altitudes, because it increases the oxygen saturation of the arterial blood
      - high-altitude adaptation of deer mouse hemoglobin involves parallel functional differentiation at multiple unlinked gene duplicates: two α-globin paralogs on chromosome 8 and two β-globin paralogs on chromosome
        
        increases in blood-O2 affinity enhance tissue O2 delivery and measures of physiological performance in rodents subjected to environmental hypoxia (Eaton et al., 1974; Turek et al., 1978a,b; Chappell and Snyder, 1984).
      - clearly indicative of local adaptation to different elevational zones.
      - The oxygen affininity of guinea pig hemoglobin is high in comparison with other animals of equivalent size and lifestyle such as rat, shrew, hedgehog and deer mice. Suggested that there is decreased stability of the T-state and an increased stability of the R2-state. (Structure of the Altitude)
      - However, if a given lowland species colonizes a high-altitude environment, it is not always clear whether an increased or decreased Hb–O2 affinity should be expected to improve tissue O2 delivery, and this has been the subject of considerable debate. For this reason, vertebrates at high altitude face the physiological challenge of optimizing the trade-off between O2 loading in the pulmonary capillaries and O2 unloading in the tissue capillaries.
      - homeotherms adapted to high altitude (e.g. bar‐headed geese and llamas) are characterized by Hb with high affinity and relative insensitivity to organic phosphates EVOL OF HAEM
      - sheep overcome altitude problems by synthesizing a high affinity isohaemoglobin, Hb‐C
      - co-expression of HbD and might be one such adaptation of insufficient oxygen supply
        
        high soaring vultures and migratory ducks and geese [3]
  - - - ice fish, high oxygen solubility in cold temperatures, increased surface area for gas exhange and large vessels
- - - - tetramer composed of both α- and β-like polypeptide subunits
      - haemoglobin molecules with different physiologic properties https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4153468/
      - precise amino acid sequence of the α‐ and β‐chains that determines the folding of each chain and it is the interaction between the subunits that refines the oxygen binding properties 1 Perutz MF. Species adaptation in a protein molecule. Mol. Biol. Evol. 1983; 1: 1–28
      - Oxygen binding is associated with small changes in the tertiary structure of segments near the haems and a large shift in the quaternary structure from the T(ense) to the R(elaxed) state, as one dimer rotates relative to the other.
      - 2 states
        
        T state
        
        Various ligands such as protons, carbon dioxide and organic phosphates bind preferentially to deoxygenated Hb, forming salt bridges within and between the chains that stabilize the T‐structure, lowering its oxygen affinity and resulting in cooperative oxygen binding.
        
        R state
        
        R2 (intermediate state)
      - vertebrate structure
        
        Hemoglobins in vertebrates show the typical globin fold accommodating a heme group which reversibly binds oxygen to its central iron atom [4], [5], [6]. In vertebrate erythrocytes hemoglobins are usually present as tetramers (α2β2) of two α-chains and two β-chains, each chain with a molecular mass of ∼15 kDa. An important step in hemoglobin evolution was oligomerization through which cooperative oxygen binding and allosteric control of binding properties were acquired. Both, cooperativity and allosteric control in conjunction, render hemoglobin a highly versatile oxygen carrier whose binding properties can be tuned (Structure of the Altitude Adapted Hemoglobin of Guinea Pig in the R2-State)
        
        The Hbs of jawed vertebrates are heterotetramers, composed of two α-type and two β-type subunits. Each of the subunit polypeptides contains a covalently bound heme group (see Glossary) that can reversibly bind a single O2 molecule when the iron atom is in the ferrous (Fe2+) state; thus tetrameric Hb binds up to four O2 molecules. The Hb tetramer, α2β2, consists of paired, semi-rigid αβ dimers that undergo a symmetrical rotation during the oxygenation-linked transition in quaternary structure between the high-affinity (oxygenated) ‘R’ state and the low-affinity (deoxygenated) ‘T’ state (Fig. 1A).
    - - hemoglobinopathies,
        
        failure can result in tissue hypoxia . https://academic.oup.com/bjaed/article/4/4/123/308019
        
        genetic regulation
        
        attempts to modulate globin gene expression are a fundamental approach to seek novel avenues to therapy
        
        https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3543078/
        
        Some mutations in the globin chain are associated with the hemoglobinopathies
        
        Nearly 1000 haemoglobinopathies have been described, most arising as a single point mutation of one amino acid and found in small patterns of familial inheritance Labie D & Elion J. Sequence polymorphisms of potential functional relevance in the beta‐globin gene locus. Hemoglobin 1996; 20: 85–101.
        
        Haemo- howick
        
        Haemoglobin‐Howick is one of about 50 mutations found in the Australasian region.6 Here, a glycine has been substituted for a tryptophan at a locus close to the α‐β contact, destabilizing the deoxy‐Hb structure with the result that the blood has a high affinity for oxygen, decreased cooperativity and reduced sensitivity to pH (Bohr effect) and DPG. (evo of haemoglobin rufus)
  - - - hameoglobin is found across species
        
        A wide range of animals, vertebrate and invertebrate, use hemoglobins to transport oxygen, carrying it from lungs, gills, or other respiratory organs to peripheral tissues that need the oxygen for efficient metabolism.
        
        https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3543078/
        
        variety of quaternary assemblies also emerged, encompassing monomeric, homo- and heterodimeric, tetrameric Hbs and giant complexes containing up to 180 globin and non-globin chains ( Tertiary and quaternary effects in the allosteric regulation of animal hemoglobins)
        
        evolution Hb responded to selection pressures by matching the supply of oxygen from the environment with the demands of the organism. (EVO HAEM)
    - - Structural and functional diversity of haemoglobin
        
        molecule properties amongst different classes and
        
        species of animals
    - - needs to adapt to exercise, hypoxia, changes in temperature, stress....functional plasticity
- - - - modulations allosteric effectors
        
        decrease oxygen affinity
        
        concentration of allosteric modulator levels (Functional adaptations of oxygen-transport proteins.
        Terwilliger NB1.)
        
        organic phosphates
        
        strong regulatory effect
        
        2,3‐diphosphoglycerate (DPG) bind to the central cavity of the Hb molecule and reduce oxygen affinity
        
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        allosteric modulation
        
        weak regulatory effect
        
        Crocodilian Hb is unusual in that it is insensitive to organic phosphates but is strongly suppressed by carbon dioxide because of oxygen‐linked binding of two bicarbonate ions per Hb tetramer at low pH which raises the respiratory Bohr effect considerably.16,19 These features appear to be adaptations for diving and under circumstances where the alkalinity of blood may be extremely high during digestion of skeletal material.
        
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        Air‐breathing lungfish and amphibians are characterized by red cell organic phosphates which have a stronger effect in regulating oxygen affinity than does ATP alone
        
        ATP and GTP
        
        ATP modulation
        
        Lizards and snakes are characterized by low affinity Hb which are strongly modulated by ATP and have large Bohr effects to support their generally high levels of aerobic activity
        
        16 Weber RE & Wells RMG. Hemoglobin structure and function. In: Lenfant C (series ed.) Comparative Pulmonary Physiology Series: Wood SC (ed.). The Lung in Health and Disease. Marcell Dekker Inc., New York. 1989; 279–310
        
        The Hb from Sphenodon does not show the highly developed cooperative oxygen binding found in modern lizards, but is effectively regulated by ATP.
        
        Wells RMG, Tetens V, Brittain T. Absence of co‐operative haemoglobin‐oxygen binding in Sphenodon: A reptilian relict from the Triassic. Nature 1983; 306: 500–2.
        
        ully aquatic salamanders, which exhibit weakly cooperative oxygen binding regulated by ATP
        
        in fish: Fish use both ATP and GTP. These bind to a phosphate "pocket" on the fish hemoglobin molecule, which stabilizes the tense state and therefore decreases oxygen affinity.[70] GTP reduces hemoglobin oxygen affinity much more than ATP, which is thought to be due to an extra hydrogen bond formed that further stabilizes the tense state.[71] Under hypoxic conditions, the concentration of both ATP and GTP is reduced in fish red blood cells to increase oxygen affinity (wikipedia)
        
        In birds: Presence of high concentrations of the extremely potent erythrocyte organic phosphate inositol polyphosphate in birds
        
        Mammals--> DPG - arising from modification to the pathway of erythrocyte glycolysis. https://onlinelibrary.wiley.com/doi/full/10.1046/j.1440-1681.1999.03091.x
        
        increase oxygen affinity
        
        Hemoglobin also carries nitric oxide (NO) in the globin part of the molecule. This improves oxygen delivery in the periphery and contributes to the control of respiration.
  - - - In addition carbon dioxide can also react with primary amino groups in the polypeptide chain to form a negatively charged carbamate
      - pH
        
        examples
        
        Fish and their extremely pH-sensitive haemoglobin (Hb)= 'The root effect'
        
        A reduction in pH reduces both Hb-O2 affinity (Bohr effect) and carrying capacity (Root effect). This, combined with a large arterial-venous pH change (ΔpHa-v) relative to other vertebrates, may greatly enhance tissue oxygen delivery in teleosts (e.g., rainbow trout) during stress, beyond that in mammals (e.g., human) . (Jodie )
        
        Suggested to Greatly Enhance General Oxygen Delivery compared to other vertebrates (jodie 2015)
        
        A decrease in the pH shifts the curve to the right, while an increase in pH shifts the curve to the left. This occurs because a higher hydrogen ion concentration causes an alteration in amino acid residues that stabilises deoxyhaemoglobin in a state (the T state) that has a lower affinity for oxygen. This rightward shift is referred to as the Bohr effect.
        
        The root effect in fish
        
        he Root effect Hb are unique to fish and are revealed by a dramatic reduction in oxygen‐carrying capacity of the blood at low pH and ensure an efficient transfer of oxygen to the retina of the eye and into the swim bladder through specialized capillary networks.16 Molecular modelling suggests that the Root effect can be largely explained by the presence of a single residue, β(93)Ser (cysteine in mammals), which stabilizes the COOH‐terminal salt bridges in the T structure.
        
        the bohr effect:
        
        here are, however, common adaptations in diving homeotherms (e.g. penguins and seals), which tend to have high haematocrits and large Bohr factors which provide oxygen storage and regulated oxygen turnover during breathholding. EVOL OF HAEM
        
        differences in sensitivies
        
        Hbs are sensitive to pH but not to temperature (e.g. tuna) https://jeb.biologists.org/content/221/17/jeb177832
    - - An increase in temperature shifts the curve to the right, whilst a decrease in temperature shifts the curve to the left. Increasing the temperature denatures the bond between oxygen and haemoglobin
      - not a huge effect
      - hypothermia and hyperthermia.
    - - CO2
        
        the accumulation of CO2 causes carbamino compounds to be generated, which bind to oxygen and form carbaminohaemoglobin. Carbaminohaemoglobin stabilizes deoxyhaemoglobin in the T state.
        
        shifts the crve to the right
        
        f CO2 causes an increase in H+ ion concentrations and a decrease in the pH,
  - - - EVOLUTION OF HAEMOGLOBIN FUNCTION: MOLECULAR ADAPTATIONS TO ENVIRONMENT
        Rufus Mg Wells
  - - - simultaneous co-expression
        
        different haemoglbin in specific compartments, body tissues
        
        Pista Pacifica: First, it circulates a giant (3400 kDa) extracellular hemoglobin with a low oxygen affinity (P50=22 mmHg at 20 °C; 1 mmHg=0.1333 kPa) in its vascular system. Blood vessels are present in thin-walled gills at the head of the worm; at high tide, these gills expand into the oxygen-rich sea water above the mudflat. Second, the lowaffinity extracellular hemoglobin readily transfers its oxygen to a moderate-affinity hemoglobin (P50=3.8 mmHg at 20 °C) in the red blood cells circulating in the coelomic fluid of the worm. Third, the coelomic cell hemoglobin in turn tranfers oxygen to a high-affinity body wall myoglobin.
        
        Alvinellid worms, also in the order Terebellida, are endemic to the deep-sea hydrothermal vents in the Pacific Ocean (Desbruyeres and Laubier, 1986). In addition to an extracellular hemoglobin in the vascular system (Terwilliger and Terwilliger, 1984; Toulmond et al. 1990), alvinellids contain a coelomic cell hemoglobin (Jouin-Toulmond et al. 1996). The coelomic cells are concentrated in an internal periesophageal pouch surrounding a plexus of thin-walled blood vessels, suggesting the presence of a complex respiratory gas-transfer system between extracellular and intracellular hemoglobins
        
        Among the Annelida, some contain red blood cells, while others, especially the oligochaetes and hirudineans, have only extracellular vascular hemoglobin. In contrast, terebellid and opheliid polychaete annelids are outstanding examples of organisms that use multiple proteins in separate body compartments simultaneously to ensure an adequate oxygen supply (Terwilliger, 1974; Mangum et al. 1975; Terwilliger et al. 1980).
        
        this has been taken advantage by parasites (functional, (Fox, 1953; Shirley et al. 1986;
        Terwilliger et al. 1986).
        
        HbA and HbD in birds and reptiles
        
        The majority of bird species co-express two functionally distinct hemoglobin (Hb) isoforms in definitive erythrocytes as follows: HbA (the major adult Hb isoform, with α-chain subunits encoded by the α(A)-globin gene) and HbD .Functional experiments involving purified HbA and HbD isoforms from 11 different bird species revealed that HbD is characterized by a consistently higher O(2) affinity in the presence of allosteric effectors such as organic phosphates and Cl(-) ions. Among birds and reptiles that have been investigated to date, HbD has a consistently higher O2 affinity than HbA. Given that the αD-globin gene is the duplicated product of an embryonic α-like globin gene, the elevated O2 affinity of HbD may reflect a retained ancestral feature that is characteristic of embryonic Hb
        
        Turtles express two major isoHbs (HbA and HbD) that differ in their O2,affinities
        
        similar ATP affinities for both Hb isoforms, so the increase in blood-O2 affinity that accompanies winter acclimation is mainly attributable to a decrease in temperature rather than in concentrations of organic phosphates. Although decrease in phosphates is probably a consequence of downregulating metabolism (Hemoglobin isoform)
        
        other mechanisms other than Hb- O2 affinity
        
        turtles submerged in aerated water at low temperatures appear able to sustain low levels of aerobic energy metabolism by extrapulmonary O2 uptake (45
        
        n principle, a change in the relative expression of Hb isoforms with distinct functional properties could potentially provide a mechanism for regulating the O2 affinity of blood. However,
      - Rather than regulating the rate of expression of a single respiratory protein, many organisms synthesize multiple oxygen carriers with different oxygen affinities. These carriers are produced and function either simultaneously, to enhance oxygen transport and transfer to different portions of the body, or sequentially, to meet oxygen demand under changing conditions. (functional)
      - sequential
        
        A more advanced branchiopod, Daphnia (Kobayashi et al. 1988), and the insect Chironomus have also been demonstrated to undergo developmental shifts in hemoglobin synthesis.
        
        fetal ---> adult hb switch
        
        Whereas adult haemoglobin is composed of two alpha and two beta subunits, fetal haemoglobin is composed of two alpha and two gamma subunits. This change in the globin chain results in a greater affinity for oxygen and allows the fetus to extract oxygen from the maternal circulation. This increased affinity for oxygen means that the oxygen dissociation curve for fetal haemoglobin is shifted to the left of that of adult haemoglobin. fetal hemoglobin (HbF, α2γ2), is found in the developing fetus, and binds oxygen with greater affinity than adult hemoglobin. This means that the oxygen binding curve for fetal hemoglobin is left-shifted (i.e., a higher percentage of hemoglobin has oxygen bound to it at lower oxygen tension), in comparison to that of adult hemoglobin. As a result, fetal blood in the placenta is able to take oxygen from maternal blood. wikipedia
        
        lack cooperative oxygen binding, have high affinity for oxygen and have weak Bohr effects (i.e. properties that may compensate for the weak development of anatomical structures for gas exchange) EVOL of HAEM- Hofmann OM, Brittain T, Wells RMG. The control of oxygen affinity in the three human embryonic haemoglobins by respiratory linked metabolites. Biochem. Molec. Biol. Int. 1997; 42: 553–66