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5.3. Not only oxygen: the other side of globin function
Abstracts / Comparative Biochemistry and Physiology, Part A 148 (2007) S24–S26
5.3. Not only oxygen: the other side of globin function Fago, A. Department of Biological Sciences, University of Aarhus, Denmark [email protected] It has recently become increasingly clear that the physiological role of globin proteins in vertebrates is not only limited to the well-known oxygen transport and storage functions of the hemoglobin in red blood cells and the myoglobin in heart and skeletal muscle, but also includes a wide variety of other functions. These involve the preserving or scavenging of vasoactive nitric oxide (NO) generated within blood vessels, formation of S-nitrosothiols involved in cellular signalling, and several redox reactions favoured by hypoxic conditions, such as the reduction of endogenous nitrite into NO for the control of vasodilation and mitochondrial respiration, the scavenging of toxic peroxynitrite and the reduction of cytochrome c, possibly preventing cellular apoptosis. Although the biological significance of many of these reactions remains controversial, the four major vertebrate globins, hemoglobin, myoglobin, neuroglobin and cytoglobin, clearly show distinctive patterns of reactivity due to differences in heme-iron coordination and reducing potentials, thiol groups accessibility and presence of external and internal cavities for non-covalent binding of cofactors or ligand diffusion. Specifically, our data indicate that neuroglobin seems to be the most likely candidate among globins for the catalysis of most of these redox-reactions, a feature that apparently relates to its most ancient phylogenetic origin. doi:10.1016/j.cbpa.2007.06.061
5.4. Big insights from little animals: allosteric modulation and thermal sensitivity of shrew and mole hemoglobins Campbell, K.L. and Weber, R.E. Biological Sciences, University of Manitoba, Canada [email protected] Mass-specific metabolic rate varies inversely with size, while pulmonary transit time, muscle O2 storage capacity, and the ability to exploit anaerobic metabolism vary directly with this variable. Thus, small mammals must exploit a suite of morphological and physiological adjustments to supply tissue mitochondria with sufficient O2 to fuel oxidative metabolism, such as blood with a high Bohr coefficient and half-saturation pressure (P50). However, a high P50 may drastically impede hemoglobin (Hb) saturation at low ambient PO2's and place a considerable strain on the hypoxia tolerance of shrews and moles. Despite these constraints, several shrew (and mole) species flourish at elevations exceeding 4500 m (where atmospheric PO2 is b 100 mm Hg), while fossorial moles
S25
excavate subterranean burrows in severely hypoxic/hypercapnic soils. As most physiological and morphological traits are likely already operating near their upper limits, what if any additional functional properties of the Hb of these species make these achievements possible? Our findings suggest that changes in the intrinsic O2-affinity of the Hb moiety (rather than phosphate sensitivity) underlie transitions to and from hypoxic environments in members of each of these groups. Comparative gene sequencing further demonstrates that the novel ‘cathodic’ Hbs of these insectivorous mammals (which are dually modulated by both phosphate and chloride ions) arose prior to the mole/ shrew radiation. doi:10.1016/j.cbpa.2007.06.062
5.5. Novel environmental adaptations in lower vertebrate erythrocytes Val, A.L., Nozawa, S.R., Honda, R.T., and de Almeida-Val, V.M.F. Instituto Nacional de Pesquisas da Amazônia-INPA, Brazil [email protected] Erythrocytic microenvironment is continuously adjusted to maintain tissue oxygen supply in fish facing either environmental or physiological constraints. During hypoxia, downregulation of protein synthesis is followed by adjustments in the levels of modulators of Hb-O2 affinity to ensure oxygen transfer to the tissues. ATP and GTP are the major modulators of Hb-O2 affinity and have been described in fish red blood cells. Compared to ATP, GTP is a stronger modulator and its concentration decreases faster in animals exposed to hypoxia. In several fish species of the Amazon, a reduction of GTP is observed within the first 10 min of hypoxia. Since protein synthesis is the second costliest energy consuming process, a decrease in the rate of translation process is vital for a cell experiencing oxygen shortage. Eukaryotic initiation factors family (eIFs) are involved with the regulation of protein synthesis, a process that begins when both mRNA and the initiator methionyl (Met)-tRNA are bound to the ribosome. This process is achieved when the eIF2ƒÑ binds to GTP producing eIF2-GTP hydrolyzing to eIF2-GDP-bound and Pi and released; the GDP must be replaced by GTP in subsequent rounds. Semiquantitative expression of eIF2ƒÑ in the red blood cells of tambaqui (Colossoma macropomum) exposed to deep hypoxia increases significantly within the first 10 min, subsequently decreasing dramatically. This is in accordance with the changes in red cell levels of GTP. We suggest that the initial increase of mRNA level eIF2ƒÑ assures the synthesis of proteins needed to face hypoxia with a subsequent shutdown to reduce energy demand. (CNPq, FAPEAM). doi:10.1016/j.cbpa.2007.06.063
5.3. Not only oxygen: the other side of globin function Fago, A. Department of Biological Sciences, University of Aarhus, Denmark [email protected] It has recently become increasingly clear that the physiological role of globin proteins in vertebrates is not only limited to the well-known oxygen transport and storage functions of the hemoglobin in red blood cells and the myoglobin in heart and skeletal muscle, but also includes a wide variety of other functions. These involve the preserving or scavenging of vasoactive nitric oxide (NO) generated within blood vessels, formation of S-nitrosothiols involved in cellular signalling, and several redox reactions favoured by hypoxic conditions, such as the reduction of endogenous nitrite into NO for the control of vasodilation and mitochondrial respiration, the scavenging of toxic peroxynitrite and the reduction of cytochrome c, possibly preventing cellular apoptosis. Although the biological significance of many of these reactions remains controversial, the four major vertebrate globins, hemoglobin, myoglobin, neuroglobin and cytoglobin, clearly show distinctive patterns of reactivity due to differences in heme-iron coordination and reducing potentials, thiol groups accessibility and presence of external and internal cavities for non-covalent binding of cofactors or ligand diffusion. Specifically, our data indicate that neuroglobin seems to be the most likely candidate among globins for the catalysis of most of these redox-reactions, a feature that apparently relates to its most ancient phylogenetic origin. doi:10.1016/j.cbpa.2007.06.061
5.4. Big insights from little animals: allosteric modulation and thermal sensitivity of shrew and mole hemoglobins Campbell, K.L. and Weber, R.E. Biological Sciences, University of Manitoba, Canada [email protected] Mass-specific metabolic rate varies inversely with size, while pulmonary transit time, muscle O2 storage capacity, and the ability to exploit anaerobic metabolism vary directly with this variable. Thus, small mammals must exploit a suite of morphological and physiological adjustments to supply tissue mitochondria with sufficient O2 to fuel oxidative metabolism, such as blood with a high Bohr coefficient and half-saturation pressure (P50). However, a high P50 may drastically impede hemoglobin (Hb) saturation at low ambient PO2's and place a considerable strain on the hypoxia tolerance of shrews and moles. Despite these constraints, several shrew (and mole) species flourish at elevations exceeding 4500 m (where atmospheric PO2 is b 100 mm Hg), while fossorial moles
S25
excavate subterranean burrows in severely hypoxic/hypercapnic soils. As most physiological and morphological traits are likely already operating near their upper limits, what if any additional functional properties of the Hb of these species make these achievements possible? Our findings suggest that changes in the intrinsic O2-affinity of the Hb moiety (rather than phosphate sensitivity) underlie transitions to and from hypoxic environments in members of each of these groups. Comparative gene sequencing further demonstrates that the novel ‘cathodic’ Hbs of these insectivorous mammals (which are dually modulated by both phosphate and chloride ions) arose prior to the mole/ shrew radiation. doi:10.1016/j.cbpa.2007.06.062
5.5. Novel environmental adaptations in lower vertebrate erythrocytes Val, A.L., Nozawa, S.R., Honda, R.T., and de Almeida-Val, V.M.F. Instituto Nacional de Pesquisas da Amazônia-INPA, Brazil [email protected] Erythrocytic microenvironment is continuously adjusted to maintain tissue oxygen supply in fish facing either environmental or physiological constraints. During hypoxia, downregulation of protein synthesis is followed by adjustments in the levels of modulators of Hb-O2 affinity to ensure oxygen transfer to the tissues. ATP and GTP are the major modulators of Hb-O2 affinity and have been described in fish red blood cells. Compared to ATP, GTP is a stronger modulator and its concentration decreases faster in animals exposed to hypoxia. In several fish species of the Amazon, a reduction of GTP is observed within the first 10 min of hypoxia. Since protein synthesis is the second costliest energy consuming process, a decrease in the rate of translation process is vital for a cell experiencing oxygen shortage. Eukaryotic initiation factors family (eIFs) are involved with the regulation of protein synthesis, a process that begins when both mRNA and the initiator methionyl (Met)-tRNA are bound to the ribosome. This process is achieved when the eIF2ƒÑ binds to GTP producing eIF2-GTP hydrolyzing to eIF2-GDP-bound and Pi and released; the GDP must be replaced by GTP in subsequent rounds. Semiquantitative expression of eIF2ƒÑ in the red blood cells of tambaqui (Colossoma macropomum) exposed to deep hypoxia increases significantly within the first 10 min, subsequently decreasing dramatically. This is in accordance with the changes in red cell levels of GTP. We suggest that the initial increase of mRNA level eIF2ƒÑ assures the synthesis of proteins needed to face hypoxia with a subsequent shutdown to reduce energy demand. (CNPq, FAPEAM). doi:10.1016/j.cbpa.2007.06.063