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Summary
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This chapter describes two important proteins that reversibly interact with O2 - myoglobin (Mb), a tissue oxygen storage molecule, and hemoglobin (Hb), a blood oxygen transport molecule. Both use an ancient heme-containing polypeptide domain motif to sequester O2 and increase its solubility. These proteins must function efficiently in rather different biochemical environments to sustain aerobic metabolism. As a tetramer of globins, Hb is one of the best-characterized examples of cooperativity in ligand interactions. With its wide variety of effector molecules, Hb is also a prototype of an allosteric protein. Conformational changes in both the tertiary and quaternary structures characterize the transition between deoxygenated and oxygenated states. Mutations to globin genes lead to a spectrum of structural and functional variants, among which are fetal Hb and sickle cell disease.
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Active learning
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  1. Discuss why some genetic mutations to α-globin or β-globin result in a pathological phenotype while the majority remain silent or benign. Which kind are the most difficult to detect?
  2. Speculate on the mechanisms by which an adult with sickle cell disease would benefits from a fetal hemoglobin (HbF) level of 20%.
  3. Many Hb-based oxygen carriers have a decreased sensitivity to pH and an increased susceptibility to oxidation. Discuss the consequences of a reduced Bohr effect to oxygen delivery to the periphery, tissue acid-base balance, and CO2 transport to the lungs.
  4. Discuss the requirement for supplemental iron during rHuEPO treatment. Comment on the use of rHuEPO by athletes as a performance-enhancing drug. Design a laboratory test that could potentially differentiate endogenous EPO from rHuEPO in human urine.
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Further reading
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Kendall RG. Erythropoietin. Clin Lab Haem 2001;23:71-80. Full articleGo to this article on the publisher's site
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Klein HG. The prospects for red-cell substitutes. New Engl J Med 2000;342: 1666-8. Full articleGo to this article on the publisher's site
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Ou CN, Rognerud CL. Diagnosis of hemoglobinopathies: electrophoresis vs. HPLC. Clin Chim Acta 2001;313:187-94. Full articleGo to this article on the publisher's site
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Perutz MF. Molecular anatomy and physiology of hemoglobin. In: Steinberg MH, Forget BG, Higgs DR, Nagel RL, eds Disorders of Hemoglobin: Genetics, Pathophysiology, and Clinical Management. Cambridge: Cambridge University Press; 2001:174-96. Full articleGo to this article on the publisher's site
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Pesce A, Bolognesi M, Bocedi A, Ascenzi P, Dewilde S, Moens L, Hankeln T, Burmester T. Neuroglobin and cytoglobin. Fresh blood for the vertebrate globin family. EMBO Reports 2002;3:1146-51. Full articleGo to this article on the publisher's site
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Roach RC, Hackett PH. Frontiers of hypoxia research: acute mountain sickness. J Exp Biol 2001;204:3161-70.
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Wittenberg JB, Wittenberg BA. Myoglobin function reassessed. J Exp Biol 2003;206:2011-20. Full articleGo to this article on the publisher's site
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Relevant websites
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Globin Gene Server (links to sites describing human hemoglobinopathies and thalassemias): globin.cse.psu.edu/globin/html/ Full articleGo to this article on the publisher's site
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The Red Cell and Anemia (a 5-part presentation by pathologist E Uthman): web2.iadfw.net/uthman/blood cells.html Full articleGo to this article on the publisher's site
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Sickle Cell Information Center (comprehensive site for both patients and professionals): www.scinfo.org/ Full articleGo to this article on the publisher's site
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Modified hemoglobins: www.1uphealth.com/health/hemoglobin_derivatives_info.html Full articleGo to this article on the publisher's site
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