| 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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- 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?
- Speculate on the mechanisms by which an adult with sickle cell disease would benefits from a fetal hemoglobin (HbF) level of 20%.
- 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.
- 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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Kendall RG. Erythropoietin. Clin Lab Haem 2001;23:71-80.
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| Klein HG. The prospects for red-cell substitutes. New Engl J Med 2000;342: 1666-8.
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| Ou CN, Rognerud CL. Diagnosis of hemoglobinopathies: electrophoresis vs. HPLC. Clin Chim Acta 2001;313:187-94.
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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.
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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.
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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.
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| Globin Gene Server (links to sites describing human hemoglobinopathies and thalassemias): globin.cse.psu.edu/globin/html/
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| The Red Cell and Anemia (a 5-part presentation by pathologist E Uthman): web2.iadfw.net/uthman/blood cells.html
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| Sickle Cell Information Center (comprehensive site for both patients and professionals): www.scinfo.org/
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| Modified hemoglobins: www.1uphealth.com/health/hemoglobin_derivatives_info.html
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