structures of myoglobin and hemoglobin
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Structures of Myoglobin and Hemoglobin. Myoglobin ( Mb ) - monomeric protein that facilitates the diffusion of oxygen in vertebrates Hemoglobin ( Hb ) - tetrameric protein that carries oxygen in the blood - PowerPoint PPT PresentationTRANSCRIPT
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Structures of Myoglobin and Structures of Myoglobin and HemoglobinHemoglobin
• Myoglobin (Mb) - monomeric protein that facilitates the diffusion of oxygen in vertebrates
• Hemoglobin (Hb) - tetrameric protein that carries oxygen in the blood
• Heme consists of a tetrapyrrole ring system called protoporphyrin IX complexed with iron
• Heme of Mb and Hb binds oxygen for transport
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Heme Fe(II)-protoporphyrin IXHeme Fe(II)-protoporphyrin IX
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Protein component of Mb and Protein component of Mb and Hb is globinHb is globin
• Myoglobin is composed of 8 helices
• Heme prosthetic group binds oxygen
• His-93 is complexed to the iron atom, and His-64 forms a hydrogen bond with oxygen
• Interior of Mb almost all hydrophobic amino acids
• Heme occupies a hydrophobic cleft formed by three helices and two loops
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Sperm whale oxymyoglobinSperm whale oxymyoglobin
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Hemoglobin (Hb)Hemoglobin (Hb)
• Hb is an tetramer (2 globin subunits, 2 globin subunits)
• Each globin subunit is similar in structure to myoglobin
• Each subunit has a heme group
• The chain has 7 helices, chain has 8 helices
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Hemoglobin tetramerHemoglobin tetramer
(a) Human oxyhemoglobin (b) Tetramer schematic
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Oxygen Binding to Mb and HbOxygen Binding to Mb and Hb
• Oxymyoglobin - oxygen bearing myoglobin
• Deoxymyoglobin - oxygen-free myoglobin
• In oxymyoglobin, six ligands are coordinated to the ferrous ion in octahedral symmetry
• Oxygen is coordinated between the iron and the imidazole sidechain of His-64
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Oxygen-binding site of Oxygen-binding site of whale oxymyoglobinwhale oxymyoglobin
• Octahedral geometry of coordination complex (six ligands around iron)
• His-93 (proximal histidine) liganded to Fe
• His-64 (distal histidine)
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Oxygen-binding curvesOxygen-binding curves
(a) Comparison of O2-binding to Mb and Hb
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Oxygen-Binding Curves of Oxygen-Binding Curves of Myoglobin and HemoglobinMyoglobin and Hemoglobin
• Curves show reversible binding of O2 to Mb and Hb
• Fractional saturation (Y) is plotted versus the partial pressure of oxygen, pO2 (oxygen concentration)
• The shape of the Hb curve shows a positive cooperativity in the binding of 4 O2 molecules (i.e. the O2 affinity of Hb increases as each O2 molecule is bound)
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Oxygen-binding curvesOxygen-binding curves
(a) Comparison of O2-binding to Mb and Hb
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OO22 binding curves (continued) binding curves (continued)
Mb-O2 binding curve is hyperbolic, indicating a single equilibrium constant for binding O2
Hb-O2 binding curve is sigmoidal, and reflects the binding of 4 molecules of O2, one per each heme group
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Oxygen-binding curvesOxygen-binding curves
(a) Comparison of O2-binding to Mb and Hb
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Oxygen-binding curvesOxygen-binding curves
Binding of the R (high-affinity) and T (low affinity) forms of Hb
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Conformational changes in a Conformational changes in a hemoglobin chain induced by hemoglobin chain induced by
oxygenationoxygenation
• Oxygen binding to Fe pulls the His toward ring plane
• Helix with His shifts position, disrupting some ion pairs between subunits (blue to red position)
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Oxygen-binding site of Oxygen-binding site of whale oxymyoglobinwhale oxymyoglobin
• Octahedral geometry of coordination complex (six ligands around iron)
• His-93 (proximal histidine) liganded to Fe
• His-64 (distal histidine)
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Hemoglobin is an Allosteric Hemoglobin is an Allosteric ProteinProtein
• Oxygen binding and release from Hb are regulated by allosteric interactions
• Allosteric effectors (modulators) bind to a protein at a site separate from the functional binding site (may be activators or inhibitors)
• The activity of an allosteric protein is regulated by allosteric effectors
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Two conformations of Two conformations of hemoglobin: T and Rhemoglobin: T and R
• Active (R state) and inactive (T state) forms are in rapid equilibrium in allosteric proteins
• Binding of substrates and allosteric activators stabilize the R state and shift the equilibrium in the R direction
• Allosteric inhibitors stabilize the T state and shift the equilibrium in the T direction
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BisBisphospho-D-glycerate phospho-D-glycerate (2,3BPG)(2,3BPG)
• 2,3BPG is an allosteric effector of Hb
• 2,3BPG lowers the affinity of deoxyHb for oxygen (raises the P50 of Hb from ~12 to ~26 torr)
• Negatively charged 2,3BPG is bound to six (+) charged groups of deoxyhemoglobin
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BisBisphospho-D-glycerate phospho-D-glycerate (2,3BPG)(2,3BPG)
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Binding of 2,3BPG to Binding of 2,3BPG to deoxyhemoglobindeoxyhemoglobin
• (-) Charges on 2,3BPG pair with (+) charges lining the central cavity, stabilizing the DeoxyHb form
• -Subunits pink, -subunits blue, heme groups red
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Oxygen-binding curvesOxygen-binding curves
(a) Comparison of O2-binding to Mb and Hb
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Bohr effectBohr effect
• Lowering the pH decreases the affinity of Hb for oxygen
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Carbamate adductCarbamate adduct
• Carbon dioxide is transported from the tissues to the lungs in two ways:(1) Dissolved bicarbonate ions(2) Carbamate adducts of hemoglobin (N-terminal globin residues react with CO2 to form carbamates)
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Review of Relevant ParametersReview of Relevant Parameters
(1) Low P50 indicates high O2 affinity
(2) Low pH (through CO2 intake) stabilizes 2,3-BPG and lowers O2 affinity
(3) Raising P50 causes unloading of O2
Oxy-Hb Deoxy-Hb
(R) (T)
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Case StudiesCase Studies
Shock victims are given intravenous HCO3-
Why?
HCO3- generates CO2 to the tissues
and lowers the O2 affinity of Hb,
thus releases O2 from HbO2 to the tissues
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Case StudiesCase Studies
Fetal Hb (HB-F) contains ser in place of the cationic his at position 143 of the chains of adult Hb (HB-A). Residue 143 faces the central cavity between the chains
Outcomes:
his in Hb-A is protonated and thus binds more tightly to negatively charged 2,3-BPG;
ser in Hb-F is not protonated and does not bind to 2,3-BPG as strongly; thus Hb-F has a greater fraction of HbO2
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Case StudiesCase Studies
Fetal Hb (HB-F) contains ser in place of the cationic his at position 143 of the chains of adult Hb (HB-A). Residue 143 faces the central cavity between the chains
Outcomes:
Hb-F has a greater fraction of HbO2 which means greater O2 affinity and lower P50 (18 torr)
Since average P50 for Hb-A is 26 torr, oxygen can efficiently be transferred from maternal blood to fetus
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Antibodies Bind Specific Antibodies Bind Specific AntigensAntigens
• Vertebrate immune systems synthesize protein antibodies (immunoglobulins) to eliminate bacteria, viruses, other foreign substances
• Antibodies specifically recognize and bind antigens
• Antibodies are synthesized by lymphocytes (white blood cells)
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Human antibody structureHuman antibody structure
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• Heavy chains (blue) and light chains (red)
• Disulfide bonds (yellow)
• Variable domains colored darker
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Stereo view of the Stereo view of the immunoglobin foldimmunoglobin fold
• Two antiparallel sheets linked by nonrepetitive segments
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Binding of three different Binding of three different antibodies to an antigenantibodies to an antigen