chapter 10personal.tcu.edu/yryu/50133/hemoglobin.pdf · chapter 10 oxygen transporting proteins....
TRANSCRIPT
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Chapter 10
Oxygen Transporting Proteins
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Oxygen-transport proteins
• Vertebrates– Myoglobin (Muscle)– Hemoglobin (Blood)
• Invertebrates– Hemerythrin– Hemocyanin
O2-binding site of hemocyanin
CuO2
Heme
O2
Cu Cu
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Myoglobin
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Myoglobin’s oxygen-binding curve is hyperbolicMb + O2 MbO2
K= [Mb][O2]
[MbO2]
Fractonal saturation (YO2)
YO2 = [MbO2]
[MbO2][Mb]+
[MbO2] = [Mb][O2]
K
YO2 =
[Mb][O2]
K
[Mb][O2]
K[Mb] +
YO2 = [O2]
[O2]K +
YO2 = pO2
pO2K +
Because
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HemoglobinA tetrameric protein with two alpha and two beta chains
Both chains fold into a Mb-like structure
An oxygen carrier protein
Provides oxygen to differenttypes of tissues
Hb has two different conformations; oxygen-bound and unbound
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Deoxyhemoglobin
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Oxyhemoglobin
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Differences between deoxy- and oxy-Hb
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Why do we need blood to transport O2?
Why do we need hemoglobin?
Why does hemoglobin have 4 subunits?
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In organisms larger than 2 mm, diffusion is too slow to supply the tissues with O2
We need hemoglobin to increase O2 solubility of blood
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Hemoglobin transports O2from the lungs to the tissues
Take up as much O2 in the lungs as possibleLeave as much O2 behind as possible in the tissues
How is the affinity to O2 controlled?
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Hemoglobin’s oxygen-binding curve is sigmoidal
26
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• Hb contains 4 O2 binding sites• Binding at one site affects the binding at other
sites• Binding of O2 to one site increases the affinity
of the remaining sites (lungs)• Release of O2 from one site reduces the
affinity of the remaining sites (tissues)
Sigmoidal binding curve suggests cooperativity
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Mathematical model (Hill equation)
Assuming that hemoglobin (Hb) bound n molecules of O2in a single step with infinite cooperativity,
n (Hill coefficient): Degree of cooperativity
n = 1: noncooperative (myoglobin)n > 1: positively cooperativen < 1: negatively cooperative
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Hill plot
Slope = nIntercept = p50
30
0.3
The last (4th) O2 to bind to hemoglobin does so with 100-fold greater affinity than the first
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Mechanism of cooperativity(Perutz Mechanism)
T State (deoxyHb)
R State (oxyHb)
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Switch between T and R state
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Stabilization of T state without Fe-O2 bonds
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Hemoglobin is the perfect O2 transporter
• Sigmoidal O2 binding curve• Decrease in pH reduces the affinity for O2
• CO2 reduces the affinity for O2
Interaction between 4 subunits
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Decrease in pH reduces the affinity for O2
• Protonation of Hb at low pH• N-amino group (α subunits)
• C-terminal His (β subunits)
When protonated these groups are involved in ion-pairs that stabilize the T form (deoxy-Hb)
HbH+ + O 2 ↔ HbO2 + H +
Bohr effect
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Stabilization of T state without Fe-O2 bonds
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The O2 affinity increase with increasing pH
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Hemoglobin and CO2
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CO2 can also bind directly to Hb
N-terminal NH2 groups reacts with CO2 to form a carbamate
R-NH2 + CO2 R-NH-COO- + H+
• The T form binds more CO2 as carbamate• The carbamate formation stabilizes the T form (O2 release)
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H+ production in tissues
• CO2 + H2O H+ + HCO3-
• Lactic acid H+ + Lactate-
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O2
H+
CO2
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• High pH• Low pCO2
• High pO2
O2 binding
• Low pH• High pCO2
• Low pO2
O2 release
TissueLung
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BPG decreases the affinity for O2
• Synthesized in red blood cells
• Lowers the affinity for O2• In the absence of BPG,
the affinity for O2 would be too high
• Binds to the central cavity of T-state Hb
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BPG plays a role in altitude adaptationand delivery of O2 to the fetus
• At high altitude the pO2 is lower• Increase in BPG concentration• Small decrease in O2-binding (lungs)• Much larger increase in O2 release
(tissues)
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• O2 binding at one site increases the affinity of the other sites for O2
• H+ decreases the affinity of Hb for O2• CO2 decreases the affinity of Hb for O2• DPG decreases the affinity of Hb for O2
Binding of a molecule to one site affects the activity ofthe protein at a different site
Allosteric effect
• Positive effector (modulator) • Negative effector (modulator)
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Allosteric models
Symmetry model Sequential model (induced-fit model)
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Symmetry model of allosterism
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Sequential model of allosterism
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Abnormal hemoglobins
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Normal vs Sickled blood cells
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HbS Fiber
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HbS fiber
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Malaria and HbSThe sickle cell gene confers resistance to malaria
Malaria parasite increases the acidity of the infected erythrocytes → Promote formation of deoxyHb→ Promote sickling of the infected erythrocytes→ Removal of the infected sickle cells by the spleen (early stage)→ Disruption of the parasite by sicking (late stage)