Structure and function of Structure and function of hemoglobinhemoglobin
GIT | 1 Lecture | Dr. Usman GhaniGIT | 1 Lecture | Dr. Usman Ghani
Hemoglobin (Hb)Hemoglobin (Hb)
A hemeprotein found only in red blood cellsA hemeprotein found only in red blood cells Oxygen transport functionOxygen transport function Contains heme as prosthetic groupContains heme as prosthetic group Heme reversibly binds to oxygenHeme reversibly binds to oxygen
The heme groupThe heme group A complex of protoporphyrin IX and ferrous A complex of protoporphyrin IX and ferrous
iron (Feiron (Fe2+2+)) FeFe2+2+ is present in the center of the heme is present in the center of the heme FeFe2+ 2+ binds to four nitrogen atoms of the binds to four nitrogen atoms of the
porphyrin ringporphyrin ring Forms two additional bonds with:Forms two additional bonds with:
Histidine residue of globin chainHistidine residue of globin chain OxygenOxygen
The heme group: Fe2+– porphyrin complex with bound O2
Types of HbTypes of HbNormal: HbA (97%)
HbA2 (2%)
HbF (1%)HbA1c
Abnormal:Abnormal: Carboxy HbMet HbSulf Hb
Hemoglobin A (HbA)Hemoglobin A (HbA) Major Hb in adultsMajor Hb in adults Composed of four polypetide chains:Composed of four polypetide chains:
Two Two αα and two and two ββ chains chains Contains two dimers of Contains two dimers of subunits subunits Held together by non-covalent interactionsHeld together by non-covalent interactions Each chain is a subunit with a heme group in the center Each chain is a subunit with a heme group in the center
that carries oxygenthat carries oxygen A Hb molecule contains 4 heme groups and carries 4 A Hb molecule contains 4 heme groups and carries 4
moelcules of Omoelcules of O22
HbA structureHbA structure
T-form of HbT-form of Hb
The deoxy form of HbThe deoxy form of Hb Taut formTaut form The movement of dimers is The movement of dimers is
constrainedconstrained Low-oxygen-affinity formLow-oxygen-affinity form
R-form of HbR-form of Hb
The oxygenated form of HbThe oxygenated form of Hb Relaxed formRelaxed form The dimers have more The dimers have more
freedom of movementfreedom of movement High-oxygen-affinity formHigh-oxygen-affinity form
Hemoglobin functionHemoglobin function
Carries oxygen from the lungs to tissuesCarries oxygen from the lungs to tissues Carries carbon dioxide from tissues back to Carries carbon dioxide from tissues back to
the lungsthe lungs Normal level (g/dL):Normal level (g/dL):
• Males: 14-16Males: 14-16• Females: 13-15Females: 13-15
Factors affecting oxygen bindingFactors affecting oxygen binding
Three allosteric effectors:Three allosteric effectors: pOpO22 (partial oxygen pressure) (partial oxygen pressure) pH of the environmentpH of the environment pCOpCO2 2 (partial carbon dioxide pressure)(partial carbon dioxide pressure) Availability of 2,3-bisphosphoglycerateAvailability of 2,3-bisphosphoglycerate
Oxygen Dissociation CurveOxygen Dissociation Curve The curve is sigmoidalThe curve is sigmoidal Indicates cooperation of Indicates cooperation of
subunits in Osubunits in O22 binding binding Binding of OBinding of O22 to one heme to one heme
group increases Ogroup increases O22 affinity affinity of othersof others
Heme-heme interactionHeme-heme interaction
PP5050
Indicates affinity of Hb to OIndicates affinity of Hb to O22 PP5050(mm Hg): the pressure at which Hb is 50% (mm Hg): the pressure at which Hb is 50%
saturated with Osaturated with O22 High affinity High affinity slow unloading of O slow unloading of O22 Low affinity Low affinity fast unloading of O fast unloading of O22 Lung pOLung pO22 is 100 mm is 100 mm Hb saturation 100% Hb saturation 100% Tissue pOTissue pO22 is 40 mm is 40 mm Hb saturation reduces Hb saturation reduces Hence OHence O22 is delivered to tissues is delivered to tissues
The Bohr effectThe Bohr effect Effect of pH and pCOEffect of pH and pCO22 on: on:
Oxygenation of Hb in the Oxygenation of Hb in the lungslungs
Deoxygenation in tissuesDeoxygenation in tissues Tissues have lower pH (acidic) Tissues have lower pH (acidic)
than lungsthan lungs Due to proton generation:Due to proton generation:
COCO22 + H + H220 0 HCO HCO33-- + H + H++
Protons reduce OProtons reduce O22 affinity of affinity of HbHb
The Bohr Effect The Bohr Effect Causing easier OCausing easier O22 release into the tissues release into the tissues The free Hb binds to two protonsThe free Hb binds to two protons Protons are released and react with HCOProtons are released and react with HCO33 –– to form CO to form CO22 gas ( gas (HCOHCO33
-- + H + H++COCO22 + H + H220 0 ))
The proton-poor Hb now has greater affinity for OThe proton-poor Hb now has greater affinity for O2 2 (in lungs)(in lungs) The Bohr effect removes insoluble COThe Bohr effect removes insoluble CO22 from blood stream from blood stream Produces soluble bicarbonateProduces soluble bicarbonate
Availability of 2,3 bisphosphoglycerateAvailability of 2,3 bisphosphoglycerate Binds to deoxy-hb and stabilizes the T-formBinds to deoxy-hb and stabilizes the T-form When oxygen binds to Hb, BPG is releasedWhen oxygen binds to Hb, BPG is released
At high altitudes:-RBC number increases-Hb conc. increases-BPG increases
High altitude and OHigh altitude and O22 affinity affinity
In hypoxia and high altitudeIn hypoxia and high altitude 2,3 BPG levels rise2,3 BPG levels rise This decreases OThis decreases O2 2 affinity of Hbaffinity of Hb Thus increases OThus increases O22 delivery to tissues delivery to tissues
High OHigh O22 affinity affinity
High OHigh O22 affinity is due to: affinity is due to: AlkalosisAlkalosis High levels of Hb FHigh levels of Hb F Multiple transfusion of 2,3 DPG-depleted Multiple transfusion of 2,3 DPG-depleted
bloodblood
Low affinity to O2
High affinity to O2
Fetal Hemoglobin (HbF)Fetal Hemoglobin (HbF) Major hemoglobin found in the fetus and Major hemoglobin found in the fetus and
newbornnewborn Tetramer with two Tetramer with two and two and two chains chains Higher affinity for OHigher affinity for O22 than HBA than HBA Transfers OTransfers O22 from maternal to fetal circulation from maternal to fetal circulation
across placentaacross placenta
HbAHbA22
Appears ~12 weeks after birthAppears ~12 weeks after birth Constitutes ~2% of total HbConstitutes ~2% of total Hb Composed of two Composed of two and two and two globin chains globin chains
HbAHbA1c1c
HbA undergoes non-HbA undergoes non-enzymatic glycosylationenzymatic glycosylation
Glycosylation depends on Glycosylation depends on plasma glucose levelsplasma glucose levels
HbA1c levels are high in HbA1c levels are high in patients with diabetes patients with diabetes mellitusmellitus
Abnormal HbsAbnormal Hbs
Unable to transport OUnable to transport O22 due to abnormal due to abnormal structurestructure
Carboxy-Hb: CO replaces OCarboxy-Hb: CO replaces O22 and binds 200X and binds 200X tighter than Otighter than O2 2 (in smokers)(in smokers)
Met-Hb: Contains oxidized FeMet-Hb: Contains oxidized Fe3+3+ (~2%) that (~2%) that cannot carry Ocannot carry O22
Sulf-HB: Forms due to high sulfur levels in Sulf-HB: Forms due to high sulfur levels in blood (irreversible reaction)blood (irreversible reaction)
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