2-Structure and Function of Hemoglobin.ppt transporting oxygen from the lungs to the tissues and facilitating the return transport of carbon dioxide.

Hemoglobin is a two-way respiratory carrier, transporting oxygen from the lungs to the tissues and facilitating the return transport of carbon dioxide. In the arterial circulation, hemoglobin has a high affinity for oxygen and a low affinity for carbon dioxide, organic phosphates, and hydrogen and chloride ions.

1. Structure and function of Structure and function of
hemoglobinhemoglobin

2. ObjectivesObjectives
By the end of this lecture, the students should be By the end of this lecture, the students should be
able to know:able to know:

the structure and function of hemoglobin.the structure and function of hemoglobin.

the factors affecting oxygen binding to the factors affecting oxygen binding to
hemoglobin.hemoglobin.

examples of normal and abnormal hemoglobin examples of normal and abnormal hemoglobin
structures.structures.

3. 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

4. The heme groupThe heme group

A complex of protoporphyrin IX and ferrous A complex of protoporphyrin IX and ferrous
iron (Feiron (Fe
2+2+
))

FeFe
2+2+
is present in the center of the heme is present in the center of the heme

FeFe
2+ 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

5. The heme group: Fe
2+
– porphyrin complex with bound O
2

6. Types of HbTypes of Hb
Normal: HbA (97%)
HbA
2 (2%)
HbF (1%)
HbA
1c
Abnormal:Abnormal: Carboxy Hb
Met Hb
Sulf Hb

7. 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 O
22

9. HbA structureHbA structure

10. 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

11. 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

12. 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

13. Factors affecting oxygen bindingFactors affecting oxygen binding

Three allosteric effectors:Three allosteric effectors:
pOpO
22 (partial oxygen pressure) (partial oxygen pressure)

pH of the environmentpH of the environment
pCOpCO
2 2 (partial carbon dioxide pressure)(partial carbon dioxide pressure)

Availability of 2,3-bisphosphoglycerateAvailability of 2,3-bisphosphoglycerate

14. Oxygen Dissociation CurveOxygen Dissociation Curve

The curve is sigmoidalThe curve is sigmoidal

Indicates cooperation of Indicates cooperation of
subunits in Osubunits in O
22 binding binding
Binding of OBinding of O
22 to one heme to one heme
group increases Ogroup increases O
22 affinity affinity
of othersof others

Heme-heme interactionHeme-heme interaction

15. PP
5050

Indicates affinity of Hb to OIndicates affinity of Hb to O
22

PP
5050(mm Hg): the pressure at which Hb is 50% (mm Hg): the pressure at which Hb is 50%
saturated with Osaturated with O
22

High affinity High affinity  slow unloading of O slow unloading of O
22

Low affinity Low affinity  fast unloading of O fast unloading of O
22

Lung pOLung pO
22 is 100 mm is 100 mm  Hb saturation 100% Hb saturation 100%

Tissue pOTissue pO
22 is 40 mm is 40 mm  Hb saturation reduces Hb saturation reduces

Hence OHence O
22 is delivered to tissues is delivered to tissues

17. The Bohr effectThe Bohr effect
Effect of pH and pCOEffect of pH and pCO
22 on: on:

Oxygenation of Hb in the lungsOxygenation of Hb in the lungs

Deoxygenation in tissuesDeoxygenation in tissues

Tissues have lower pH (acidic) Tissues have lower pH (acidic)
than lungsthan lungs

Due to proton generation (two Due to proton generation (two
reactions):reactions):
COCO
22 + H + H
220 0  HCO HCO
33
--
+ H + H
++
Protons reduce OProtons reduce O
22 affinity of Hb affinity of Hb

18. The Bohr Effect The Bohr Effect
Causing easier OCausing easier O
22 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 HCO
33

––
to form CO to form CO
22 gas ( gas (HCOHCO
33
--
+ H + H
++
COCO
22 + H + H
220 )0 )
The proton-poor Hb now has greater affinity for OThe proton-poor Hb now has greater affinity for O
2 2 (in lungs)(in lungs)
The Bohr effect removes insoluble COThe Bohr effect removes insoluble CO
22 from blood stream from blood stream

Produces soluble bicarbonateProduces soluble bicarbonate

19. 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

20. High altitude and OHigh altitude and O
22 affinity affinity

In hypoxia and high altitudeIn hypoxia and high altitude

2,3 BPG levels rise2,3 BPG levels rise

This decreases OThis decreases O
2 2 affinity of Hbaffinity of Hb

Thus increases OThus increases O
22 delivery to tissues delivery to tissues

21. High OHigh O
22 affinity affinity
High OHigh O
22 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

22. Low affinity to O
2
High affinity to O
2

23. 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 O
22 than HBA than HBA
Transfers OTransfers O
22 from maternal to fetal circulation from maternal to fetal circulation
across placentaacross placenta

24. HbAHbA
22

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

25. HbAHbA
1c1c

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

26. Abnormal HbsAbnormal Hbs
Unable to transport OUnable to transport O
22 due to abnormal due to abnormal
structurestructure

Carboxy-Hb: CO replaces OCarboxy-Hb: CO replaces O
22 and binds 220X and binds 220X
tighter than Otighter than O
2 2 (in smokers)(in smokers)

Met-Hb: Contains oxidized FeMet-Hb: Contains oxidized Fe
3+3+
(~2%) that (~2%) that
cannot carry Ocannot carry O
22

Sulf-HB: Forms due to high sulfur levels in Sulf-HB: Forms due to high sulfur levels in
blood (irreversible reaction)blood (irreversible reaction)

27. ReferenceReference
Lippincott’s Illustrated Reviews Biochemistry: Lippincott’s Illustrated Reviews Biochemistry:
Unit I, Chapter 3, Pages 25 -42.Unit I, Chapter 3, Pages 25 -42.