Hemoglobin

HaemoglobinHaemoglobin
By:By: Aya zakryaAya zakrya
Aya khairyAya khairy
AyaAya
ayaaya
Under supervision of:Under supervision of:
Dr/ Mamdoh M. ElshishtawyDr/ Mamdoh M. Elshishtawy

 The main function of red blood cellThe main function of red blood cell
 Transfer of OTransfer of O22 from lungs to tissuefrom lungs to tissue
 Transfer of COTransfer of CO22 from tissue to lungsfrom tissue to lungs
 To accomplish this function red cells hasTo accomplish this function red cells has
haemoglobin (Hb)haemoglobin (Hb)
 Each red cell has 640 million molecules ofEach red cell has 640 million molecules of
HbHb
IntroductionIntroduction

IntroductionIntroduction
 Haemoglobin (Hb), protein constituting 1/3 of theHaemoglobin (Hb), protein constituting 1/3 of the
red blood cellsred blood cells
 Synthesis begins in proerythroblastSynthesis begins in proerythroblast
 65% at erythroblast stage65% at erythroblast stage
 35% at reticulocyte stage35% at reticulocyte stage
 Two partsTwo parts
 HaemHaem
 GlobinGlobin

Synthesis of Haemoglobin (Hb)Synthesis of Haemoglobin (Hb)
 Haem & globin produced at two differentHaem & globin produced at two different
sites in the cellssites in the cells
 Haem in mitochondriaHaem in mitochondria
 Globin in polyribosomesGlobin in polyribosomes

Structure of hemoglobinStructure of hemoglobin
 Hemoglobin is a globular protein made up of four
subunits, each of which contains a polypeptide chain
called globin and a heme group.
The globin tertiary structure comprises a helical
structures joined by non-helical segments. Four such
globins are arranged together, giving rise to the spherical
quaternary structure of hemoglobin
Hemoglobins are classified into different types,
depending on the combination of the two sets of globin
units. Most of the hemoglobin present in adult humans
comprises 2 α globins and 2 β globins

 The heme group bound to each globin is an organic
macromolecule with an iron at the center. It serves as
the prosthetic group of hemoglobin. The prosthetic group
of a protein refers to any tightly-bound non-protein entity,
that is essential for the structural and functional integrity
of the protein.
The heme group comprises a structure called the
porphyrin ring, which is formed by the combination of
four heterocyclic rings called pyrroles. An iron ion (Fe2+)
is present at the center of this structure, and is bound to
the nitrogen atoms of the four pyrrole rings. It is this
central iron which provides the reversible binding to
oxygen and carbon dioxide molecules.

made up of four subunits each of which
contains globin and a heme group
The heme group: Fe2+
–
porphyrin complex with bound
O2

HB structure animationHB structure animation

Oxygen transportOxygen transport

Functions
 Oxygen transport is the main function of hemoglobin,
and more than 98% of the oxygen in blood is carried
through hemoglobin. In addition, it also transports carbon
dioxide released by peripheral tissues to the lung
tissues. During this process, the hemoglobin
macromolecule undergoes conformational changes due
to the binding and unbinding of oxygen and carbon
dioxide.and it include :
1_ Oxygen Pickup
 2_ Oxygen Delivery
3_ Carbon Dioxide Pickup
4_ Carbon Dioxide Delivery

Functions
 NotesNotes
1_Oxygenation not oxidation1_Oxygenation not oxidation
2_One Hb can bind to four O2 molecules2_One Hb can bind to four O2 molecules
3_Less than .01 sec required for3_Less than .01 sec required for
Oxygenation..Oxygenation..

Functions
Oxygen Pickup Oxygen Delivery

Functions
Carbon Dioxide Pickup Carbon Dioxide Delivery

Oxy & deoxyhaemoglobinOxy & deoxyhaemoglobin

Factors affecting oxygenFactors affecting oxygen
bindingbinding
 In order to function most efficiently, hemoglobinIn order to function most efficiently, hemoglobin
needs to bind to oxygen tightly in the oxygen-needs to bind to oxygen tightly in the oxygen-
rich atmosphere of the lungs and be able torich atmosphere of the lungs and be able to
release oxygen rapidly in the relatively oxygen-release oxygen rapidly in the relatively oxygen-
poor environment of the tissuespoor environment of the tissues
 Essentially, hemoglobin is an allosteric proteinEssentially, hemoglobin is an allosteric protein
that has more than one shape and can undergothat has more than one shape and can undergo
conformational changes in its structure based onconformational changes in its structure based on
environment conditionsenvironment conditions

bindingbinding
 The ability of hemoglobin to take up oxygenThe ability of hemoglobin to take up oxygen
molecules in the lungs and then release them inmolecules in the lungs and then release them in
the tissues is regulated by several factors boththe tissues is regulated by several factors both
within the hemoglobin molecule itself andwithin the hemoglobin molecule itself and
through external chemical factorsthrough external chemical factors
 allosteric effectors:allosteric effectors:
– pOpO22 (partial oxygen pressure)(partial oxygen pressure)
– pH of the environmentpH of the environment
– pCOpCO22 (partial carbon dioxide pressure)(partial carbon dioxide pressure)
– Availability of 2,3-bisphosphoglycerateAvailability of 2,3-bisphosphoglycerate

bindingbinding
1.1. Heme-heme interactionsHeme-heme interactions
 One of the biggest regulators of the oxygenOne of the biggest regulators of the oxygen
affinity of the hemoglobin is theaffinity of the hemoglobin is the presence ofpresence of
oxygenoxygen itselfitself
 In the lungs where the oxygen levels are high,In the lungs where the oxygen levels are high,
the hemoglobin has a higher affinity for oxygenthe hemoglobin has a higher affinity for oxygen
and this affinity increases disproportionately withand this affinity increases disproportionately with
the number of molecules it already has bound tothe number of molecules it already has bound to
itit

bindingbinding
 In other words, after the oxyhemoglobinIn other words, after the oxyhemoglobin
binds one molecule of oxygen its affinitybinds one molecule of oxygen its affinity
for oxygen increases until the hemoglobinfor oxygen increases until the hemoglobin
is fully saturated.is fully saturated.
 In the same way, the deoxyhemoglobinIn the same way, the deoxyhemoglobin
has a lower affinity for oxygen and thishas a lower affinity for oxygen and this
affinity decreases disproportionately withaffinity decreases disproportionately with
the number of molecules it already hasthe number of molecules it already has
bound .bound .

bindingbinding
 Thus, the loss of one oxygen molecule from theThus, the loss of one oxygen molecule from the
deoxyhemoglobin lowers the affinity for thedeoxyhemoglobin lowers the affinity for the
remaining oxygen. This regulation is known asremaining oxygen. This regulation is known as
CooperativityCooperativity
 Cooperativity is essential to the functioning ofCooperativity is essential to the functioning of
the hemoglobin because it allows thethe hemoglobin because it allows the
oxyhemoglobin to carryoxyhemoglobin to carry the maximum amount ofthe maximum amount of
oxygen to the tissues and then allows theoxygen to the tissues and then allows the
deoxyhemoglobin to releasedeoxyhemoglobin to release the maximumthe maximum
amount of oxygen into the tissues .amount of oxygen into the tissues .

bindingbinding
 Net effect is that the affinity of Hb for theNet effect is that the affinity of Hb for the
last oxygen bound is 300 times greaterlast oxygen bound is 300 times greater
then its affinity for the first oxygen bound.then its affinity for the first oxygen bound.
 This effect is called heme- hemeThis effect is called heme- heme
interaction.interaction.

Oxygen-haemoglobin dissociationOxygen-haemoglobin dissociation
curvecurve
 OO22 carrying capacity of Hb at different Pocarrying capacity of Hb at different Po22
 Sigmoid shapeSigmoid shape
 Binding of one molecule facilitate the secondBinding of one molecule facilitate the second
molecule bindingmolecule binding
 PP 5050 (partial pressure of O(partial pressure of O22 at which Hb is halfat which Hb is half
saturated with Osaturated with O22) 26.6mmHg) 26.6mmHg

 The normal position of curve depends onThe normal position of curve depends on
 Concentration of 2,3-DPGConcentration of 2,3-DPG
 HH++
ion concentration (pH)ion concentration (pH)
 COCO22 in red blood cellsin red blood cells
 Structure of HbStructure of Hb
Hb-oxygen dissociation curveHb-oxygen dissociation curve

Hb-oxygen dissociation curveHb-oxygen dissociation curve

PP5050
– Indicates affinity of Hb to OIndicates affinity of Hb to O22
– PP5050(mm Hg): the pressure at(mm Hg): the pressure at
which Hb is 50% saturated withwhich Hb is 50% saturated with
OO22
– High affinityHigh affinity  slow unloading ofslow unloading of
OO22
– Low affinityLow affinity  fast unloading offast unloading of
OO22
– Lung pOLung pO22 is 100 mmis 100 mm  HbHb
saturation 100%saturation 100%
– Tissue pOTissue pO22 is 40 mmis 40 mm  HbHb
saturation reducessaturation reduces

Dissociation curveDissociation curve

bindingbinding
2.2. Bohr EffectBohr Effect::
 When COWhen CO22 is released into the blood from theis released into the blood from the
tissues it acidifies the blood by increasing thetissues it acidifies the blood by increasing the
concentration of hydrogen ions.concentration of hydrogen ions.
 This lowering in pH causes the oxygen affinity ofThis lowering in pH causes the oxygen affinity of
the hemoglobin to decrease, which is known asthe hemoglobin to decrease, which is known as
thethe Bohr effectBohr effect

bindingbinding
 The molecular basis behind the Bohr effectThe molecular basis behind the Bohr effect
is that the T structure of hemoglobin bindsis that the T structure of hemoglobin binds
hydrogen more readily than the Rhydrogen more readily than the R
structure, so under a condition of low pHstructure, so under a condition of low pH
(high hydrogen ion concentration) the T(high hydrogen ion concentration) the T
structure, which has a decreased oxygenstructure, which has a decreased oxygen
affinity, dominates.affinity, dominates.
 Bohr effect is because of the ionizableBohr effect is because of the ionizable
groups plus histidine side chaingroups plus histidine side chain

bindingbinding
 When the conc of ions increase these groups areWhen the conc of ions increase these groups are
charged and are able to form ionic bonds. These bondscharged and are able to form ionic bonds. These bonds
stabilize the T form and so the affinity for oxygenstabilize the T form and so the affinity for oxygen
decreasesdecreases
 Bohr effect causesBohr effect causes the shift to the rightthe shift to the right in the oxygenin the oxygen
dissociation curvedissociation curve
Sources of Protons:Sources of Protons:
a.a. Hydrogen ions and COHydrogen ions and CO22 more in the metabolically activemore in the metabolically active
tissues.tissues.
b.b. Organic acids produced during anaerobic metabolismOrganic acids produced during anaerobic metabolism
( role of carbonic( role of carbonic anhydraseanhydrase..

bindingbinding
Mechanism of Bohr effect:Mechanism of Bohr effect:
 Bohr effect reflects that the deoxyform of Hb hasBohr effect reflects that the deoxyform of Hb has
got a greater affinity for protons than oxyHb.got a greater affinity for protons than oxyHb.
 It is because of the ionizable groupsIt is because of the ionizable groups
 When conc of protons increases these groupsWhen conc of protons increases these groups
become charged and form ionic bonds.become charged and form ionic bonds.
 These bonds stabilize the deoxyform of Hb andThese bonds stabilize the deoxyform of Hb and
produces a decrease affinity forproduces a decrease affinity for oxygen.oxygen.

bindingbinding
3.3. 2,3 – Bisphosphoglycerate2,3 – Bisphosphoglycerate ::
 2,3 - bisphosphoglycerate2,3 - bisphosphoglycerate is an allostericis an allosteric
effector that changes the oxygen affinity ofeffector that changes the oxygen affinity of
hemoglobin by binding to the hemoglobin itself.hemoglobin by binding to the hemoglobin itself.
 It decreases the oxygen affinity of hemoglobinIt decreases the oxygen affinity of hemoglobin
by binding to deoxy form. This stabilizes the tautby binding to deoxy form. This stabilizes the taut
structure.structure.
HbOHbO22 + 2,3BPG+ 2,3BPG
Hb-2,3BPG + OHb-2,3BPG + O22

bindingbinding
 2,3 BPG binds to a pocket formed by two2,3 BPG binds to a pocket formed by two
beta- globin chains in the center of thebeta- globin chains in the center of the
tetramer.tetramer.
 Pocket has got positively charged aminoPocket has got positively charged amino
acids that forms ionic bonds with 2,3BPG.acids that forms ionic bonds with 2,3BPG.
 When OWhen O22 binds then 2,3 BPG is expelledbinds then 2,3 BPG is expelled
 2,3 BPG causes2,3 BPG causes the shift to the rightthe shift to the right in thein the
oxygen dissociation curve.oxygen dissociation curve.

bindingbinding
 2,3 BPG levels are increased in chronic hypoxia2,3 BPG levels are increased in chronic hypoxia
(high altitudes, COPD) and chronic anemia.(high altitudes, COPD) and chronic anemia.
 2,3 BPG absent in fetal Hb.2,3 BPG absent in fetal Hb.
 Role in transfused blood (acid citrate dextrose)Role in transfused blood (acid citrate dextrose)
(Inosine hypoxanthine ribose).(Inosine hypoxanthine ribose).
 2,3 BPG is essential for the normal transport2,3 BPG is essential for the normal transport
function of Hb. Storing of blood in acid citratefunction of Hb. Storing of blood in acid citrate
medium decreases 2,3 BPG and the affinity ofmedium decreases 2,3 BPG and the affinity of
Hb for oxygen increasesHb for oxygen increases

bindingbinding
 Fetal Hb has got a gamma globin chain,Fetal Hb has got a gamma globin chain,
this has got less positive charge so doesthis has got less positive charge so does
not bind 2,3 BPG.not bind 2,3 BPG.
 This allows the HbF to facilitate theThis allows the HbF to facilitate the
transfer of oxygen from the maternal bloodtransfer of oxygen from the maternal blood
to the fetal blood.to the fetal blood.

bindingbinding
4.4. Binding of COBinding of CO22 ::
 COCO22 has a similar effect on the hemoglobin, buthas a similar effect on the hemoglobin, but
instead of binding to the heme molecule likeinstead of binding to the heme molecule like
oxygen, COoxygen, CO22 binds to the N-terminus of the alphabinds to the N-terminus of the alpha
globin molecule.globin molecule.
 The COThe CO22 binds better to the globin in the Tbinds better to the globin in the T
structure, so the release of oxygen in the tissuesstructure, so the release of oxygen in the tissues
by the T structure of hemoglobin facilitates theby the T structure of hemoglobin facilitates the
uptake of COuptake of CO22

bindingbinding
 COCO22 is mostly transported in the form ofis mostly transported in the form of
bicarbonate.bicarbonate.
 Some is transported by Hb. It is calledSome is transported by Hb. It is called
carbamino hemoglobin or carbamate,carbamino hemoglobin or carbamate,
because it is attached to the unchargedbecause it is attached to the uncharged αα
-amino groups-amino groups

Ligand bindingLigand binding
 Besides the oxygen ligand which binds toBesides the oxygen ligand which binds to
hemoglobin in a cooperative manner,hemoglobin in a cooperative manner,
hemoglobin ligands also includehemoglobin ligands also include
competitive inhibitors such as carboncompetitive inhibitors such as carbon
monoxide (CO) and allosteric ligands suchmonoxide (CO) and allosteric ligands such
as carbon dioxide (COas carbon dioxide (CO22).).

CompetitiveCompetitive
 Hemoglobin's oxygen-binding capacity isHemoglobin's oxygen-binding capacity is
decreased in the presence of carbon monoxidedecreased in the presence of carbon monoxide
because both gases compete for thebecause both gases compete for the samesame
binding sitesbinding sites on hemoglobin, carbon monoxideon hemoglobin, carbon monoxide
binding preferentially in place of oxygen.binding preferentially in place of oxygen.
 The binding of oxygen is affected by moleculesThe binding of oxygen is affected by molecules
such as carbon monoxide (CO) (for examplesuch as carbon monoxide (CO) (for example
from tobacco smoking, car exhaust andfrom tobacco smoking, car exhaust and
incomplete combustion in furnaces). COincomplete combustion in furnaces). CO
competes with oxygen at the heme binding site.competes with oxygen at the heme binding site.

 Hemoglobin binding affinity for CO is 200 timesHemoglobin binding affinity for CO is 200 times
greater than its affinity for oxygen, meaning thatgreater than its affinity for oxygen, meaning that
small amounts of CO dramatically reducesmall amounts of CO dramatically reduce
hemoglobin's ability to transport oxygenhemoglobin's ability to transport oxygen
 When hemoglobin combines with CO, it forms aWhen hemoglobin combines with CO, it forms a
very bright red compound calledvery bright red compound called
carboxyhemoglobin, which may cause the skin ofcarboxyhemoglobin, which may cause the skin of
CO poisoning victims to appear pink in death,CO poisoning victims to appear pink in death,
instead of white or blueinstead of white or blue
 When inspired air contains CO levels as low asWhen inspired air contains CO levels as low as
0.02%, headache and nausea occur; if the CO0.02%, headache and nausea occur; if the CO
concentration is increased to 0.1%,concentration is increased to 0.1%,
unconsciousness will follow. In heavy smokers,unconsciousness will follow. In heavy smokers,
up to 20% of the oxygen-active sites can beup to 20% of the oxygen-active sites can be
blocked by COblocked by CO

In similar fashion, hemoglobin also has competitive bindingIn similar fashion, hemoglobin also has competitive binding
affinity for cyanide(CNaffinity for cyanide(CN--
), sulfur monoxide (SO), nitrogen), sulfur monoxide (SO), nitrogen
dioxide(NOdioxide(NO22), and sulfide(S), and sulfide(S2-2-
), including hydrogen sulfide (H), including hydrogen sulfide (H22S).S).
All of these bind to iron in heme without changing its oxidationAll of these bind to iron in heme without changing its oxidation
state, but they nevertheless inhibit oxygen-binding, causingstate, but they nevertheless inhibit oxygen-binding, causing
grave toxicitygrave toxicity
AllostericAllosteric
 Carbon dioxide occupies a different binding site on theCarbon dioxide occupies a different binding site on the
hemoglobin. Carbon dioxide is more readily dissolved inhemoglobin. Carbon dioxide is more readily dissolved in
deoxygenated blood, facilitating its removal from the body afterdeoxygenated blood, facilitating its removal from the body after
the oxygen has been released to tissues undergoingthe oxygen has been released to tissues undergoing
metabolism. This increased affinity for carbon dioxide by themetabolism. This increased affinity for carbon dioxide by the
venous blood is known as thevenous blood is known as the Haldane effectHaldane effect

 Through the enzyme carbonic anhydrase, carbon dioxide reactsThrough the enzyme carbonic anhydrase, carbon dioxide reacts
with water to give carbonic acid, which decomposes intowith water to give carbonic acid, which decomposes into
bicarbonate and protons:bicarbonate and protons:
 CO2 + H2O → H2CO3 → HCO3ˉ + H⁺CO2 + H2O → H2CO3 → HCO3ˉ + H⁺
 Hence blood with high carbon dioxide levels isHence blood with high carbon dioxide levels is
also lower in pH (more acidic). Hemoglobin canalso lower in pH (more acidic). Hemoglobin can
bind protons and carbon dioxide which causesbind protons and carbon dioxide which causes
a conformational change in the protein anda conformational change in the protein and
facilitates the release of oxygenfacilitates the release of oxygen
HbOHbO22 + H+ H⁺_______HbH + O⁺_______HbH + O22

Types of HbTypes of Hb
Normal HbA (97%)
HbA2 (2%)
HbF (1%)
HbA1c
abnormal Carboxy Hb
Met Hb
Sulf Hb

Hemoglobin A (HbA)Hemoglobin A (HbA)
 Major Hb in adultsMajor Hb in adults
 Composed of four polypetide chains:Composed of four polypetide chains:
– TwoTwo αα and twoand two ββ chainschains
 Contains two dimers ofContains two dimers of αβαβ subunitssubunits
 Held together by non-covalent interactionsHeld together by non-covalent interactions
 Each chain is a subunit with a heme groupEach chain is a subunit with a heme group
in the center that carries oxygenin the center that carries oxygen
 A Hb molecule contains 4 heme groupsA Hb molecule contains 4 heme groups
and carries 4 moelcules of Oand carries 4 moelcules of O22

T-form of HbT-form of Hb
_The deoxy form of Hb
_Tout form
_The movement of dimers is
constrained
_Low-oxygen-affinity form

R-form of HbR-form of Hb
_The oxygenated form of Hb
Relaxed form
_The dimers have more freedom of
movement
_High-oxygen-affinity form

Normal Hemoglobin LevelsNormal Hemoglobin Levels
 It (Hb) is measured with a unit called gm/dl.It (Hb) is measured with a unit called gm/dl.
 Newborn BabiesNewborn Babies 17- 2217- 22
 ChildrenChildren 11-1311-13
 Adults (Male)Adults (Male) 14-1814-18
 Adults (Female)Adults (Female) 12-1612-16
 Elderly (Male)Elderly (Male) 12.4-14.912.4-14.9
 Elderly (Female)Elderly (Female) 11.7-13.811.7-13.8

Causes of Low HemoglobinCauses of Low Hemoglobin
LevelsLevels
 Nutritional Deficiency
 Inability to Absorb Iron
 Blood Loss
 Lowered Production of Red Blood Cells
 Destruction of Blood Cells

Symptoms of Low HemoglobinSymptoms of Low Hemoglobin
LevelsLevels

How to Increase HemoglobinHow to Increase Hemoglobin
LevelsLevels
 Food Sources and SupplementsFood Sources and Supplements
 Avoid iron blockers
 Reduce intake of foods with oxalic acid
 Avoid foods with gluten
 Increase intake of vitamin C

Hemoglobin

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