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Protein FunctionProtein Function
Myoglobin and Myoglobin and HemoglobinHemoglobin
Chapter 7Chapter 7
OO22 Binding and Allosteric Properties of Binding and Allosteric Properties of HemoglobinHemoglobin
• Hemoglobin binds and transports HHemoglobin binds and transports H++, O, O22 and COand CO22 in an allosteric manner in an allosteric manner
• Allosteric interactionAllosteric interaction – – of, relating to, undergoing, of, relating to, undergoing, or being a change in the shape and activity of a protein (as an or being a change in the shape and activity of a protein (as an enzyme) that results from combination with another substance enzyme) that results from combination with another substance at a point other than the chemically active siteat a point other than the chemically active site
• a regulatory mechanism where a small a regulatory mechanism where a small molecule (effector) binds and alters an molecule (effector) binds and alters an enzymes activityenzymes activity
Protein FunctionProtein FunctionOO22 does not easily diffuse in muscle and O does not easily diffuse in muscle and O22 is toxic to biological is toxic to biological
systems, so living systems have developed a way around this.systems, so living systems have developed a way around this.
Physiological roles of:Physiological roles of:– MyoglobinMyoglobin
Transports OTransports O22 in rapidly respiring muscle in rapidly respiring muscle Monomer - single unitMonomer - single unit Store of OStore of O22 in muscle high affinity for O in muscle high affinity for O22
Diving animals have large concentration of myoglobin to Diving animals have large concentration of myoglobin to keep Okeep O2 2 supplied to musclessupplied to muscles
– HemoglobinHemoglobin Found in red blood cells Found in red blood cells Carries OCarries O22 from lungs to tissues and removes CO from lungs to tissues and removes CO22 and H and H++
from blood to lungsfrom blood to lungs Lower affinity for OLower affinity for O2 2 than myoglobinthan myoglobin Tetrameter - two sets of similar units (Tetrameter - two sets of similar units (2222))
x-ray x-ray crystallography crystallography of myoglobinof myoglobin
– Small protein found in Small protein found in musclemuscle
– Made up of 153 residues Made up of 153 residues grouped into 8 grouped into 8 helix A helix A to H (proline near end)to H (proline near end)
– very small due to the very small due to the foldingfolding
44 x 44 x 25 Å44 x 44 x 25 Å
– hydrophobic residues hydrophobic residues oriented towards the oriented towards the interior of the proteininterior of the protein
– only polar AAs inside are only polar AAs inside are 2 histidines2 histidines
– Red indicates Heme Red indicates Heme groupgroup
x-ray x-ray crystallography crystallography of myoglobinof myoglobin
– Hemoglobin and Hemoglobin and myoglobin are only myoglobin are only slightly related in primary slightly related in primary sequence. sequence.
– Although most amino Although most amino acids are different acids are different between the two between the two sequences, the amino acid sequences, the amino acid changes between the two changes between the two proteins are generally proteins are generally conservative. conservative.
– More strikingly, the More strikingly, the secondary structures of secondary structures of myoglobin and the myoglobin and the subunits of hemoglobin subunits of hemoglobin are virtually identical.are virtually identical.
Myoglobin and HemoglobinMyoglobin and Hemoglobin Hemoglobin is structurally related to Hemoglobin is structurally related to
myoglobinmyoglobin very different primary sequence about an very different primary sequence about an
18% homology in the primary sequence18% homology in the primary sequence 2 alpha subunits and 2 beta subunits2 alpha subunits and 2 beta subunits in adults there are very small amount of in adults there are very small amount of
alpha alpha 22delta delta 2 2 hemoglobinhemoglobin
- significance of conserved amino - significance of conserved amino acids between myoglobin and acids between myoglobin and hemoglobinhemoglobin
•these are the important aas these are the important aas which keep hemes in contact with which keep hemes in contact with the proteinthe protein
•Stabilizes helical arraignmentStabilizes helical arraignment•Interacts with heme/ironInteracts with heme/iron
3D structure of hemoglobin and 3D structure of hemoglobin and myoglobinmyoglobin
11- - 1 1 units have 35 units have 35 interactions interactions
11- - 22 units have 19 units have 19 interaction sitesinteraction sites
similar units have few similar units have few polar contactspolar contacts
the two the two and two and two subunitssubunitsface each face each other through aqueous other through aqueous channelschannels
Synthesis of hemoglobin Hemoglobin synthesis requires
the coordinated production of heme and globin.
REMEMBER: – Heme is the prosthetic
group that mediates reversible binding of oxygen by hemoglobin.
– Globin is the protein that surrounds and protects the heme molecule.
Synthesis of heme Heme is synthesized in a complex
series of steps involving enzymes in the mitochondrion and in the cytosol of the cell .
(1) the condensation of succinyl CoA and glycine by ALA synthase to form 5-aminolevulic acid (ALA). – transported to the cytosol
(2) A series of reactions produce a ring structure - co-proporphyrinogen III.
– returns to the mitochondrion
Synthesis of heme Back in the
mitochohdrion:-
(3) an additional reaction produces protoporhyrin IX
– This step Primes the center of the ring structure
(4) The enzyme ferrochelatase inserts iron into the ring structure of protoporphyrin IX to produce heme!!
Structure of heme prosthetic groupStructure of heme prosthetic group
Protoporphyrin ring w/ iron Protoporphyrin ring w/ iron = heme= heme
Four Pyrrole groups [A to D] Four Pyrrole groups [A to D] linked by methane bridgeslinked by methane bridges
FeFe+2+2 coordinated by coordinated by prophyrin N atoms and a N prophyrin N atoms and a N from Histidine (blue)from Histidine (blue)– This is known as His F8 This is known as His F8
(8(8thth residue of the F residue of the F helix helix
Iron is out of plane due to His 8 Iron is out of plane due to His 8 bondbond
A molecule of OA molecule of O22 acts as 6 acts as 6thth ligandligand
Structure of heme prosthetic groupStructure of heme prosthetic group Two hydrophobic sidechains Two hydrophobic sidechains
on O2 binding site of heme on O2 binding site of heme elp hold it in placeelp hold it in place– Valine E11 and Valine E11 and
phenylalanine CD1phenylalanine CD1
oxygenation changes state of oxygenation changes state of FeFe– Purple to red color of Purple to red color of
blood, Feblood, Fe+3+3 – brown – brown
Oxidation of FeOxidation of Fe+2+2 destroys destroys biological activity of biological activity of myoglobinmyoglobin
Physical barrier of protein is Physical barrier of protein is to maintain oxidation state to maintain oxidation state of Feof Fe+2+2
free vs. bound heme - free vs. bound heme - role of apoproteinrole of apoprotein
ApoproteinApoprotein - - the protein moiety the protein moiety
of a molecule or complex of a molecule or complex
restricts heme dimersrestricts heme dimers
keeps iron reduced keeps iron reduced
stabilizes transition state stabilizes transition state (O(O22 binding) binding)
CO, NO and HCO, NO and H22S binding - S binding - greater affinity than Ogreater affinity than O22
His E 7 decreases affinity of His E 7 decreases affinity of ligands (CO and Oligands (CO and O22 ) for Fe ) for Fe+2+2
Synthesis of globin
Alpha gene cluster: Each chromosome 16 has two
alpha globin genes that are aligned one after the other on the chromosome. For practical purposes, the two alph globin genes (termed alpha1 and alpha2) are identical.
The transiently expressed embryonic genes that substitute for alpha very early in development, designated zeta, are also in the alpha globin locus.
Synthesis of globin
Beta gene cluster: The genes in the beta globin locus
are arranged sequentially from 5' to 3' beginning with the gene expressed in embryonic development (the first 12 weeks after conception; called epislon).
The beta globin locus ends with the adult beta globin gene. The sequence of the genes is: epsilon, gamma, delta, and beta.
Synthesis of globin
Beta gene cluster:
There are two copies of the gamma gene
on each chromosome 11.
The others are present in single copies.
Therefore, each cell has two beta globin genes, one on each of the two chromosomes 11 in the cell.
These two beta globin genes express their globin protein in a quantity that precisely matches that of the four alpha globin genes.
The mechanism of this balanced expression is still mostly unknown.
What about the other genes? Two distinct globin chains (each with
its individual heme molecule) combine to form hemoglobin. One of the chains is designated alpha.
The second chain is called "non-alpha". With the exception of the very first weeks of embryogenesis, one of the globin chains is always alpha.
A number of variables influence the nature of the non-alpha chain in the hemoglobin molecule.
The fetus has a distinct non-alpha chain called gamma.
After birth, a different non-alpha globin chain, called beta, pairs with the alpha chain. The combination of two alpha chains and two non-alpha chains produces a complete hemoglobin molecule.
What about the other genes? The combination of two alpha chains
and two gamma chains form "fetal" hemoglobin, termed "hemoglobin F".
With the exception of the first 10 to 12 weeks after conception, fetal hemoglobin is the primary hemoglobin in the developing fetus.
The combination of two alpha chains and two beta chains form "adult" hemoglobin, also called "hemoglobin A".
Although hemoglobin A is called "adult", it becomes the predominate hemoglobin within about 18 to 24 weeks of birth.
Developmental gene expression!!!!!
Embryonic hemoglobinsEmbryonic hemoglobins
zeta(2), epsilon(2) zeta(2), epsilon(2) alpha(2), epsilon (2) alpha(2), epsilon (2) zeta(2), gamma (2)zeta(2), gamma (2)
Fetal hemoglobinFetal hemoglobin
hemoglobin F- alpha(2), hemoglobin F- alpha(2), gamma(2)gamma(2)
Adult hemoglobinsAdult hemoglobins
hemoglobin A- alpha(2), hemoglobin A- alpha(2), beta(2) beta(2) hemoglobin A2- alpha(2), hemoglobin A2- alpha(2), delta(2)delta(2)
Developmental gene expression!!!!!
The globin genes are activated in The globin genes are activated in sequence during development, moving sequence during development, moving from 5' to 3' on the chromosome. from 5' to 3' on the chromosome.
The zeta gene of the alpha globin gene The zeta gene of the alpha globin gene cluster is expressed only during the cluster is expressed only during the first few weeks of embryogensis. first few weeks of embryogensis.
Thereafter, the alpha globin genes take Thereafter, the alpha globin genes take over. over.
For the beta globin gene cluster, the For the beta globin gene cluster, the epsilon gene is expressed initially epsilon gene is expressed initially during embryogensis. during embryogensis.
The gamma gene is expressed during The gamma gene is expressed during fetal development. fetal development. – The combination of two alpha genes The combination of two alpha genes
and two gamma genes forms fetal and two gamma genes forms fetal hemoglobin, or hemoglobin, or hemoglobin Fhemoglobin F..
Developmental gene expression!!!!!
Around the time of birth, the production Around the time of birth, the production of gamma globin declines in concert of gamma globin declines in concert with a rise in beta globin synthesis. A with a rise in beta globin synthesis. A significant amount of fetal hemoglobin significant amount of fetal hemoglobin persists for seven or eight months after persists for seven or eight months after birth. birth.
Most people have only trace amounts, if Most people have only trace amounts, if any, of fetal hemoglobin after infancy. any, of fetal hemoglobin after infancy.
two alpha genes and two beta genes two alpha genes and two beta genes comprises the normal adult hemoglobin, comprises the normal adult hemoglobin, hemoglobin A. hemoglobin A.
The The deltadelta gene, which is located gene, which is located between the gamma and beta genes on between the gamma and beta genes on chromosome 11 produces a small chromosome 11 produces a small amount of delta globin in children and amount of delta globin in children and adults. The product of the adults. The product of the delta delta globin globin gene is called gene is called hemoglobin A2hemoglobin A2, and , and normally comprises less than 3% of normally comprises less than 3% of hemoglobin in adults, is composed of hemoglobin in adults, is composed of two alpha chains and two delta chains.two alpha chains and two delta chains.
Oxygenation Oxygen binding to hemoglobin
is due to the effect of the ligand-binding state of one heme group on the ligand-binding affinity of another.
Too far apart to interact! (25 to 37 Å apart)
Mechanically transmitted between heme groups by motions of the proteins
This means the molecule changes shape!
• There are two general structural states There are two general structural states - the deoxy or - the deoxy or T form and the oxy or R form.T form and the oxy or R form.
One type of interactions shift is the polar bonds One type of interactions shift is the polar bonds between the alpha 1 and the beta 2 subunits.between the alpha 1 and the beta 2 subunits.
The two states
– The T form finds the terminals in several important H bonds and salt bridges.
– In the T form the C terminus of each subunit are "locked" into position through several hydrogen and ionic bonds.
– Shifts into the R state break these and allow an increased movement throughout the molecule.
Note that binding of one or more oxygen can have a dramatic affect on the other subunits that have not yet bound an O2.
Binding of oxygen dramatically alters the interactions and brings about a twisting of the two halves (alpha beta pairs)
Much of the quaternary changes takes place in the salt bonds between the C terminals of all four chains
oxy and deoxy quaternary structures are different
– change takes place between 1 - 2 and 2 - 1
– amino acids between 1 and 2 help to stabilize each forms
Oxygen binding shifts Oxygen binding shifts quaternary structure at quaternary structure at long distanceslong distances
–binding of O2 ligand at 6th coordinate position pulls Fe into heme
–moves proximal histadine (F8) and the alpha helix it is attached to.
–shift in the helix is transmitted throughout of molecule
T and R State of HemoglobinT and R State of Hemoglobin Below are the two major conformations of hemoglobin as Below are the two major conformations of hemoglobin as
predicted by the models for allosteric activation. predicted by the models for allosteric activation.
Oxygen will bind to hemoglobin in either state; however, it Oxygen will bind to hemoglobin in either state; however, it has a signficantly higher affinity for hemoglobin in the R has a signficantly higher affinity for hemoglobin in the R state.state.
T and R State of HemoglobinT and R State of Hemoglobin In the absence of oxygen, hemoglobin is more stable in the T In the absence of oxygen, hemoglobin is more stable in the T
state, and is therefore the predominant form of state, and is therefore the predominant form of deoxyhemoglobin. R stands for relaxed, while T stands for deoxyhemoglobin. R stands for relaxed, while T stands for tense, since this is stabilized by a greater number of ion pairs. tense, since this is stabilized by a greater number of ion pairs.
Upon a conformational change from the T state to the R state, Upon a conformational change from the T state to the R state,
ion pairs are broken mainly between the aion pairs are broken mainly between the a11bb22 subunits. subunits.
– The T form finds the terminals in several important H bonds and salt bridges.
– In the T form the C terminus of each subunit are "locked" into position through several hydrogen and ionic bonds.
– Shifts into the R state break these and allow an increased movement throughout the molecule.
Note that binding of one or more oxygen can have a dramatic affect on the other subunits that have not yet bound an O2.
How Do Myoglobin (Hemoglobin) Bind How Do Myoglobin (Hemoglobin) Bind to Oxygento Oxygen
NNH
His E7
Move downupon O2 binding
How Do Myoglobin (Hemoglobin) Bind How Do Myoglobin (Hemoglobin) Bind to Oxygento Oxygen
NNH
His E7
Move downupon O2 binding
So what also allows this to
change shape?
Functional Structure of Hemoglobin - allosteric
regulations Allosteric interactionAllosteric interaction - - the binding of one the binding of one ligand at one site in a protein that affects the ligand at one site in a protein that affects the binding of other ligands at other sites in the binding of other ligands at other sites in the protein. protein.
This can affect binding and can be cooperative This can affect binding and can be cooperative (pos or neg). (pos or neg).
Allosterism is typically seen when sigmoidal Allosterism is typically seen when sigmoidal binding / activity curves.binding / activity curves.
diphosphoglycerate BPG present in human red present in human red
blood cells at blood cells at approximately 5 approximately 5 mmol/L. mmol/L.
It binds with greater It binds with greater affinity to deoxygenated affinity to deoxygenated hemoglobinhemoglobin
– In bonding to partially In bonding to partially deoxygenated deoxygenated hemoglobin it hemoglobin it allosterically allosterically upregulatesupregulates the release of the release of the remaining oxygen the remaining oxygen molecules bound to the molecules bound to the hemoglobin, thus hemoglobin, thus enhancing the ability of enhancing the ability of RBCs to release oxygen RBCs to release oxygen near tissues that need it near tissues that need it most most
So why is this important.So why is this important. Look at the Hill plot and the Look at the Hill plot and the plot of the of binding vs pO2 (figs 7-8 and 7-7 respectively). Think plot of the of binding vs pO2 (figs 7-8 and 7-7 respectively). Think of when hemoglobin should be mostly saturated and when it would of when hemoglobin should be mostly saturated and when it would be best if it had a low saturation / affinity and thus "give up" its be best if it had a low saturation / affinity and thus "give up" its oxygen. Use the table below to help your thoughts.oxygen. Use the table below to help your thoughts.
Oxygen pressure in various fluids
Region or fluid
Inspired Air
Aveolar Air
Arterial Blood
Capilary
Insterstitual Fluid
Cell Cytosol
pO2 (Torr)
158
100
90
40
30
10
2,3 bisphosphoglycerate (BPG)
– Purified Hb has a different O2
– affinity than it does in blood 26 fold decrease change in
affinity is due to 2,-3 diphosphoglycerate BPG– (BPG replaced by nucleotides
IHP and ATP in fish and birds)– - 1 BPG per Hb - binds in
central cavity of Hb– - binds preferentially to
deoxy Hb– - hydrophobic bonds with Lys
and salt bridge with His
– - O2 binding changes conformation and “kicks out” BPG
– change in altitude increases concentration of BPG
Fetal F Hb has replaced His 143 with Ser - What might the consequences be?
Cooperative interactions between Cooperative interactions between subunitssubunits
Both models do not fully account for the effects of allosteric effectors– sequential model (D Koshland)
binding of one O2 induces T-R conformation change 1st change is most difficult due to influence by 3 other
subunits binding of next three subunits happens sequentially, with
higher affinity (easier T-R changes) kinetics increase to the fully oxy Hb state as more O2 is
bound
Concerted model (J Monod) All R or all T no in between as in the All R or all T no in between as in the
Koshland modelKoshland model concerted model means as more O2
binds, the R conformation is favored until all units are in the R conformation regardless of the total units bound to O2
Affinities do NOT change until conformation changes
1 O2 - all T; 2 O2 - nearly even equilibrium; 3 O2 mostly R; 4 O2 - mostly R form
energy from O2 binding causes the change in equilibrium
this model best fits O2 dissociation curve but with limits.
Simple definition of the concept of Simple definition of the concept of cooperativity.cooperativity. In its simplest meaning, In its simplest meaning, cooperativity is a measure of communication cooperativity is a measure of communication between binding sites.between binding sites. Positive cooperativity Positive cooperativity describes a relationship in which the binding describes a relationship in which the binding to one site facilitates the binding to the to one site facilitates the binding to the second, third, ect.second, third, ect.
No cooperativity puts all sites on equal footing No cooperativity puts all sites on equal footing and indicates no site to site influence. and indicates no site to site influence.
Negative cooperativity implies binding to one Negative cooperativity implies binding to one site hinders binding to subsequent sites.site hinders binding to subsequent sites.
How is this cooperation actually forced on How is this cooperation actually forced on hemoglobin?hemoglobin?
The structures in one subunit effects the othersThe structures in one subunit effects the others• Structural differences of bound and unbound HbStructural differences of bound and unbound Hb
– Two structures - T and R form depending on the Two structures - T and R form depending on the oxygenation of Hboxygenation of Hb
– T is the deoxy form, R is oxy formT is the deoxy form, R is oxy form– allosteric modifiers shift or stabilize one particular allosteric modifiers shift or stabilize one particular
conformation over the otherconformation over the other– Monomer interactions, most chain interaction occurs between Monomer interactions, most chain interaction occurs between
and and chains chains» through mostly hydrophobic residuesthrough mostly hydrophobic residues and and interactions are few and polarinteractions are few and polar and and contact act as a switch contact act as a switch
COCO22 effects effects - In the red blood cells the picture is even - In the red blood cells the picture is even
more complicated. COmore complicated. CO22 is removed by converting CO is removed by converting CO22 to to bicarbonatebicarbonate
CO2 + H2O <-> HCO3- + H+
bicarbonate (HCObicarbonate (HCO33--) formed by the enzyme carbonic ) formed by the enzyme carbonic
anhydraseanhydrase–H+ produced by this enzyme is removed by the Hb as H+ produced by this enzyme is removed by the Hb as described abovedescribed above
–This allows more COThis allows more CO2 2 to be removed in the form of to be removed in the form of bicarbonatebicarbonate
COCO22 binding aids in reducing O binding aids in reducing O22 affinity by affinity by changing conformation by the production changing conformation by the production of more H+ (R to T change)of more H+ (R to T change)
In the lungs the OIn the lungs the O22 binds Hb and binds Hb and forces the R conformationforces the R conformation
Bohr EffectBohr EffectThe Bohr effect is the reversible shift in Hb affinity for OThe Bohr effect is the reversible shift in Hb affinity for O22 with changes in with changes in pH.pH.
H+ Transport (effect) -H+ Transport (effect) - O O22 binding to Hb releases H binding to Hb releases H++ due to conformational due to conformational changes in Hbchanges in Hb- - deoxyform (T form) brings Asp 94 close to His 146 (fig 7-11 (b))deoxyform (T form) brings Asp 94 close to His 146 (fig 7-11 (b))- the proximity of an acidic amino acid increases the pK of histidine (pKa - the proximity of an acidic amino acid increases the pK of histidine (pKa is now above the pH) and results in His now above the pH) and results in H++ “binding” to deoxyHb - in other “binding” to deoxyHb - in other words the His becomes protonated where it normally would be ionizedwords the His becomes protonated where it normally would be ionized
- increasing pH stimulates Hb to bind to Oincreasing pH stimulates Hb to bind to O22
- Bottom line - when OBottom line - when O22 binds Hb, H+ is released from several amino binds Hb, H+ is released from several amino acid's functional groups. When Oacid's functional groups. When O22 is released, the amino acids become is released, the amino acids become protonized and then "picks" up a H+.protonized and then "picks" up a H+.
So when the H+ is high (acidic conditions) the H+ is driven onto the So when the H+ is high (acidic conditions) the H+ is driven onto the terminal amino acids driving it into the T conformationterminal amino acids driving it into the T conformation
This all aids the function of Hb. In active tissues respiration, (glycolysis) results in lactic acid formation. These tissues need more O2. Without the H+ effect Hb would hold on to more of the O2. The H+ induces Hb to dump 10% more of it's O2.
– CO2 reversibly binds to N term (carbamate) to remove remaining CO2
R - NH2 + CO2 <-> R - NH - COO- + H+
R is the Hb N term amide
The carbamide increases the T formation - deoxy form. The reverse occurs in the lungs. This results in 1/2 of CO2
removal from tissues.
O
C
O
C C
R
H
O
ProteinH2N
Amino Terminus
C C
R
H
O
ProteinHN
Carbamate on Amino Terminus
C
O
O
H+
A quick look at what happens to blood when
it all goes wrong
Sickle-Cell Anemia, a Molecular Sickle-Cell Anemia, a Molecular DiseaseDisease
One of the first “molecular” diseases found - sickle cell anemia– sickle cell - blood cell is elongated , mis-shaped
(sickle) occurs at low O2 concentration caused by hemoglobin aggregates inflammation in capillaries and pain red blood cells break down - anemia
– between 10% of American blacks and 25% of African blacks are heterozygous for sickle cell anemia
– homozygous usually do not survive into adult hood– heterozygous individuals usually have no problem
except when in severe oxygen deprivation
Single amino acid (point mutation) HbS vs. HbA changes structure– sickle cell b chains have a valine in place of glutamate– leads to more Hb S (sickle cell) has 2 more + charges
than normal hemoglobin Glu -Val occurs on exterior of protein - does not
change O2 dissociation/allosteric properties of protein
Deoxy HbS precipitatesDeoxy HbS precipitates– oxyHb phenylalanine b85 oxyHb phenylalanine b85
and leucine b88 interiorand leucine b88 interior– phe and leu shift to exteriorphe and leu shift to exterior
– create a sticky patch with create a sticky patch with valine (hydrophobic valine (hydrophobic bonding)bonding)
– nucleation (cluster of nucleation (cluster of aggregate) occurs aggregate) occurs logarithmicallylogarithmically– homozygous - 1000 times homozygous - 1000 times
faster than heterozygousfaster than heterozygous– that means mixed genes that means mixed genes
can re-oxygenate faster can re-oxygenate faster than polymerization can than polymerization can occuroccur
Malaria – an agent of natural Selection New traits are produced by mutation and are then
subject to natural selection.
The traits that survive are adaptations.
Malaria causes 110 million cases of illness each year– Close to 2 million deaths each year.
Rare before the invention of agriculture – Did much to change the selective pressure on human
populations
Figure 7.10A small change in a gene can have many phenotypicconsequences.
Malaria – an agent of natural Selection Most victims of malaria are young children
Where malaria occurrence is high, so is the HBs allele– Odd, as Sickle Cell Anemia is nearly always fatal
before reproductive age– HBs allele confers resistance to malaria
So in areas of high occurrence to malaria, the HBs allele may cause a genetic disorder, but increases the overall fitness of a population where malaria occurs.
Malaria – an agent of natural Selection
Rh Factor There are four blood groups but eight blood types.
The Rh-factor!!
85% Positive (US population) 15% Negative Genetic factor Can cause Hemolytic Disease and death of infants.
The genetics of the Rh factor Another blood grouping system independent of ABo – the Rh-
factor– three genes: located very close together on the same chromosome.
First C & c, second D & d, third E & e
Unlike the ABo system there is no co-dominance, c, d, and e are recessive to C, D, and E.
ccddee is known as Rh-negative. All others Rh-positive.
Hemolytic disease If a child is Rh+, a Rh- Mother can begin to
produce antibodies Rh+ red blood cells– Rh factor crosses placenta and mother makes
antibodies In subsequent pregnancies these antibodies can
cross the placenta and cause hemolysis of a Rh+ Childs red blood cells.– Can lead to mental retardation or death
Prevented by giving Rh- women a Rh immunoglobulin injection no later than 72 hours after birth. Attacks any of the babies Abs in mother before her own antibodies are produced
Figure 7.5 (1)Hemolytic disease
Figure 7.5 (2)Hemolytic disease
Figure 7.5 (3)Hemolytic disease
•Prevented by giving Rh- women a Rh immunoglobulin injection no later than 72 hours after birth.
•Attacks any of the babies Abs in mother before her own antibodies are produced.
OO22 affinity affinity pH affects the binding of
oxygen to Hb
In the lungs (pO2 = 100 mm Hg), Hb is
98% saturated at both pH 7.4 and 7.2.
binding of oxygen to Hb in the lungs is not affected by changing the pH and oxygen will load normally.
OO22 affinity affinity at the tissues
The change in the pH results is a lower % saturation of Hb even though the pO2 in the tissues has remained at 40 mm Hg (for this example).
the % saturation at pH 7.4 with a pO2 of 40 mm Hg is about 70%
– meaning 30% of the oxygen coming to the tissue is released.
OO22 affinity affinity at the tissues
At a pH of 7.2, the value is close to 60% (meaning 40% of the oxygen coming to the tissue is released).
Thus more oxygen is delievered to tissues at a lower pH even when the pO2 remains unchanged.
Lowering the pH appears to shift the entire red curve to the right.
Alteration in oxygen binding Alteration in oxygen binding by:by:
- H+, COH+, CO22 2,3 bisphosphoglycerate (BPG) 2,3 bisphosphoglycerate (BPG)
In deoxyhemoglobin, the N-terminal amino groups of the α-subunits and the C-terminal Histidine of the β-subunits participate in ion pairs. The formation of ion pairs causes them to decrease in acidity. Thus, deoxyhemoglobin binds one proton for every two O2 released.
In oxyhemoglobin, these ion pairings are absent and these groups increase in acidity. Consequentially, a proton is released for every two O2 bound. Specifically, this reciprocal coupling of protons and oxygen is the Bohr effect.
Alteration in oxygen binding Alteration in oxygen binding by:by:
- H+, COH+, CO22 2,3 bisphosphoglycerate 2,3 bisphosphoglycerate (BPG)(BPG)
Simple rule of thumb-– High H+ conc and High H+ conc and
higher COhigher CO22 levels levels decrease Odecrease O22 affinity for affinity for HbHb
– High OHigh O2 2 concentration concentration decrease H+ and COdecrease H+ and CO22 affinity for Hbaffinity for Hb
Hb acts as a H+ buffer in respiring tissue
The End, at last!The End, at last!
