Hemoglobin & O2 Delivery Flashcards
Structure of Hemoglobin
4 proteins = golbins
2α types, 2β types
arranged as 2αβ dimers
4 heme prosthetic groups
Globin chains within a dimer held together by
Hydrophobic bonds
Dimers held together by
Ionic bonds
2α type encoded on chromosome
16 = ζ και α
4 β type encoded on chromosome
11=ε, γ, δ, β
expression of globin genes is ________
Regulated developmentally
In two places
During formation of RBC
During development of person
Why are ionic bonds between dimers important
They can easily be broken and reformed
It allows Hb’s binding affinity for oxygen to change in different conditions
ζ and ε only expressed when
In embryo
HbA compostion
α2β2
ΗbF composition
α2γ2
where are β chains made
Fetal liver, then the bone marrow
As ___ chain increases γ chain decreases
β
why is HbF more prominent in fetal and newborn
Because it has a higher affinity for O2 than HbA
This is crucial because baby needs to pick up O2 from mom so it has to be a higher affinity
HbF is ______ susceptible to a specific type of allosteric regulation
LESS
What could a high number of F cells in an adult indicate
Defective β globin genes
Milder forms of β thalassemia or sickle cell disease
Heme synthesis is coordinated with _____
Iron availability
Heme synthesis is coordinated with _____
Globin synthesis
Heme _____ transcription of Globin and stabilizes their mRNAs
Increases
_____ levels of heme activate a kinase that causes ___________ of translation. The kinase is called
Low
Inhibition
Heme regulated inhibitor (HRI)
Review slides
Kinase that inhibits translation of heme
Heme regulated inhibitor (HRI)
If heme is low we don’t want to ______ globin chains
Translate
If there a lot of globin chains but no heme what would happen
Globin chains would precipitate and there would be cell death
What does HRI phosphorylate
eIF-2-GDP
HRI prevents its reactivation
When eIF-2 is phosphorylated what happens
It becomes inactive
which histidine helps prevent oxidation of fe2+ to fe3+
The distal histidine of the E helix
What is methemoglobin
MetHb
Oxidized Hb (Fe3+)
Can’t bind O2
Distal histidine ______ oxidation and ______ Hb affinity for CO
Prevents
Reduces
T form is in what state
T stands for
Deoxygenated state
Tight/taut
What does O2 do to the T form
Creates strain on Fe2+
Creates oxygenated state
R form
R form is
Oxygenated
The movement of the first globin chain causes ____________ to the entire hemoglobin molecule
Conformational change
1st globin binds and what happens to the other globin that bind
Why
What’s this called
Their affinity is higher for oxygen
Because there is less strain to overcome
Cooperative binding of O2
T form has dimers held by _____ bonds
Ionic and hydrogen
The bonds in the T form _____
Constrain the movement
The R form is _____ and has a ______ affinity for O2
Relaxed/oxygenated
Higher
What happens to the bonds when T goes to R form
Bonds rupture
Partial pressure of O2 in the lungs
100mmHg
Partial pressure in the peripheral tissue
40mmHg
As partial pressure of oxygen _______ when Hb travels to the lungs, the saturation of Hb _______
Increases
Increases
Loading of Hb with O2 vs Unloading
Loading: pp increases and saturation increases toward the lungs
Unloading: pp decreases and saturation decreases to periphery
P50 represents what
Point at which hemoglobin is 50% saturated
What pp does Hb hit p50
26mmHg
Allosteric inhibitors _____ Hb affinity for O2 in the tissues
Decrease
Myoglobin curve explanation
Myglobin does not experience coopertivity in binding of O2
It holds onto O2 and hangs out in muscles until its needed.
Why does the sigmoidal curve have a small change in the saturated part and a big change in the middle
Saturated part is when its in the lungs.
If there is a small decrease we don’t want to have a huge drop.
Always want it saturated
Middle part is when its at the tissues
We WANT TO LOSE O2, UNLOADING
What is 2,3BPG
An inhibitor
Made from glycolytic intermediate
Binds deoxygenated Hb
Stabilizes the T form
which decreases O2 affinity in tissues
γ globin chains have _______ positive charges in center pocket
Fewer
HbF has a very low affinity for 2,3BPG because
It has FEW positive charges in center pocket
That’s where 23BPG binds!
HbA vs HbF p50
A: higher p50, takes more pp to saturate it
F: lower p50, takes less pp to saturate it
Individuals at high altitude have______ 23BPG because
More
Increasing the concentration of 2,3-BPG in our blood shifts the oxygen binding curve to the right side. This means that hemoglobin will have a lower affinity for oxygen and will be able to release more oxygen to the tissues and cells of our body.
When H+ concentrations are high they _____ the ionic bonds between dimers, _______ the T form and facilitate ___________
Stabilize
Stabilize
Unloading
Most CO2 produced in metabolism is converted to ______ in RBC by _______
Bicarbonate
Carbonic anhydrase
What is the chloride shift
Exchange of bicarbonate and Cl-
What does chloride shift do
Increases capacity of RBC to carry CO2
Increases unloading of O2 in tissues
α thalassemia from
From deletion of 1 or more of the 4 α globin genes
Hemoglobin Barts Syndrome
= all 4 α genes deleted
Fatal
Hb = γ4
has increased O2 aff but can’t drop off O2 very well
Hemoglobin H disease
= 3 α genes deleted
HbH = β4
unstable tetramer
β thalassemia key point
Excess α chains precipitate causing hemolysis and anemia
β TH. Minor vs Major
Minor:
heterozygous
usually asymp.
Major:
“Cooley anemia”
homozygous
severe anemia
suffer from iron overload
What is the most common single gene genetic disorder
Thalassemia
Sickle cell disease key points
Auto recessive
Hb S = missense mutation
glu —> Val
Decreased solubility
in deoxygenated form only so insoluble that precipitates in RBC = sickling
Intense exercise can tell us
Sickle cell disease
Hemoglobin C is a missense mutation changing what AA
Glutamate to lysine
HbC is ______ severe than sickle cell
Less
____ is the most common fatal poisoning in US
Carbon monoxide poisoning
How does carbon monoxide poisoning work
1.CO competes with O2 for binding to Hb
- Increases O2 affinity of remaining sites of Hb
- Hb unable to unload O2 to tissues
- Leads to hypoxia (which is low levels of O2 in TISSUES)
When does methemoglobinemia occur
- When oxidation exceeds capacity of reduction
too much Fe3+ - Mutation limits ability to reduce
can’t get back to Fe2+
Methemoglobinemia key points
Chocolate (blue) blood
Could lead to death if mHb goes over 70%
Treated with reducers
Hemoglobin M
Rare Congenital form of methemoglobinemia
Auto Dominant
Mutation in heme binding pocket
NADH cytochrome b5 reductase deficiency
Rare congenital form of methemoglobinemia
Auto recessive
Type I - only in erythrocytes
Type II - in all cells
Cell reduces Fe3+ to Fe2+ with __________ enzyme and ______ cofactor
NADH cytochrome b5 reductase
NADH—->NAD+
Fe2+ —> Fe3+
Enzyme/thing=?
Drugs endogenous oxidants
Developmental regulation of globin chains is controlled by differentiation-specific ____
Transcription factors
Globin genes are transcribed at a _____ stage of development. ____ days from proethyroblast to enucleation
Narrow
5-7
MRNAs are very ____ within globin chains
Stable
Translation of cloning chains happens after
Enucleation
Increase synthesis of ____ to bring more iron into the early erythroblasts
Transferrin
ALAS2 sythesis increased by ___
Iron
Which is regulated by IRE 5’ UTR
Normally ferrous (Fe2+) becomes _______ but not oxidized(fe3+)
Oxygenated - binds o2 reversibly
T form affinity for O2
Low
Where would the t form be located
Tissues
Where would the r form be located
Lungs
Affinity of Hb for O2 increases ____x when transitioning from T to R
300x
Sigmoidal curve suggest
Allosteric regulation
What pocket does 23BPG bind Hb
In the positively charged pocket between β globins
3 things happen when you’re adapting to high altitude
Increased number of RBC
And
Increased number of Hb conc in RBC
AND
Increased sythesis of 2,3BPG
2,3BPG increased in higher altitudes and _____
In hypoxia - low O2 in tissues
Because want to release O2 easier
When H+ is high O2 affinity is _____ and the curve is shifted _____
Low
Right
At a lower pH, a greater ___ is required to achieve any given oxygen saturation
PO2
How do the concentrations of Cl- and bicarb differ in venous and arterial blood
Venous Cl- is 102
Venous bicarbonate is 25.2
Arterial Cl- is 104
Arterial HCO3- is 23
A smaller amount of CO2 is transported to the lungs on Hb as ____
Carbamino hemoglobin
The carbamino Hb produces H+ what does this do
Binding CO2 promotes release of O2 from Hb in the tissues
What are the allosteric inhibitors of Hb
1 = 2,3BPG
2 = H+
3 = CO2
What do the allosteric inhibitors of Hb do
They stabilize T form, shift the curve to the RIGHT
Decrease Hb affinity for O2
Help Hb drop off O2 in tissues !!
When you increase the temperature what does this do to the O2 affinity
This decreases O2 affinity
Precipitating factors of sickle cell
Acidosis, hypoxia, infection, stress
Hemoglobin SC is when
A person is heterozygous for both sickle cell mutation and Hemoglobin C mutation.
One allele carries sickle cell
One allele carries HC
Someone with hemoglobin SC would be called a
Compound heterozygote
There disease phenotype is milder than sickle cell, less painful crises
