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CBFM Final > Hemoglobin & O2 Delivery > Flashcards

Hemoglobin & O2 Delivery Flashcards

1
Q

Structure of Hemoglobin

A

4 proteins = golbins
2α types, 2β types
arranged as 2αβ dimers
4 heme prosthetic groups

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2
Q

Globin chains within a dimer held together by

A

Hydrophobic bonds

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3
Q

Dimers held together by

A

Ionic bonds

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4
Q

2α type encoded on chromosome

A

16 = ζ και α

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5
Q

4 β type encoded on chromosome

A

11=ε, γ, δ, β

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6
Q

expression of globin genes is ________

A

Regulated developmentally

In two places
During formation of RBC
During development of person

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7
Q

Why are ionic bonds between dimers important

A

They can easily be broken and reformed

It allows Hb’s binding affinity for oxygen to change in different conditions

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8
Q

ζ and ε only expressed when

A

In embryo

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9
Q

HbA compostion

A

α2β2

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10
Q

ΗbF composition

A

α2γ2

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11
Q

where are β chains made

A

Fetal liver, then the bone marrow

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12
Q

As ___ chain increases γ chain decreases

A

β

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13
Q

why is HbF more prominent in fetal and newborn

A

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

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14
Q

HbF is ______ susceptible to a specific type of allosteric regulation

A

LESS

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15
Q

What could a high number of F cells in an adult indicate

A

Defective β globin genes

Milder forms of β thalassemia or sickle cell disease

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16
Q

Heme synthesis is coordinated with _____

A

Iron availability

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17
Q

Heme synthesis is coordinated with _____

A

Globin synthesis

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18
Q

Heme _____ transcription of Globin and stabilizes their mRNAs

A

Increases

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19
Q

_____ levels of heme activate a kinase that causes ___________ of translation. The kinase is called

A

Low

Inhibition

Heme regulated inhibitor (HRI)

Review slides

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20
Q

Kinase that inhibits translation of heme

A

Heme regulated inhibitor (HRI)

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21
Q

If heme is low we don’t want to ______ globin chains

A

Translate

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22
Q

If there a lot of globin chains but no heme what would happen

A

Globin chains would precipitate and there would be cell death

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23
Q

What does HRI phosphorylate

A

eIF-2-GDP
HRI prevents its reactivation

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24
Q

When eIF-2 is phosphorylated what happens

A

It becomes inactive

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25
Q

which histidine helps prevent oxidation of fe2+ to fe3+

A

The distal histidine of the E helix

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26
Q

What is methemoglobin

A

MetHb
Oxidized Hb (Fe3+)
Can’t bind O2

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27
Q

Distal histidine ______ oxidation and ______ Hb affinity for CO

A

Prevents

Reduces

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28
Q

T form is in what state
T stands for

A

Deoxygenated state
Tight/taut

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29
Q

What does O2 do to the T form

A

Creates strain on Fe2+

Creates oxygenated state
R form

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30
Q

R form is

A

Oxygenated

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31
Q

The movement of the first globin chain causes ____________ to the entire hemoglobin molecule

A

Conformational change

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32
Q

1st globin binds and what happens to the other globin that bind

Why

What’s this called

A

Their affinity is higher for oxygen

Because there is less strain to overcome

Cooperative binding of O2

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33
Q

T form has dimers held by _____ bonds

A

Ionic and hydrogen

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34
Q

The bonds in the T form _____

A

Constrain the movement

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35
Q

The R form is _____ and has a ______ affinity for O2

A

Relaxed/oxygenated

Higher

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36
Q

What happens to the bonds when T goes to R form

A

Bonds rupture

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37
Q

Partial pressure of O2 in the lungs

A

100mmHg

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38
Q

Partial pressure in the peripheral tissue

A

40mmHg

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39
Q

As partial pressure of oxygen _______ when Hb travels to the lungs, the saturation of Hb _______

A

Increases

Increases

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40
Q

Loading of Hb with O2 vs Unloading

A

Loading: pp increases and saturation increases toward the lungs

Unloading: pp decreases and saturation decreases to periphery

41
Q

P50 represents what

A

Point at which hemoglobin is 50% saturated

42
Q

What pp does Hb hit p50

A

26mmHg

43
Q

Allosteric inhibitors _____ Hb affinity for O2 in the tissues

A

Decrease

44
Q

Myoglobin curve explanation

A

Myglobin does not experience coopertivity in binding of O2

It holds onto O2 and hangs out in muscles until its needed.

45
Q

Why does the sigmoidal curve have a small change in the saturated part and a big change in the middle

A

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

46
Q

What is 2,3BPG

A

An inhibitor
Made from glycolytic intermediate
Binds deoxygenated Hb
Stabilizes the T form
which decreases O2 affinity in tissues

47
Q

γ globin chains have _______ positive charges in center pocket

A

Fewer

48
Q

HbF has a very low affinity for 2,3BPG because

A

It has FEW positive charges in center pocket
That’s where 23BPG binds!

49
Q

HbA vs HbF p50

A

A: higher p50, takes more pp to saturate it

F: lower p50, takes less pp to saturate it

50
Q

Individuals at high altitude have______ 23BPG because

A

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.

51
Q

When H+ concentrations are high they _____ the ionic bonds between dimers, _______ the T form and facilitate ___________

A

Stabilize
Stabilize
Unloading

52
Q

Most CO2 produced in metabolism is converted to ______ in RBC by _______

A

Bicarbonate

Carbonic anhydrase

53
Q

What is the chloride shift

A

Exchange of bicarbonate and Cl-

54
Q

What does chloride shift do

A

Increases capacity of RBC to carry CO2

Increases unloading of O2 in tissues

55
Q

α thalassemia from

A

From deletion of 1 or more of the 4 α globin genes

56
Q

Hemoglobin Barts Syndrome

A

= all 4 α genes deleted
Fatal
Hb = γ4
has increased O2 aff but can’t drop off O2 very well

57
Q

Hemoglobin H disease

A

= 3 α genes deleted
HbH = β4
unstable tetramer

58
Q

β thalassemia key point

A

Excess α chains precipitate causing hemolysis and anemia

59
Q

β TH. Minor vs Major

A

Minor:
heterozygous
usually asymp.

Major:
“Cooley anemia”
homozygous
severe anemia
suffer from iron overload

60
Q

What is the most common single gene genetic disorder

A

Thalassemia

61
Q

Sickle cell disease key points

A

Auto recessive

Hb S = missense mutation
glu —> Val

Decreased solubility
in deoxygenated form only so insoluble that precipitates in RBC = sickling

62
Q

Intense exercise can tell us

A

Sickle cell disease

63
Q

Hemoglobin C is a missense mutation changing what AA

A

Glutamate to lysine

64
Q

HbC is ______ severe than sickle cell

A

Less

65
Q

____ is the most common fatal poisoning in US

A

Carbon monoxide poisoning

66
Q

How does carbon monoxide poisoning work

A

1.CO competes with O2 for binding to Hb

  1. Increases O2 affinity of remaining sites of Hb
  2. Hb unable to unload O2 to tissues
  3. Leads to hypoxia (which is low levels of O2 in TISSUES)
67
Q

When does methemoglobinemia occur

A
  1. When oxidation exceeds capacity of reduction
    too much Fe3+
  2. Mutation limits ability to reduce
    can’t get back to Fe2+
68
Q

Methemoglobinemia key points

A

Chocolate (blue) blood

Could lead to death if mHb goes over 70%

Treated with reducers

69
Q

Hemoglobin M

A

Rare Congenital form of methemoglobinemia

Auto Dominant

Mutation in heme binding pocket

70
Q

NADH cytochrome b5 reductase deficiency

A

Rare congenital form of methemoglobinemia

Auto recessive

Type I - only in erythrocytes

Type II - in all cells

71
Q

Cell reduces Fe3+ to Fe2+ with __________ enzyme and ______ cofactor

A

NADH cytochrome b5 reductase

NADH—->NAD+

72
Q

Fe2+ —> Fe3+
Enzyme/thing=?

A

Drugs endogenous oxidants

73
Q

Developmental regulation of globin chains is controlled by differentiation-specific ____

A

Transcription factors

74
Q

Globin genes are transcribed at a _____ stage of development. ____ days from proethyroblast to enucleation

A

Narrow
5-7

75
Q

MRNAs are very ____ within globin chains

A

Stable

76
Q

Translation of cloning chains happens after

A

Enucleation

77
Q

Increase synthesis of ____ to bring more iron into the early erythroblasts

A

Transferrin

78
Q

ALAS2 sythesis increased by ___

A

Iron
Which is regulated by IRE 5’ UTR

79
Q

Normally ferrous (Fe2+) becomes _______ but not oxidized(fe3+)

A

Oxygenated - binds o2 reversibly

80
Q

T form affinity for O2

A

Low

81
Q

Where would the t form be located

A

Tissues

82
Q

Where would the r form be located

A

Lungs

83
Q

Affinity of Hb for O2 increases ____x when transitioning from T to R

A

300x

84
Q

Sigmoidal curve suggest

A

Allosteric regulation

85
Q

What pocket does 23BPG bind Hb

A

In the positively charged pocket between β globins

86
Q

3 things happen when you’re adapting to high altitude

A

Increased number of RBC
And
Increased number of Hb conc in RBC
AND
Increased sythesis of 2,3BPG

87
Q

2,3BPG increased in higher altitudes and _____

A

In hypoxia - low O2 in tissues

Because want to release O2 easier

88
Q

When H+ is high O2 affinity is _____ and the curve is shifted _____

A

Low
Right

89
Q

At a lower pH, a greater ___ is required to achieve any given oxygen saturation

A

PO2

90
Q

How do the concentrations of Cl- and bicarb differ in venous and arterial blood

A

Venous Cl- is 102
Venous bicarbonate is 25.2

Arterial Cl- is 104
Arterial HCO3- is 23

91
Q

A smaller amount of CO2 is transported to the lungs on Hb as ____

A

Carbamino hemoglobin

92
Q

The carbamino Hb produces H+ what does this do

A

Binding CO2 promotes release of O2 from Hb in the tissues

93
Q

What are the allosteric inhibitors of Hb

A

1 = 2,3BPG
2 = H+
3 = CO2

94
Q

What do the allosteric inhibitors of Hb do

A

They stabilize T form, shift the curve to the RIGHT

Decrease Hb affinity for O2

Help Hb drop off O2 in tissues !!

95
Q

When you increase the temperature what does this do to the O2 affinity

A

This decreases O2 affinity

96
Q

Precipitating factors of sickle cell

A

Acidosis, hypoxia, infection, stress

97
Q

Hemoglobin SC is when

A

A person is heterozygous for both sickle cell mutation and Hemoglobin C mutation.

One allele carries sickle cell
One allele carries HC

98
Q

Someone with hemoglobin SC would be called a

A

Compound heterozygote
There disease phenotype is milder than sickle cell, less painful crises

CBFM Final (18 decks)

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