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Biochemistry > Lecture 11: Hemoglobin > Flashcards

Lecture 11: Hemoglobin Flashcards

1
Q

Erythrocyte function

A

Transport oxygen from the lungs to the tissue

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2
Q

Hemoglobin occupies what % of volume and weight in erythrocyte

A

33% of volume and 90% of dry weight

2lbs of hemoglobin in a person

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3
Q

65% of hemoglobin is synthesized

A

Before the extrusion of the nucleus

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4
Q

What makes remaining 35% of hemoglobin

A

Reticulocyte

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5
Q

Red blood cells are made where at what stages

A

Yolk sac in first month of development
Liver and spleen and next few months
Bone marrow after birth

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6
Q

Predominant form of hemoglobin in the adult

A

HbA

2 alpha 2 beta subunits (a2b2)

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7
Q

Fetal hemoglobin

A

0.5% of adult hemoglobin

HbF (a2y2) (alpha2gamma2)

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8
Q

beta globin genes located

A

Chromosome 11

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9
Q

Alpha globin genes located

A

Chromosome 16

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10
Q

HbF predominately made where

A

Mostly liver, but also bone marrow

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11
Q

Switch from fetal to adult hemoglobin is controlled by

A

Time

Switching is closely related to gestational age

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12
Q

HbS mutation

A

Substitution of valine for glutamic acid in AA 6 in Beta globin gene
Non-functioning globin protein

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13
Q

How many alpha globin genes are there

A

Two

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14
Q

Heme structure

A

4 pyrrole rings form tetrapyrrole ring
4 methyl, 2 vinyl, 2 propionate side chains
Iron atom lies in the center of the protoporphyrin bonded to 4 pyrrole nitrogen atoms

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15
Q

Amino acid naming- F8 histidine

A

8th AA residue in the F helix

F helix is the 6th segment in a globin subunit

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16
Q

Proximal and distal histidine

A 
F8= proximal, binds to heme group
E7 = distal, O2 binds iron between the heme and distal histidine
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17
Q

Hemoglobin conformation change

A

Upon oxygenation, the iron atom moves into the plane of heme and pulls the proximal F8 histidine
This is incredibly important for hemoglobin function

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18
Q

Myoglobin is

A

An O2 storage protein

Hemoglobin is an O2 transport protein

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19
Q

Where is myoglobin commonly found

A

Muscle cells, storing oxygen for use

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20
Q

Myoglobin affinity Vs hemoglobin

A

Myoglobin has very high affinity of O2 and will not release it until pressure in tissues is very low (~0 torr)

21
Q

p50 for Hb and myoglobin

A

P50= oxygen pressure at which molecule is half saturated with O2
P50 Hb = 26 torr
P50 myoglobin = 2.8 torr

22
Q

Positive cooperativity of hemoglobin

A

When one molecule of O2 binds to one heme, it facilitates the binding of an O2 to another heme
Conformation change in one globin induces conformation change in another subunit in Hb

23
Q

Reversability

A

As Hb loses oxygen in the tissue, the loss of an oxygen molecule makes it more likely the next subunit will lose its oxygen molecule

24
Q

2,3-BPG

A

Major modulator of Hb
Intermediate by-product of glycolysis
In active tissue, there is lots of 2,3-BPG, signaling Hb to let go of O2

25
No 2,3-BPG - effect on hemoglobin
Hemoglobin would be an extremely inefficient oxygen transporter
26
2,3-BPG concentrations in lung/tissue
Lung- NO 2,3-BPG= high affinity for O2 | Tissues- High [2,3-BPG]= low affinity for O2
27
T and R forms of Hb
T form- low affinity - in non-oxygenated hemoglobin, beta chains are farther apart R form- High affinity - in oxygenated hemoglobin, beta chains are closer together
28
2,3-BPG and T/R forms
2,3-BPG stabilizes the T form of Hb, allowing it to maintain low affinity Low 2,3-BPG in lungs leads to R form with high affinity
29
Smoking and 2,3-BPG
Smoking causing higher levels of 2,3-BPG, causing more T form Hb with lower affinity. Smokers have reduced O2 carrying capacity
30
pH and Hb
pH is lower in active tissues. Binding affinity of Hb for O2 decreases as pH decreases Free H+ is picked up from tissue by an amino acid in Hb, changing the conformation and favoring release of O2
31
Fetal hemoglobin and why O2 flows from mom to fetus
Fetal Hb does not bind well to 2,3-BPG and therefore has a higher affinity for O2 HbF is mostly locked in R form
32
Sequential model of cooperativity
At each level of oxygen loading, it causes an adjacent globin chain to change from T to R state, leading to increased affinity for oxygen with each new one bound
33
Carboxyhemoglobin
Occurs when heme is combined with Carbon monoxide The bond is 210x stronger than with oxygen Transport of O2 to tissues is impaired, death
34
HbA1c
Post translational glycosylation of Hb Usually the level is 3% Varies with the level of blood glucose concentration that RBCs have been exposed to in 120 day lifespan HbA1c is increased 2-3x in diabetic patients (6-9%)
35
Thalassemias definition
Reduced synthesis of one or more of the globin chains leads to - imbalanced globin-chain synthesis - defective Hb production - Damage to red cells from effects of excess globin subunits
36
a-Thalassemia
Involves both alpha globin genes Deletion of 1, 2, 3 or 4 alpha globin genes a-globin chains are present in both fetal and adult Hbs, so deficiency of a-globin chains affects Hb production in fetal and adult life
37
Effect of a-Thalassemia in fetal life
Excess y(gamma)-globin chains for y^4 tetramers called Hb Barts
38
Effect of a-Thalassemia in adult life
Excess B-globin chains for B^4 tetramers or Hb H
39
a+-thalassemia
Silent carrier, one gene deleted
40
a-thalassemia trait
Two alpha genes deleted -Low mean cell volume MCV -Low mean cell hemoglobin MCH Normal percentages of HbA2 and HbF
41
Hb H disease
3 alpha genes deleted -Moderately severe anemia -Low MCV and MCH Excess Beta chains cause HbHB4 tetramers to precipitate and form Heinz bodies which lead to hemolytic anemia
42
Hydrops fetalis with Hb Barts
Both alpha genes completely inactivated (4 alpha genes deleted) Make y^4 Hb (Barts) -Stillborn or death within hours -Few are saved by exchange transfusion -Fetal onset of generalized edema and severe hypochromic anemia
43
What is the problem with Hb Barts
Hb barts has high O2 affinity Binds O2 delivered by mother but releases almost none to fetal tissues Severe hypoxia occurs and leads to profound edema Massive hepatosplenomegaly
44
B-thalassemia overview
Reduced B chain synthesis from beta globin genes Excess alpha chains precipitate and damage red cells and precursors Severe anemia, splenomegaly, bone changes - "Cooley's Anemia"
45
B-Thalassemia major form
No B-chain expression, severe homozygous condition | 0% B-globin synthesis
46
B-Thalassemia minor form
Partial deficiency in B-chains Heterozygous condition with milder anemia 50% B-globin synthesis
47
B-thalassemia cause
Beta-globin gene mutation can affect transcription, RNA processing or translation of B-globin RNA Excess a-chains cannot form tetramers, and aggregate and precipitate to form inclusion bodies Cause oxidative damage to red cells, destruction of immature erythroblasts in bone marrow Leads to ineffective erythropoiesis
48
Initial presentation of B-thalassemia
Disease seen when switch from HbF to HbA occurs (usually in neonates) Clinically emerges at 6-12 months Switch from HbF to HbA should occur at this time, but switch from y to B does not occur Hb levels progressively drop, severe anemia occurs
49
Therapy for B-thalassemia
``` Transfusions (this is the cause of death typically) Iron chelation Stem cell transplantation Prevention by genetic counseling Upregulation of HbF expression ```

Biochemistry (20 decks)

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