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Biochem Exam 1 > 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
Q

No 2,3-BPG - effect on hemoglobin

A

Hemoglobin would be an extremely inefficient oxygen transporter

26
Q

2,3-BPG concentrations in lung/tissue

A

Lung- NO 2,3-BPG= high affinity for O2

Tissues- High [2,3-BPG]= low affinity for O2

27
Q

T and R forms of Hb

A

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
Q

2,3-BPG and T/R forms

A

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
Q

Smoking and 2,3-BPG

A

Smoking causing higher levels of 2,3-BPG, causing more T form Hb with lower affinity. Smokers have reduced O2 carrying capacity

30
Q

pH and Hb

A

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
Q

Fetal hemoglobin and why O2 flows from mom to fetus

A

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
Q

Sequential model of cooperativity

A

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
Q

Carboxyhemoglobin

A

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
Q

HbA1c

A

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
Q

Thalassemias definition

A

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
Q

a-Thalassemia

A

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
Q

Effect of a-Thalassemia in fetal life

A

Excess y(gamma)-globin chains for y^4 tetramers called Hb Barts

38
Q

Effect of a-Thalassemia in adult life

A

Excess B-globin chains for B^4 tetramers or Hb H

39
Q

a+-thalassemia

A

Silent carrier, one gene deleted

40
Q

a-thalassemia trait

A

Two alpha genes deleted
-Low mean cell volume MCV
-Low mean cell hemoglobin MCH
Normal percentages of HbA2 and HbF

41
Q

Hb H disease

A

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
Q

Hydrops fetalis with Hb Barts

A

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
Q

What is the problem with Hb Barts

A

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
Q

B-thalassemia overview

A

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
Q

B-Thalassemia major form

A

No B-chain expression, severe homozygous condition

0% B-globin synthesis

46
Q

B-Thalassemia minor form

A

Partial deficiency in B-chains
Heterozygous condition with milder anemia
50% B-globin synthesis

47
Q

B-thalassemia cause

A

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
Q

Initial presentation of B-thalassemia

A

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
Q

Therapy for B-thalassemia

A 
Transfusions (this is the cause of death typically)
Iron chelation
Stem cell transplantation
Prevention by genetic counseling
Upregulation of HbF expression

Biochem Exam 1 (22 decks)

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