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Proteins > Haemoglobinopathies > Flashcards

Haemoglobinopathies Flashcards

1
Q

What are the typical properties of globular proteins?

Where are they found?

A
  1. They are compact
  2. They are usually soluble
  3. Found in the cytosol, blood and extracellular fluid
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2
Q

Why are globular proteins usually soluble?

A

They have hydrophilic residues on the outside of the molecule and hydrophobic residues hidden inside

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3
Q

What are the typical properties of fibrous proteins?

A
  1. They are elongated
  2. They have repeating amino acid sequences
  3. Insoluble
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4
Q

Why are fibrous proteins insoluble?

A

They have a high hydrophobic amino acid content

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5
Q

What is significant about membrane proteins?

A

They are embedded either fully or partially within the membrane

They must interact with the soluble phase on either side of the membrane and the hydrophobic core of the membrane

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6
Q

How are most mutant haemoglobins formed?

What effect does this have?

A

Most abnormal Hbs differ from normal due to a single amino acid change

Most changes have no clinical effect

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7
Q

What are haemoglobinopathies?

A

Mutated haemoglobins that are responsible for disease

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8
Q

What is the difference between the 2 main types of oxygen binding proteins?

A

Myoglobin is an oxygen STORE that is mainly found in muscle

Haemoglobin is involved in oxygen and CO2 TRANSPORT

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9
Q

Why do cells need oxygen?

A

To act as an electron acceptor in the electron transport chain

This is involved in ATP production

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10
Q

Why is an oxygen transport and storage system needed?

A

As it is only sparingly soluble in the blood

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11
Q

Where is myoglobin mainly found?

What is its structure like?

A

Mainly found in skeletal and cardiac muscle

Small protein made from 153 amino acids

Very compact

Contains haem prosthetic group

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12
Q

What is the secondary and tertiary structure of myoglobin like?

A

It is a globular protein that is mainly a-helical

It contains 8 a-helices

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13
Q

What is the haem group comprised of?

A

A protoporphyrin IX ring with an Fe2+ ion in the centre

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14
Q

How is the haem group held in place within the haemoglobin molecule?

A

It is tightly bound in a hydrophobic crevice in the Hb molecule

There is NO covalent bonding

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15
Q

How can mutations affect the haem group?

A

Mutations may affect the hydrophobic crevice

This means the haem group is lost from the molecule

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16
Q

How many ligands can Fe2+ coordinate with?

What bonds form?

A

Fe2+ can coordinate with 6 ligands

4 bonds form with the N from the porphyrin ring

1 bond forms to the histidine residue at position F8

1 bond forms to an oxygen atom

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17
Q

What happens when oxygen binds to haemoglobin, in relation to the haem group?

A

Binding of oxygen alters the position of the iron ion relative to the porphyrin ring

It moves from below the plane of the ring to be parallel to the centre of the plane

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18
Q

What residue is involved in forming a hydrogen bond to the oxygen?

A

The distal histidine (E7)

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19
Q

What are the 2 advantages of associating the haem unit with a protein molecule?

A
  1. It keeps Fe atoms in the Fe2+ form

2. Binding of other small molecules is inhibited

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20
Q

What happens if carbon monoxide binds to haem instead of oxygen?

A

It has a much higher affinity for haem

Oxygen cannot bind to Hb so tissues are starved of oxygen

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21
Q

Why is carbon monoxide poisoning difficult to detect at first?

A

Symptoms of CO poisoning often begin like the flu

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22
Q

What is involved in the quaternary structure of haemoglobin?

A

2 alpha and 2 beta polypeptide chains held together by non-covalent forces

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23
Q

How many oxygen molecules can one Hb bind to?

A

4

This is because each polypeptide chain contains a haem group

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24
Q

How does the structure of Hb relate to myoglobin?

A

Each chain of Hb has a very similar 3D structure to Mb

Very different primary structures can produce similar looking tertiary structures

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25
Q

What are the 2 pairs of subunits in the Hb tetramer?

A

a1b1 and a2b2

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26
Q

What is meant by Hb being an allosteric protein?

A

The binding of oxygen to one subunit affects interactions with other subunits

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27
Q

How do the following factors vary between myoglobin and Hb?

i. oxygen binding
ii. oxygen affinity
iii. regulation

A

i. binding is co-operative in Hb but non-cooperative in Mb
ii. affinity is pH and CO2 dependent for Hb, but not for Mb
iii. Hb is regulated by BPG, but Mb is not

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28
Q

Does Hb or Mb have a greater affinity for oxygen?

Why?

A

Mb has a greater affinity for oxygen

It is a storage molecule that only releases oxygen in times of need

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29
Q

What is meant by the binding of oxygen to Hb being co-operative?

What does this produce?

A

As oxygen levels drop, Hb readily releases oxygen to the tissues

This produces a binding curve which is sigmoidal

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30
Q

What is cooperative binding?

A

When oxygen binding increases the affinity of haemoglobin for more oxygen

This makes the binding of the next O2 molecule much easier

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31
Q

What happens when oxygen binds to Hb and the iron atom moves down into the plane of the ring?

A
  1. it pulls the F8 histidine down with it

This drags the F8 helix into a different position

  1. the E7 histidine then moves, as it is incorporates with the oxygen

This changes the distance between F8 and E7

32
Q

What happens when one oxygen molecule binds to Hb, in relation to bonds?

A

Some interchain salt bridges are ruptured

33
Q

What is the tense (T) state of haemoglobin?

What is the affinity for oxygen like?

A

This is the state where oxygen is NOT bound to haemoglobin

Hb has a low affinity for oxygen

34
Q

What are bonds and oxygen binding sites like in the tense state?

A

There are more salt bridges between subunits that hold the molecule in position

Oxygen binding sites are not very accessible

35
Q

What happens to oxygen binding sites after one O2 molecule has bound to Hb?

A

The binding sites are brought into a position where they are more accessible

36
Q

What is the relaxed (R) state of haemoglobin?

What is the affinity for oxygen like?

A

The relaxed state has fewer salt bridges

Haemoglobin has a much higher affinity for oxygen

37
Q

What is the Bohr effect?

A

It describes the effect of pH on the affinity of haemoglobin for oxygen

38
Q

How does a lower pH affect the affinity of haemoglobin for oxygen?

A

It reduces the affinity

More oxygen is released to respiring tissues

Hb becomes less saturated with oxygen

39
Q

How will increased levels of CO2 or lactic acid affect Hb?

A

The pH becomes lower

This leads to increased release of oxygen to respiring tissues

40
Q

How does the Bohr curve shift in lower pH?

What are the axes labels?

A

The curve shifts to the right

x - pO2

y - Hb saturation

41
Q

How does pH affect amino acid residues in Hb?

A

pH affects the protonation state of amino acid residues

42
Q

What happens to amino acid residues when pH is lower?

A

[H+] is higher

This leads to additional residues being protonated

This particularly affects histidine residues

43
Q

What is the pKa value of histidine?

How does pH affect this?

A

pKa = 6

When pH is 6 or below, the group is positively charged

It becomes less charged above pH 6

44
Q

What happens to amino acid residues as pH drops, in terms of Hb affinity for oxygen?

A

Residues become increasingly positive

This means more salt bridges are formed

This stabilises the T state and decreases the affinity for oxygen

45
Q

Under what conditions will BPG levels increase?

A
  1. high altitude

2. hypoxia (poor oxygenation of peripheral tissues)

46
Q

How does BPG affect the affinity of Hb for oxygen?

A

BPG decreases the affinity of Hb for oxygen

It causes more oxygen to be released to peripheral tissue

47
Q

What does BPG actually stand for?

A

2,3-biphosphoglycerate

48
Q

Where does BPG bind?

What is significant about this?

A

BPG binds in the spaces between the B subunits

This can only occur during the T-state

49
Q

Why can BPG only bind during the T state?

A

The negative charges on BPG interact with the positive amino acid residues lining the space

The +ve AA residues are only in the correct position during the T state

50
Q

What happens to BPG during the R state?

A

BPG will not bind well

This allows oxygen to be released

51
Q

Where will CO2 bind to Hb and what will it form?

A

It binds to amino groups on the globin protein

This forms carbaminohaemoglobin

52
Q

How do the effects of H+, BPG and CO2 all affect Hb?

A

They all bind to different sites on the Hb molecule so their effects are additive

53
Q

How does foetal Hb bind to oxygen compared to adult Hb?

How does this affect the Hb saturation curve?

A

Foetal Hb has a higher affinity for oxygen than adult Hb

It binds more strongly

This causes the curve to shift to the left

54
Q

What are the subunits in foetal Hb?

A

2 alpha and 2 gamma subunits

55
Q

Why does HbF have a higher affinity for oxygen than adult Hb?

A

It contains no beta subunits

It binds to BPG much less effectively

56
Q

What do haemoglobinopathies affect?

A

They are a range of inherited disorders that affect Hb synthesis, structure and function

57
Q

What causes sickle cell anaemia?

A

A single amino acid mutation which alters an area on the outside of the Hb molecule

This causes Hb molecules to stick together

58
Q

What is significant about having sickle-shaped red blood cells?

A

They are fragile and prone to rupture

59
Q

What causes B-thalassaemia?

A

An inability of the body to produce enough B-globin

60
Q

What is the consequence of someone not being able to produce enough B-globin?

A

Not enough Hb is produced

The patient becomes anaemic

61
Q

What 5 things may mutations in Hb affect?

A
  1. the amount of Hb that is synthesised
  2. The structure of the Hb
  3. the stability of the Hb
  4. The affinity of Hb for oxygen
  5. the affinity for regulators (e.g. BPG)
62
Q

How can mutations affecting the structure of Hb lead to haemolytic anaemia?

A
  1. Hb keeps denaturing
  2. the body breaks down abnormal RBCs in the spleen or liver
  3. The body cannot synthesise enough RBCs to keep up with the rate at which they are denatured
63
Q

What is meant by critical amino acid residues?

A

They are 9 residues that are always the same in a healthy individual

64
Q

What are the 9 critical amino acids and their role?

A

F8 His - proximal His

E7 His - distal His

CD1 Phe - haem contact

F4 Leu - haem contact

B6 Gly - B and E helices contact

C2 Pro and HC2 Tyr - H bonds between H and F helices

65
Q

What is His involved with?

A

Oxygen binding and the effect of binding on the tertiary structure

66
Q

What are Phe and Leu involved with?

A

They are part of the hydrophobic pocket in which the haem group sits

67
Q

What is Gly involved with?

A

It is found at the point where 2 helices come close together

They are pushed apart if a larger residue is present

68
Q

What is the role of Pro?

A

The R group in Pro forms part of peptide bonds

Proline is inflexible and cannot form part of an a-helix

69
Q

What happens if Pro residue is removed through a mutation?

A

The a-helix continues through further residues

70
Q

What is the role of Tyr?

A

It maintains the position of the helices relative to each other

71
Q

What are the 2 types of mutations that can occur in Hb?

A

A mutation can be conservative or non-conservative

This depends on the R-group of the substituted amino acid

72
Q

Which mutations will affect the function of Hb?

A

A mutation of a critical residue

73
Q

What is a conservative substitution?

A

The replacement of an amino acid residue with one that has similar properties

74
Q

How do conservative substitutions affect Hb structure and function?

A

They are unlikely to have much of an effect

75
Q

What is a non-conservative substitution?

How does it affect Hb structure and function?

A

The amino acid residue is substituted for one that has very different properties

This has a major effect on structure and function

Proteins (5 decks)

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