Lecture 6: Variants of haemoglobin

Question 1

What are the main feature of foetal haemoglobin HbF?

Answer 1

• has 2-alpha chains & 2-gamma chains
• has a greater affinity for oxygen
• binds less strongly to BPG

Question 2

How does the foetus receive oxygen from the mother blood?

Answer 2

The foetus receives oxygen as HbF has a greater affinity to oxygen than HbA (adult haemoglobin), so oxygen will flow from HbA to HbF so the foetus receives oxygen from the mothers blood via the placenta

Question 3

Why doesn’t HbF bind as strongly to BPG?

Answer 3

HbF has 2-gamma chains instead of 2-beta chains.
The B-globin has His 143 which forms an electrostatic interaction with BPG
The Y-globin has Ser 143 which DOES NOT form an electrostatic interaction with BPG
—-> so the BPG isn’t held as tightly

Question 4

What are 3 ways in which abnormal variants arise in haemoglobin?

Answer 4

MUTATIONS
- transcription/mRNA processing defects causing failures of globin protein synthesis
- point mutations in DNA resulting in amino acid changes or truncation of global protein products
- point mutations that lead to instability of the
‘tense’ -deoxy or ‘relaxed’-ocy conformation of the haemoglobin tetramer

Question 5

What are the main features of HbM - methaemoglobin?

Answer 5

• iron is its ferric Fe3+ form
• —-> causes the haemoglobin to move very little
• —-> causes the haemoglobin to be stuck in its TENSE -deoxy state, so it has a low affinity to oxygen

Question 6

How does HbM variant arise?

58 His ——> 58 Try

Answer 6

HbM has its 58 His changed to a 58 Tyr.
- the 58 His was originally located just opposite the iron causing steric hindrance, but when changed to Tyr the ion bind to the Tyr instead

Question 7

What is another way in which the HbM variant can arise?

67 Val ——-> 67 Glu

Answer 7

67 Val is changed to 67 Glu

• Glu has a side chain COOH, which can be ionised to COO- which stabilises the iron to be in its ferris 3+ state.
• —> Glu side chain, COO- stabilises Fe3+ state

Question 8

What is the HbC variant?
A3 - Glu ——> Lys
What are its effects?

Answer 8

• amino acid 6 is changed from Glu +ve ——> Lys -ve

- People with HbC are more resistant to malaria

Question 9

What is Hb Christchurch variant?

Phe ——> Ser

Answer 9

Phe (large & non-polar) is changed to Ser (small & polar) at amino acid 71, E15
- change in amino acid is near the heme and this change slightly destabilises the heme

Question 10

What is the HbS variant - sickle cell?

Glu(polar) ——> Val(non-polar)

Answer 10

This mutation occurs on the surface of the protein and can cause proteins to aggregate

• —–> HbS(deoxy) is likely to aggregate & crystallise to form sickle cells due to interactions btw the non-polar reigions
• —> different shape —–> different structure
• occurs at amino acid 6