Lecture 12 - O2 Transport and Storage by Haemoglobin and Myoglobin Pt. II

Question 1

What does the haem look like in deoxyhaemoglobin?

Answer 1

dished

Question 2

What happens to the haem upon the formation of oxyhaemoglobin?

Answer 2

oxygen flattens the haem and pulls HisF8 and helix F toward the binding site

Question 3

What will weaken oxygen binding?

Answer 3

anything that keep helix F away from the binding site

Question 4

What are conformational changes?

Answer 4

shifts in the orientation of protein secondary elements

Question 5

What are some mechanisms that work together to shift between T and R states

Answer 5

• Allosteric regulation
• pH
• Physiological/genetic changes

Question 6

What can change the balance of T & R state haemoglobin?

Answer 6

Conformational changes

Question 7

When is co-operativity prominent?

Answer 7

In the presence of allosteric inhibitors of binding

Question 8

What stabilises the T-state?

Answer 8

allosteric inhibitors BPG, CO2, and H+. this allows better cooperativity

Question 9

What state is ‘stripped’ haemoglobin predominantly in in the absence of inhibitors?

Answer 9

R-state, shows little co-operativity

Question 10

What is Haemoglobin allosterically controlled by?

Answer 10

2,3 - biphosphoglycerate (BPG)

Question 11

How does BPG bind to deoxy-Hb?

Answer 11

electrostatic interactions

Question 12

What does BPG do to Hb?

Answer 12

stabilises Hb in the deoxy T-state reducing oxygen affinity

Question 13

How is BPG produced?

Answer 13

during respiration in peripheral tissues

Question 14

What does BPG promote?

Answer 14

oxygen release where it is required

Question 15

What does CO2 do to oxygen affinity?

Answer 15

reduce oxygen affinity

Question 16

How does CO2 reduce the affinity of haemoglobin for O2?

Answer 16

The Bohr effect - elevated CO2 and lower pH (higher [H+]) in metabolising tissues both reduce the affinity of haemoglobin for O2

Question 17

How does lower pH decrease oxygen binding affinity?

Answer 17

favours protonation and stronger ionic interactions in the T-state

Question 18

How does CO2 reduce oxygen binding affinity directly?

Answer 18

binds to amino-terminal amino group stabilising the deoxy-Hb conformation in T-state

Question 19

What alternate isoforms of haemoglobin does Foetal haemoglobin have?

Answer 19

zeta equivalent to alpha, epsillon, and gamme equivalent to beta

Question 20

What differs between foetal and normal haemoglobin?

Answer 20

Different amino acid sequences of normal haemoglobin subunits alter their oxygen binding properties

Question 21

Does foetal or normal haemoglobin hold oxygen tighter?

Answer 21

foetal

Question 22

Why can foetal haemoglobin bind oxygen more tightly?

Answer 22

It is less sensitive to BPG

Question 23

Why is foetal haemoglobin less sensitive to BPG?

Answer 23

the gamma chain replaces the beta chain in foetal Hb. The gamma chain has a serine place of a histidine in the BPG binding site.

Question 24

What causes sickle cell haemoglovin?

Answer 24

The beta E6V variant of haemoglobin

Question 25

What is the consequence of sickle cell haemoglobin?

Answer 25

Sickle shape red blood cells get stuck in capillaries

Question 26

What is one benefit of sicle cell haemoglobin?

Answer 26

resistance to malaria

Question 27

What does the beta E6V variant of haemoglobin do?

Answer 27

enables an abnormal hydrophobic interaction between Hb tetramers

Question 28

When is the beta E6V variant particuarly exposed?

Answer 28

when in the deoxy haemoglobin form, as this causes polymerisation of Hb into chains that distort the RBC’s

Question 29

How does CRISPR-based therapy treat Sickle cell disease?

Answer 29

Up-regulation of foetal haemoglobin replaces faulty normal haemoglobin production

Question 30

How does Voxelotor treat sickle cell disease?

Answer 30

It is an oxygen affinity modulator, stabilises the oxygenated state, increases oxygen affinity