Lecture 12 - O2 Transport and Storage by Haemoglobin and Myoglobin Pt. II Flashcards
What does the haem look like in deoxyhaemoglobin?
dished
What happens to the haem upon the formation of oxyhaemoglobin?
oxygen flattens the haem and pulls HisF8 and helix F toward the binding site
What will weaken oxygen binding?
anything that keep helix F away from the binding site
What are conformational changes?
shifts in the orientation of protein secondary elements
What are some mechanisms that work together to shift between T and R states
- Allosteric regulation
- pH
- Physiological/genetic changes
What can change the balance of T & R state haemoglobin?
Conformational changes
When is co-operativity prominent?
In the presence of allosteric inhibitors of binding
What stabilises the T-state?
allosteric inhibitors BPG, CO2, and H+. this allows better cooperativity
What state is ‘stripped’ haemoglobin predominantly in in the absence of inhibitors?
R-state, shows little co-operativity
What is Haemoglobin allosterically controlled by?
2,3 - biphosphoglycerate (BPG)
How does BPG bind to deoxy-Hb?
electrostatic interactions
What does BPG do to Hb?
stabilises Hb in the deoxy T-state reducing oxygen affinity
How is BPG produced?
during respiration in peripheral tissues
What does BPG promote?
oxygen release where it is required
What does CO2 do to oxygen affinity?
reduce oxygen affinity
How does CO2 reduce the affinity of haemoglobin for O2?
The Bohr effect - elevated CO2 and lower pH (higher [H+]) in metabolising tissues both reduce the affinity of haemoglobin for O2
How does lower pH decrease oxygen binding affinity?
favours protonation and stronger ionic interactions in the T-state
How does CO2 reduce oxygen binding affinity directly?
binds to amino-terminal amino group stabilising the deoxy-Hb conformation in T-state
What alternate isoforms of haemoglobin does Foetal haemoglobin have?
zeta equivalent to alpha, epsillon, and gamme equivalent to beta
What differs between foetal and normal haemoglobin?
Different amino acid sequences of normal haemoglobin subunits alter their oxygen binding properties
Does foetal or normal haemoglobin hold oxygen tighter?
foetal
Why can foetal haemoglobin bind oxygen more tightly?
It is less sensitive to BPG
Why is foetal haemoglobin less sensitive to BPG?
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.
What causes sickle cell haemoglovin?
The beta E6V variant of haemoglobin
What is the consequence of sickle cell haemoglobin?
Sickle shape red blood cells get stuck in capillaries
What is one benefit of sicle cell haemoglobin?
resistance to malaria
What does the beta E6V variant of haemoglobin do?
enables an abnormal hydrophobic interaction between Hb tetramers
When is the beta E6V variant particuarly exposed?
when in the deoxy haemoglobin form, as this causes polymerisation of Hb into chains that distort the RBC’s
How does CRISPR-based therapy treat Sickle cell disease?
Up-regulation of foetal haemoglobin replaces faulty normal haemoglobin production
How does Voxelotor treat sickle cell disease?
It is an oxygen affinity modulator, stabilises the oxygenated state, increases oxygen affinity
