Haemoglobin structure and synthesis Flashcards
Why doesn’t Hb get carried free in circulation?
The large molecules could make the fluid highly viscous and hard to circulate
What are the two major structures in Hb?
Goblin chains
Prosthetic group Haem
What structure does haem have?
- Tetrameric structure
- Tetrapyrolle ring structure
- Fe(II) at centre
What is step one of Haem synthesis?
- Formation of Aminolaevulinic Acid (ALA)
- Condensation reaction
- ALA synthase involved
What is step two of Haem synthesis?
- Condensation reaction to form Porphobilinogen (PBG)
- ALA dehydratase involved
What is step three of Haem synthesis?
- Polymerisation of PBG
- x4 PBG come together to form a tetra-pyrolle ring structure
- Two enzymes involved: PBG Deaminase and Uroporphyrinogen III Cosynthetase
- One pyrolle ring is reversed during this process
What is step four of Haem synthesis?
- Decarboxylation
- Acetyl to Methyl through loss of CO2
- x4 CO2 liberated
- Enzyme used: uroporphyrinogen III decarboxylase
- last stage to occur in cytoplasm
What is step five of Haem synthesis?
- Conversion of proprionyl to vinyl
- Uses coproporphyrinogen oxidase
- oxidative decarboxylation + dehydrogenation of two propionyl groups at 2, 4, positions
- Molecular oxygen rewuired
What is step six of Haem synthesis?
- Oxidation, removal of 6H+ atoms
- Uses protoporphyrinogen oxidase
- Some rearrangement to double bonds
What is step seven of Haem synthesis?
- Insertion of Fe(II) into ring
- Use ferrochelatase/haem synthetase
- Specific to ferrous form of iron
Where does each stage of haem synthesis occur?
Stages 1-4 = Cytoplasm
Stages 5-7 = mitochondria
How is iron absorbed?
- Divalent metal transporter-1 (DMT-1)
- Absorbed by membranes of the duodenum
What transports Fe out of cells?
Ferroportin
In what state is Iron most effectively carried?
Fe3+
How can Iron enter developing RBCs?
Fe-Tr complex can only enter by binding Transferrin receptor (TfR)
What regulates Ferroportin?
Hepcidin
Outline Hepcidin
- Produced by liver
- Leads to degradation of ferroportin
- 25 amino acid peptide, HAMP gene, chrom. 19
- Raised levels = anemia of chronic disease
Which pathway do erythrocytes rely on for energy? Outline it
Embden-Meyerhof
- Glycolysis of glucose to pyruvate
- Free energy forms ATP
- Leaves oxygen free due to lack of mitochondria
How many levels of structure does Hb have?
Polymeric, so four (primary, secondary, tertiary, quaternary)
What families do globin chains derive from?
Alpha and beta chain families
How many globins do Hb molecules contain
2 from each family
Where are the globin genes found?
Long arms of chromosomes 11 and 16
Outline the beta globin chain family
- β, γ, δ, and ε
- 146 amino acid length
Outline the alpha globin chain family
- α and ζ
- 141 amino acid length
Where are amino acid residues found?
- Areas of contact between globins/ globin and the haem group
Outline the secondary structure of Hb
- 75% of alpha and beta globin chains form alpha-helices
- Remaining 25% are residues connecting helices
Outline the tertiary structure of Hb
- Amino acids on the outside of the protein are hydrophilic (so can remain in solution)
- Glucose-6-phosphate Dehydrogenase (G6PD) maintains NADPH
- G6PD deficiency results in lack of oxidative stress management
What are heinz bodies?
A structure containing denatured Hb caused by oxidant damage
Outline the quaternary structure of Hb
- Only has this structure as Hb is a polymer made of 4 monomers
- Hydrophobic bonds between adjacent areas
- Main contact between B and H helices
- Functional contacts allow conformational changes
How does Fe(II) move in Hb depending on the oxygen state?
Deoxygenated: slightly above plane of haem moiety
Oxygenated: into the plane of the porphyrin group
What is the function of 2,3-Biphosphoglycerate (2,3-BPG)?
- Found in large amounts in RBCs
- Binds to beta chains in centre of thr tetramer
- combines with deoxyHb to reduce Hb affinity for O2
- Reversibly bound
What factors effect oxygen binding affinity?
Using bohr effect:
- PCO2
- PO2
- pH
- Temperature
- 2,3-BPG
Why does foetal Hb have a greater affinity for O2?
It binds less easily to 2,3-BPG, allowing it to carry 20-30% more O2 than maternal HbA.
