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Haemoglobin Structure + Synthesis - Coggle Diagram
Haemoglobin Structure + Synthesis
Structure
2 basic constiruents
Haem
Binds iron atoms in central part
Prosthetic grup
Tetrapyrolle ring structure with Fe(II) at centre
Protein
\(\alpha\)-globin + \(\beta\)-globin
Primary structure
2 families of polypeptides
\(\alpha\) and \(\beta\) chains
Synthesis under control of globin genes
Encoded on chromosomes 11 + 16
\(\alpha\) family on 16
\(\beta\) family on 11
Genes for each family
Location on chromosome is in order of expression
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Dotted between active genes in these clusters
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\(\alpha + \gamma\) genes duplicated
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\(\beta\) family
\(\beta\)
\(\gamma\)
\(\epsilon\)
\(\delta\)
All 146 amino acid length
\(\gamma + \alpha\) chains differ at 39 of 146 residues
HbF has higher affinity for O\(_2\) than HbA
\(\alpha\) family
\(\alpha\)
\(\zeta\)
Both 141 amino acid length
Invariant residues
Do not change
Vital to stability and function
Areas of contact between globin + haem group tend to be invariant
Ontogeny of globin chains
Throughout life of individual, globin chains in Hb vary
Embryonic Hb
Hb Gower
2\(\zeta\) + 2\(\epsilon\)
Hb Portland
2\(\zeta\) + 2\(\gamma\)
Hb Gower 2
2\(\alpha\) + 2\(\epsilon\)
Foetal Hb
HbF
2\(\alpha\) + 2\(\gamma\)
Adult Hb
Functionally identical
HbA
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HbA\(_2\)
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Despite 6 cysteine residues
There are no S-S bonds between globin chains
Secondary structure
75% of \(\alpha\) and \(\beta\) globin chains in from of \(\alpha\)-helices
All functional Hb molecules have same helical content
8 helices labelled A - H
25% residues in linear portions
Connect helices
Proline residues
Allow flexibility
Nomenclature
BC3
3rd residue between helices B + C
Proximal histidine at F8 in both globin chains is crucial
Forms bond with Fe\(^{2+}\) in centre of prosthetic group
Distal histidine at E7 is crucial
Interacts with oxygen without forming a chemical bond with it
Tertiary structure
Haem group of each globin sits deep in hydrophobic pocket/crevice between E and F helices
For Hb molecule to stay in solution within RBC
All residues on outside of globular protein must be hydrophilic
Any alterations to residue composition in this area may affect stability and liability to precipitation
Precipitated Hb is useless
RBC destroyed
Heinz bodies
RBCs with denatured Hb caused by oxidant damage
Due to lack of G6PD and therefore NADPH
Maintenance of reduced glutathione to combat oxidative stress lost
Quaternary structure
Hb is complex of 4 monomers
Held together by hydrophobic bonds between adjacent areas of polymer
2 pairs of contacts
\(\alpha1\beta1\) with \(\alpha2\beta2\)
Extensive
Consisting of 32 interactive residues
Structural contacts
\(\alpha1\beta2\) with \(\alpha2\beta1\)
Less extensive
Only 9 interactive residues
Contacts between C helix + F-G corner
Structural contacts
Functional contacts
O\(_2\) binding
Histidine residues bind to oxygen
Shifts Fe(II) into plane of haem molecule
Simultaneous changes in conformational parts of globin
Effects neighbouring globin conformation
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Help to uptake O\(_2\) quickly
Allosteric protein action
Hb containing Fe\(^{3+}\) - MetHb
Cannot bind oxygen
MetHb reductase pathway ensures MetHb is converted back to functional Hb
Quarternary structure
Tetrameric
2 x \(\alpha\)-globin + 2 x \(\beta\)-globin
Evolution
Change from anaerobic to aerobic lifestyle
Use of oxygen
Energy extraction from glucose more efficient
~18 fold
2 main mechanisms of vertebrates to supply oxygen to tissues
Circulatory system
Allowed aerobic animals to be much larger than anaerobes
Not reliant on diffusion through body surfaces
Large SA:V no longer needed
O\(_2\) transport molecules
Because O\(_2\) is sparingly soluble in water
Haemoglobin
Main oxygen carrier in blood
Tetrameric protein
Why in RBCs?
If Hb was free in circulation
Large Mw molecules would make circulating fluid highly viscous
Difficult to circulate
Hb occupies ~33% RBC vol + ~90% dry weight
Myoglobin
Oxygen storage in muscle cells
Better oxygen carrier
Monomeric protein
Importance of Hb in homo sapiens
To rely on dissolved oxygen in solution
Blood vol. would need to be 30x greater
or
Circulation would need to be 30x faster
Haem synthesis
2 compounds - precursors
Succinyl A
Glycine
Series of chemical reactions
2 compounds come together to form 1 ring
From 1 ring, all 4 join together
Ready to accept Fe\(2^+\)
Step 1
Condensation
Catalysed by ALA synthase
Formation of aminolaevulinic acid (ALA)
Step 2
Condensation
Loss of H\(_2\)O
Catalysed by ALA dehydratase
Formation of porphobilinogen (PBG)
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2 x ALA come together
Where?
Mitochondria
Loss of CO\(_2\)
Shemin Pathway
Rate limiting step in haem formation
Where?
Developing RBCs
Mitochondria
Sources of iron
Dietary intake
Absorbed by divalent metal transporter-1 (DMT1)
In enterocytes of duodenum and jejunum
Stored in
Liver
Pancrease
Spleen
Bone marrow
Transported in plasma
Transporters
Transferrin
Transport of Fe\(^{3+}\) in plasma to liver and bone marrow
Carries 2 molecules of Fe\(^{3+}\)
60-80kD
Fe-Tr complex can only enter developing RBC by binding transferrin receptor (TfR)
Ferroportin
Transports iron out of cells
Carried more efficiently as Fe\(^{3+}\)
Albumin
Lactoferrin
Regulation f transport
Hepcidin
Regulates iron movement into plasma
Via control of ferroportin expression
Produced by liver
Binds to ferroportin
Causes degradation
25 amino acid peptide
Controls export of iron from
Enterocytes
Macrophages
Kupffer cells
Hepatocytes
Placental cells
Raised hepcidin
Anaemia
Decrease hepcidin
Hypoxic conditions
Leads to iron defficiency
No control over iron transport
Haemoglobin synthesis
~65% occurs in late normoblast stage of RBC devel.
Remaining 35% after reticulocyte - after loss of nucleus
Reticulocyte still contains RNA, ER + mitochondria
Normal function
Haem + globin synthesis are synchronous
No excess of one over the other
Haem build-up inhibits own synthesis + stimulates globin chain production
Each RBC contains 27-37pg
Drop in Hb
Hypochromic anaemias
If RBC has insufficient Hb levels
Destroyed before leaving bone marrow
Ineffective erythropoiesis
Regulation of release of O\(_2\) from Hb
RBCs contain large amounts of 2,3-BPG
2,3-BPG binds to \(\beta\) chains in middle of tetramer
Combines with deoxyHb + reduces affinity for Hb
Reversibly bound, alters Hb conformation + releases O\(^2\)
O\(^2\) dissociation curve shifted to lower-right
More 2,3-BPG = more oxygen release
Foetal Hb has higher affinity to oxygen because it cannot bind 2,3-BPG