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CLINICAL ASPECTS OF BIOCHEMISTRY PROTEINS AND DISEASE HAEMOGLOBIN AND HAPTOGLOBIN

CLINICAL ASPECTS OF BIOCHEMISTRY PROTEINS AND DISEASE HAEMOGLOBIN AND HAPTOGLOBIN. Haemoglobin - revision Haemoglobin variants - haemoglobinopathies Haemoglobin S Thalassaemia Haptoglobins. HAEMOGLOBIN - REVISION.

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CLINICAL ASPECTS OF BIOCHEMISTRY PROTEINS AND DISEASE HAEMOGLOBIN AND HAPTOGLOBIN

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  1. CLINICAL ASPECTS OF BIOCHEMISTRY PROTEINS AND DISEASE HAEMOGLOBIN AND HAPTOGLOBIN Haemoglobin - revision Haemoglobin variants - haemoglobinopathies Haemoglobin S Thalassaemia Haptoglobins

  2. HAEMOGLOBIN - REVISION Myoglobin (Mb)Oxygen binding/storage protein in muscle; may also play a part in local oxygen transport. O2 binds to haem. Maintenance of haem in Fe2+ form is necessary for O2 binding. Mb is a monomeric protein of about 150 aa. Haemoglobin A (HbA) O2 carrier in blood (red cells). Tetramer: 22. Quaternary structure allows allostery - co-operative binding of O2 modulated by pH (Bohr effect), CO2 binding, bisphosphoglycerate (BPG) binding. 3D structure of each chain is similar to that of Mb.

  3. HAEMOGLOBIN

  4. TERTIARY STRUCTURE OF MYOGLOBIN AND HAEMOGLOBIN b SUBUNIT

  5. Different types of Hb in man: HbA 22 HbA222 ~2% of adult Hb;  chain differs from  at ~ 10% of residues; function (if any) unclear HbF 22 late foetus and neonate; replaced by HbA 3-6 months after birth;  chain differs from at ~of residues. In presence of BPG HbF has higher affinity for O2 than HbA, allowing transfer of O2 to foetus (2 HbFs in man, g chains differing at 1 aa) HbGower Gower I 22 Embryonic.  similar to  (~20% differences) Gower II 22 Embryonic.  similar to  (~40% differences) So, at least 5 different Hbs (6 chains) in normal human. , , d,  chains can all form tetramers,  can't.

  6. DEVELOPMENTAL PATTERN OF HAEMOGLOBIN IN MAN Based on Voet & Voet (1995)

  7. Mb z a d b g EVOLUTIONARY TREE RELATING HUMAN GLOBIN CHAINS e

  8. Hbs in lower organisms: Mammals. Adult Hbs all similar to human HbA, but may be variants unlike those seen in human. Developmental patterns of Hbs differ considerably Other vertebrates Most vertebrates have 22 type structure. Variant types differ considerably. Lamprey (most primitive fish) has only a single chain - more similar to Mb than mammalian Hbs (no allostery) Invertebrates, plants, bacteria. Hb-like proteins frequently found, but not 22

  9. HAEMOGLOBIN VARIANTS - HAEMOGLOBINOPATHIES • Exterior of molecule • e.g. Glu6Val[haemoglobin S (HbS)] • GluB8Lys(harmless?) • Alteredtertiary structure • PheCD1Ser [Hb Hammersmith] • GlyB6Arg [Hb Riverdale-Bronx] • Altered 'active site’ • HisF8Tyr [Hb Iwate] (proximal His) ) • HisE7Tyr [Hb Boston] (distal His) )(cyanosis; methaemoglobinaemia) • Alterations at subunit interfaces • AspG1His [Hb Yakima] ) • AsnG4Thr [Hb Kansas] ) (polycythaemia or cyanosis)

  10. SICKLE CELL ANAEMIA - HbS - FIBRES Based on Voet & Voet (1995)

  11. HbS - AGGREGATION Based on Voet & Voet (1995)

  12. HAEMOGLOBIN S (HbS) • Possible therapies: • Disruption of intramolecular interactions (peptides?) • Use of agents to increase O2 binding affinity • Lower HbS concentration (increase erythrocyte permeability) • Keep HbF switched on (hydroxyurea) • Vasodilators • Gene therapy

  13. a and b THALASSAEMIAS a0 and b0 thalassaemias- corresponding globin chain missing completely  and b+ thalassaemias - corresponding globin chain produced in reduced amount •  thalassaemia • Silent carrier state: 1 (of 4) a genes missing • a thalassaemia trait: 2 a genes missing • Hb H disease: 3a genes missing • Hydrops fetalis: 4 a genes missing [lethal] • [ Hb Barts: excess g4; HbH: excess b4 ] • Also a thalassaemia due to other causes. E.g. Hb Constant Spring: • Mutant stop codon and read-through of 31 aas, but mRNA degraded, so little protein

  14. a b kbp 20 60 40 z yz ya1 a1 a2 Ag yb b e Gg d HAEMOGLOBIN GENE CLUSTERS Chromosome 16 Chromosome 11

  15. kbp b0 thalassaemia Hb Lepore GgAgdb thalassaemia GgAg HPFH Gg HPFH Hb Kenya Ag yb b e Gg d 20 60 40 DELETIONS IN THE HAEMOGLOBIN b GENE CLUSTER HPFH = hereditary persistent fetal haemoglobin

  16. b thalassaemia Point mutations that can cause b thalassaemia: 1. Nonsense mutations 2. Frameshift 3. Point mutation in promoter 4. Point mutations that inactivate or generate splice sites 5. Point mutations of the AATAAA sequence

  17. 54 71 113 143 Lys Glu HAPTOGLOBINS a & b chains; S-S linked; tend to form oligomers (ab)2 etc. In human a chain is polymorphic: aI (83 residues): aIF (Lys54) and aIS (Glu54) aII (143 residues): Partial gene duplication Gene frequencies:aIF 0.16 aIS 0.24 aII 0.60

  18. a b Hp1F Hp1S Hp2 PROPOSED MECHANISM FOR PARTIAL GENE DUPLICATION OF HAPTOGLOBIN

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