The thalassaemia syndromes / D.J. Weatherall.

  • Weatherall, D. J.
Date:
1972
Catalogue details

Licence: Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)

Credit: The thalassaemia syndromes / D.J. Weatherall. Source: Wellcome Collection.

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    HAEMOGLOBIN AND ITS GENETIC CONTROL 3I treatment with puromycin which strips partially finished chains from the ribosomes (Felicetti et al, 1966). This finding suggests that the iron is bound to the ribosomes in a non-specific way and is not associated with globin. Incorporation of'^•'Fe into haemoglobin proceeds for up to 15 min after artificially stopping globin synthesis and this has been interpreted as further evidence for the combination of haem with a pool of globin after globin is released from the ribosome. While these experiments do, indeed, suggest that the haem-globin association takes place in free solution, it is still possible that completed chains combine with haem before their release. All these experiments with '^■Te-labelled haem are complicated by the distinct possibility of exchange of haem associated with ribosomal globin with that in the free pool of haem in the cell. With the information currently available it seems likely, therefore, that haemoglobin synthesis is achieved by the association of the aß subunit with haem probably after ribosomal release of the globin. The in vitro addition of haemin to the aß subunit results in the rapid formation of a stable tetramer (Winterhalter and Huehns, 1964). Haem synthesis The structure of haem and the steps involved in its biosynthesis are summarised in Fig, 2,13. Haem is synthesised by an enzymatically controlled series of steps starting with the condensation of glycine and active succinate derived from the tricarboxylic acid cycle. This condensation is controlled by an enzyme, S-aminolaevulinic acid (ALA) synthetase which requires pyridoxyl phosphate and ferrous ions for maximal activity. The end result of this reaction is a-amino-/3-ketoadipic acid which is rapidly decarboxylated to S-aminolaevulinic acid (ALA). Two molecules of ALA combine under the action of an enzyme, ALA dehydrase, to form the first pyrrole unit, porphobilinogen (PBG). The por¬ phyrins consist of four pyrrole units and are synthesised by the condensa¬ tion of four molecules of PBG. Thus protoporphyrin is synthesised via a series of porphyrin III precursors as shown in Fig. 2.13. The combination of protoporphyrin with iron requires an enzyme, haem synthetase. ALA synthetase and haem synthetase are localised in the mitochondria while the other haem-synthetic enzymes are found in the cytoplasm. A full account of haem synthesis will be found in several more extensive reviews (Rimmington, 1959; Bannerman, 1961 ; Granick and Levere, 1964).