Biosynthesis of Haem 



are of protoporphyrin IX (isomeric series III). On the supposition 

 that the porphyrin ring is built up from pre-fabricated pyrrole units, 

 containing substituent groups in the (3-positions, all four position 

 isomers would be chemically and biologically possible but no repre- 

 sentatives of isomers II and IV have ever been found in nature. 



That there does exist a relationship between coproporphyrin 

 production and the synthetic events of erythropoiesis seems to follow 

 from the finding of increased urinary coproporphyrin excretion by 

 animals during regeneration following blood withdrawal. There is no 

 evidence of the normal degradation of haemoglobin passing through 

 a porphyrin stage. 



In order to explain the excretion of coproporphyrin I and of its 

 increase during erythropoietic activity, I postulated in 1938 1 an 



/ P III 

 enzymic system in the bone marrow A f which visualized 



\ P I 

 the possible synthesis from precursor materials ' A ' of porphyrins 

 belonging to either isomeric series (P III and P I) but suggested that 

 the events leading to one of these products were specifically accel- 

 erated thus making that isomer the main and the other the by-product. 

 But we must approach more closely to the mechanism of synthesis 

 and the sequence of chemical events. Some possible systems for such 

 studies may be arranged as follows : 



Bone marrow in intact animal. 

 Bacteria, especially C. diphtheriae. 

 Yeast. 



Yeast press juice. 



Porphobilinogen-containing porphyria urines. 

 Maturing reticulocytes (Watson). 

 Nucleated erythrocytes. 

 Before dealing with the uses to which these systems have been put 

 and, in particular, with the latest contributions based on the use of 

 isotopes, I will summarize briefly the various theoretical speculations 

 which have been put forward concerning the building up of the 

 porphin ring. 



The earliest serious suggestion which I have been able to trace is 

 in a paper 2 by Sir Robert Robinson in the Proceedings of the University 

 of Durham Philosophical Society for 1928. Although based upon the 

 old Kuster formula for haematin, this scheme is of historical interest. 

 Denoting - CH 3 by Me and - CHaCHaCOOH by S, condensation 

 is envisaged between two aliphatic chains followed by combination 

 with ammonia and further elimination of water as cyclization occurs 



243 



