THE HAEM-GLOBIN LINKAGE 



3, The Relationship between Molecular Structure and 

 Physiological Activity of Haemoglobins* 



By J. E. O'Hagan 



Red Cross Blood Transfusion Service, Brisbane, 

 Queensland, Australia 



The reactions of haemoglobins have been interpreted in terms of the 

 imidazole, steric hindrance, haem-haem interaction and intermediate com- 

 pound hypotheses, which have had wide acceptance. However, the opinion 

 that the haem iron was linked by groups other than imidazoles has been 

 expressed by Haurowitz (1954, 1959) and by O'Hagan (1959a). Theorell and 

 Ehrenberg (1951) considered that a more acid group was responsible for this 

 linkage in horse myoglobin, while Wyman (1948) in expounding the imidazole 

 hypothesis, made a reservation that the evidence for the identification as 

 imidazole of the more acid of the groups co-ordinating the iron in horse 

 haemoglobin was not completely certain. Recent X-ray studies of ferri- 

 myoglobin by Kendrew, Bodo, Dintzis, Parrish, Wyckoff and Phillips (1958), 

 neither appear to support a hypothesis of co-ordination of the haem iron 

 between two amino acid side-chains of the protein, nor confirm steric 

 hindrance relationships. Roughton (1944), while paying tribute to the value 

 of Wyman's work, pointed out that it did not account for the important 

 carbamino reaction. 



Strong arguments against the steric hindrance (or embedded haem) concept 

 were presented by Keilin (1953), and these were supported to a certain extent 

 by the preparation of artificial haemoglobins from haems of dimensions 

 larger than protohaem (namely coprohaem III and tetramethyl-coprohaem 

 III (O'Hagan, 1955, I960)). George and Lyster (1958), after a careful analysis 

 of the evidence, considered steric hindrance effects unlikely, at least for small 

 ligands, which, after all, are the physiologically important ones. 



The haem-haem interaction hypothesis as proposed by Pauling (1935) to 

 interpret the sigmoid dissociation curve of oxyhaemoglobins has not been 

 able to account for a number of apparent exceptions. The addition of 

 oxygen to ferrohaemoglobin is linear when measured by either spectro- 

 photometric (Nahas, 1951) or magnetometric methods (Coryell, Pauling and 



* Part I, O'Hagan; Part 2, O'Hagan and George; Biochem. J., 74, 417, 424 (1960). 



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