458 coRRADo ba(;lk)NI 



'riu' rate of synthesis of an aluioiiiial peptide chain is, in general, 

 lower than thai of the eorresponding normal chain. The lib-A/abnornial 

 hemoglobin ratio, which is assumed to be e(|uivalent to the ratio normal 

 chain/abnormal chain, is ([uite variabh' for different abnormal hemo- 

 globins and for different individuals. Itano (1953) has reported the 

 distribution of lib-S and llb-(" in members of several families, pointing 

 out tlie \aiiability of the latio lib-A/Hb-S or Hb-A/Hb-C, and intro- 

 ducing the concept of relative rate.s of synthesis as tlie determining 

 factor in hemoglobin ratios. Itano (1953) suggests that the variability 

 in the ratio Hb-A/abnormal hemoglobin may be dependent on the rela- 

 tive ability to synthesize Hb-A, rather than on the different rate of 

 synthesis of the abnormal hemoglobin. Chernoff (1956) has reported the 

 distribution of Hb-S, Hb-C, and Hb-D in heterozygotes, observing con- 

 spicuous variations in the amount of these hemoglobins relative to 

 Hb-A. Several genetic and environmental factors are likely to deter- 

 mine this variability; no definite correlation has, however, been estab- 

 lished between the Hb-A/abnormal hemoglobin ratio and any specific 

 factor. 



Different abnormal liemoglobins arc present in different amounts 

 relative to Hb-A. On examining data reported in the literature one 

 observes a fairly wide range of variation; it may thus be supposed that 

 the abnomial peptide chains are synthesized at a characteristic rate, 

 determined by the specific alteration of these peptide chains. How does 

 a single amino acid substitution affect the rate of synthesis of peptide 

 chains 141-146 amino acids in length? At which stage in the synthesis 

 of a peptide chain does the amino acid substitution become a rate- 

 limiting factor? It does not seem likely that an amino acid substitution 

 may decrease the rate at which the amino acids are aligned along the 

 ribosomal template and bound in peptide linkage for the synthesis of a 

 peptide chain. If this were the case, abnormal hemoglobins having the 

 same type of amino acid substitution should have an identical rate of 

 synthesis; this docs not seem to happen for Hb-C, Hb-E, and Hb-OArahia, 

 which have a glutamic acid substituted by a lysine in different positions 

 of the fi chain. The ratio Hb-A/abnormal hemoglobin in heterozygotes 

 for Hb-C, Hb-E, and Hb-OArabia has been found to be different. 



The following steps in the synthesis of the hemoglobin molecule are 

 the folding of the individual [leptide chains, the dimerization of identical 

 chains, and the association of symmetric dimers. As far as we know, 

 any of these processes can be disturbed by the presence of a wrong 

 amino acid in a peptide chain; however, the most likely to be disturbed 

 seems to be the folding of a peptide chain to assume its secondary or 

 tertiarv configuration. 



