CHEMICAL PATHWAYS 113 



retained the attention. One hypothesis assumed that proteins are made 

 stepwise as the other substances, the other one that they are assembled in 

 one stroke by a template process. The template hypothesis remained sterile 

 for a long time because it was beyond the reach of experimentation ; the 

 current developments of genetics and molecular biology have now given so 

 much consistency to this old daydream that it appears at present an almost 

 certain reality. 



The hypothesis of a stepwise formation of polypeptides has not been very 

 successful; it never tried to account for the genetic control of protein 

 synthesis. But it suggested many experiments, and gathered a number of 

 data which will have to be integrated in the final scheme of protein synthesis. 



As will be seen, the two hypotheses are incompatible only when they are 

 both taken in their extreme form, and it is quite possible that the actual 

 mechanism of protein synthesis presents facets in which both hypotheses 

 can find some justification. 



1. Are there Free Peptide Intermediates? 



The question as to the existence of peptide intermediates between amino 

 acids and proteins was the subject of much discussion a few years ago ; it 

 was thereafter disregarded, but it cannot yet be answered unequivocally at 

 the present time. Intermediate stages must of course exist between 

 separate amino acids and a polypeptide containing for instance thirty amino 

 acid residues. The problem is to know whether polypeptides are made 

 stepwise from oligopeptides or peptide derivatives having an independent 

 existence and being handled by a series of separate catalysts, or whether 

 all the linkages between the amino acids which make a polypeptide are 

 formed, in more or less rapid succession, under the control of one single 

 catalyst, the organizer molecule or template. 



The direct search for oligopeptides in living cells has not been very 

 rewarding. If common small peptides, like glutathione or carnitine, are 

 discarded — for they do not seem to be intermediates in protein synthesis 

 — no notable amount of free peptides have been detected in cells. Excep- 

 tions may be some plant material (Fogg, 1952; Dagley and Johnson, 1956) 

 and resting bacteria maintained under adverse conditions (Gale and Van 

 Halteren, 1952; Weinbaum and Malette, 1959; Sorm and Cerna, 1960). 

 Tracer experiments designed to find out whether growing bacteria could 

 form enzymes from inactive precursors (Monod et ah, 1952; Halvorson 

 and Spiegelman, 1952; Rotman and Spiegelman, 1954; Hogness et al, 

 1955) did not detect any accumulation of complex intermediates between 

 amino acids and proteins. These experiments of course do not prove that 

 intermediate peptides do not exist, but they show that if they exist their 

 concentration is so low as to escape detection by the sensitive tracer 

 methods used, and that they are renewed very rapidly. 



