The Biosynthesis of Peptide Hoi ids 109 



Despite the attractiveness of the concept that the cleavage of pyro- 

 phosphate bunds of ATP is linked to the biosynthesis of the peptide 

 bonds of proteins, it is not possible at present to specify the chemical 

 nature of the "reactive" form of the amino acids. Efforts to demon- 

 strate a direct enzyme-catalyzed reaction between ATP and the a- 

 carboxyl group or the a-amino group of amino acids have been incon- 

 clusive thus far. Although carboxyl phosphates and phosphoamides 

 of amino acids have been synthesized in the chemical laboratory, there 

 is no evidence that they play a role in the biosynthesis of CO-NH 

 bonds. Hence, in a discussion of the synthesis of proteins from amino 

 acids, one cannot write even the first chemical reaction on the way 

 to the completed protein, in the sense that one can specify that, in 

 the biosynthesis of glycogen from glucose, the first step is the formation 

 of glucose-6-phosphate in the glucokinase reaction. 



Attempts to identify the "reactive" form of a-amino acids in protein 

 formation have involved the study of the biosynthesis of the CO-NH 

 bonds of compounds such as acetylsulfanilamide. These studies have 

 been of exceptional importance to biochemistry, since they led to the 

 discovery of coenzyme A (CoA) and have shown that, in the presence 

 of suitable enzyme systems, the cleavage of ATP is associated with 

 the formation of acetyl CoA. :i Like other thiol esters, this acyl mer- 

 captan reacts with amines such as sulfanilamide to form amides. 

 Similarly, in the biosynthesis of hippuric acid, the acylating agent is 

 benzoyl CoA, whose formation from benzoic acid and CoA requires 

 the participation of ATP. However, in the instance of hippuric acid 

 synthesis by animal tissues, the enzyme that catalyzes the reaction 

 between benzoyl CoA and glycine appears to be specific for glycine 

 as the amine. In view of the limited specificity of this enzyme, it 

 cannot be assigned a general role in protein formation, although the 

 synthesis of acylamino acids such as hippuric acid illustrates a bio- 

 chemical mechanism whereby energy may be "pushed" into the forma- 

 tion of a CO-NH bond. However, there is no evidence as yet for the 

 enzymic conversion of the a-carboxyl groups of free amino acids or 

 peptides to thiol esters similar to acetyl CoA or benzoyl CoA. 



In the search for alternative mechanisms that may be operative in 

 peptide bond synthesis, attention has also been given to the formation 

 of pantothenic acid from pantoic acid and ^-alanine. Here, CoA does 

 not appear to be involved, ami it has been assumed that ATP is cleaved 

 to adenosine monophosphate with the formation of a reactive "enzyme 

 pyrophosphate" compound which reacts with pantoic acid to form a 

 "pantoyl enzyme" compound; this, in turn, is believed to react with 



