Abstract
During recent years much attention has been given to the mechanism of synthesis of proteins in biological systems.' Although the process is by no means fully understood, some of the steps involved appear to be well established.2-4 Before amino acids can be incorporated into polypeptide chains they must first be activated. The activation process involves ribonucleic acids of comparatively low molecular weight, known as transfer or soluble ribonucleic acids (sRNA), adenosine-5' triphosphate (ATP) as an energy source, and a specific enzyme for each amino acid. In the first step of the activation process, the amino acid reacts with ATP to form a mixed anhydride with adenosine-5' phosphate (AMP) releasing inorganic pyrophosphate; this mixed anhydride then acylates a specific sRNA on its terminal nucleoside (adenosine) residue to yield a 2' (or 3')-aminoacyl ester-the activated amino-acid. These processes are reversible. ATP + amino acid = aminoacyl-AMP + pyrophosphate (1) sRNA + aminoacyl-AMP = aminoacyl-sRNA + AMP (2) Beyond this point our knowledge of the process of polypeptide synthesis is less certain. The activated amino acids are believed to be transferred to the ribosomes-the site of assembly of polypeptide chains-and then the amino acids become linked together in a genetically controlled order to synthesize a specific protein.5 Although there is as yet no definite evidence regarding this final step, it is frequently assumed that it involves a simple acylation as indicated in step (3). Aminoacyl-sRNA + peptide -- aminoacyl-peptide + sRNA (3) If this assumption is correct, then the peptide chain-lengthening step is simply the common reaction between an ester and an amine to form an amide. Although it is well known that esters of amino acids are usually more susceptible to nucleophilic attack than those of simple carboxylic acids,6 it was clear from a variety of observations that aminoacyl-sRNA possessed a remarkable reactivity, behaving rather like an acid anhydride.2 Several previous studies have indicated but not clarified some possible reasons for this. Wieland et al.7 found that 2'- and 3'leucyl esters of 5'-ribonucleotides were cleaved more rapidly by hydroxylamine than was the monoleucyl ester of cis-cyclopentane-l,2-diol. This result suggested that the known substantial effect of a cis-vicinal hydroxyl group on hydrolysis rates of esters, which has been studied by Bruice and Fife,8 could not of itself account for the observed high reactivity of the aminoacyl-nucleotides. Wieland et al.7 suggested that both the glycosidic nitrogen and the ring-oxygen of the sugar residue might be involved. Zachau9 reported that valyl-ribonucleotides and -nucleosides were hydrolyzed by alkali at about the same rate as valyl-sRNA so that the macromolecular character of the latter seemed unimportant; he also found that the nature of the pyrimidine or purine base in the nucleotide had little effect. Zachau and Karau6 further showed by experiments using esters of various 440
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More From: Proceedings of the National Academy of Sciences of the United States of America
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