Effects of fluoropyrimidines on the synthesis of bacterial proteins and nucleic acids.

The recognition of the control mechanisms through which the cell maintains the specific properties of its high molecular components is condemned to ,being posthumous; it is necessary to kill or poison the cell before its way of life can be revealed. It is, therefore, not surprising that many of the pathways through which the cell accomplishes its integration have remained largely speculative. As regards the connection between proteins and nucleic acids, some evidence has been produced in the recent past pointing to the existence of a close metabolic link between these cellular polymers which are presumably all characterized by a rigidly specified arrangement of their monomeric constituents. It seems probable that the nucleic acids carry, in their primary structure, at least part of the information that determines, directly or indirectly, the specificity of the protein molecule. Hence, it is conceivable that an alteration in the structure of a nucleic acid molecule specifying a given protein will produce a change in the latter. Were such a process susceptible of closer inspection, a better understanding of the mechanisms governing the synthesis of both protein and nucleic acid might be attained. Of the substances with a profound effect on cellular metabolism, the 5-fluoropyrhnidines are of particular interest in this connection. 5-Fluorouracil has been shown to interfere with the appearance of the elements of formic acid in the thymine component of nucleic acids (4, 5), presumably by inhibiting the enzyme responsible for the introduction of the methyl group (6); it intervenes in the synthesis of ribonucleic acid, as evidenced by the blocking of the utilization of uracil or erotic acid as precursors of the uracil component of nucleic acids (5, 7-9) ; it also inhibits the enzymic conversion of uracil to uridine (10). Moreover, this fluoropyrimidine is incorporated into the ribonucleic acid of rat liver and spleen and of various mouse tumors (4, 11) and, to a considerably larger degree, into the ribonucleic acid of Escherichia coli (2) and of tobacco mosaic virus (12). These effects made it appear interesting to examine the influence of fluoropyrimidines on the synthesis of protein. It is with this problem that the present study is concerned; dealing with the effect of fluoropyrimidines on several strains of E. co&i, it extends observations briefly described in a previous