COMPETITIVE ANALOGUE-METABOLITE INHIBITION 459 



However, the addition of a catalytic factor normally limiting the biosyn- 

 thesis of the metabolite may also cause an increased synthesis, resulting 

 in a higher concentration of the metabolite in the biological system. 

 Further, if the metabolite is utilized in reactions which are not essential 

 for the response of the biological system, substances which prevent the 

 loss of the metabolite by such pathways may also increase the effective 

 concentration of the metabolite; but the magnitude of such an effect 

 would usually be relatively small in comparison with other precursor 

 effects. 



A relatively simple testing technique has been developed which charac- 

 terizes the precursor type of effect on a competitive analogue-metabolite 

 inhibition of a biological system. The increased metabolite concentration 

 resulting from enhanced synthesis by the biological system results in a 

 corresponding increase in the amount of analogue (inhibitor) necessary 

 for a defined inhibition. However, if the metabolite is supplied to the 

 system in concentrations in excess of that from the enhanced synthesis 

 by the biological system, substances which exert such a precursor effect 

 do not appreciably influence the amount of inhibitor necessary for the 

 defined inhibition in the presence of the metabolite at such a concentra- 

 tion. Thus, the minimum inhibitory concentration of the analogue is 

 increased by such substances, but the inhibition index determined over 

 the remainder of a range of concentrations of the metabolite is not altered. 



In many instances increasing concentrations of a limiting precursor of 

 a metabolite may prevent the inhibition caused by the analogue over a 

 rather wide range of concentrations. However, the conversion of the pre- 

 cursor to the metabolite usually becomes less efficient at higher concen- 

 trations, and the concentration of precursor relative to the inhibitory 

 analogue of the metabolite for a defined inhibition increases markedly 

 with increasing concentrations. 



(2) Product Effect. If the product of the inhibited enzymatic reaction 

 is of such a nature that it can be supplied to the biological system from 

 an external source, the inhibited enzyme system becomes nonessential for 

 the biological process as a whole when this product is made available to 

 the system in adequate quantities. If the analogue does not prevent the 

 functioning of any other enzymes utilizing the metabolite, it is no longer 

 inhibitory to the biological system. 



However, the metabolite (substrate) may be utilized by several differ- 

 ent enzymes involved in the synthesis of several products, Pi, P 2 , P 3 , etc., 

 and the specific analogue, 7, may prevent the conversion of the metabo- 

 lite, S, to one or more of these products. If more than one system is 

 inhibited by the analogue, one of these enzyme systems, e.g., E u would 

 be expected to become the limiting reaction of the biological process 



