144 Arthur L. Koch 



Now if in addition we assume that some step is either rapid in the direction 

 of synthesis or irreversible, then it may easily be seen that the reaction velocity 

 V, is completely independent of subsequent steps. Thus, the synthetic rate can 

 be made to depend on the level of a few catalysts or other reactants involved 

 earlier in the sequence. Consequently, increased protein synthesis would cause 

 increased synthesis of a very few enzymes critical for nucleic acid biosynthesis, 

 and this would lead smoothly to increased DNA synthesis without requiring 

 exact synchronization in the increase of each enzyme on the biosynthetic path- 

 way. The concentration of the last intermediate i'j_i can be seen from equation 

 (4) to be vlW^, and thus is completely independent of any step that has no effect 

 on the reaction velocity, v. 



This case does not therefore satisfy the requirements suggested above to 

 explain the mutagenic effects of the plant alkaloids. The independence of 

 growth rate in the presence of caffeine could be explained simply by assuming 

 that the inhibition occurs after some fast or irreversible reaction; but the 

 action of the inhibitor on any but the final step has no effect on the concentration 

 of the immediate precursor of the macromolecule, and thus cannot affect the 

 probability of mutation. 



The scheme considered above has two desirable features: it permits a 

 reciprocal control of nucleic acid by the level of protein synthesis, and it prevents 

 the accumulation of large amounts of intermediates. Let us now turn to a 

 possible mechanism that will do these two things but also will fulfill the conditions 

 imposed by our ideas of the mutation event. Such a mechanism occurs in 

 systems showing product inhibition. Here the rate of production of the final 

 product will depend on the level of some enzyme catalyzing a step late in the 

 reaction sequence, but at the same time, the inhibition prevents the unlimited 

 synthesis of earlier intermediates. 



Product inhibition is of common occurrence. It has been suggested as having 

 metabolic significance in two cases (23, 24) in which the product of a reaction 

 sequence inhibits some earlier reaction than its own formation. In the present 

 case it has been shown that adenine deoxyriboside is an inhibitor of the phos- 

 phorylase (12) as well as purine bases. Let us assume that all of these agents 

 are competitive inhibitors of enzyme action, although this remains to be demon- 

 strated conclusively. 



Under such conditions the reaction velocity is given by the well-known 

 expression for competitive inhibition (see, for example, (25)) 



K, K, + Ul) + US) 



where Kis the maximal velocity obtainable, K^ is the Michaelis-Menten constant 

 for the substrate S, and Ki is the constant for the binding of the enzyme with 

 the inhibitor, 1. If Kj{I) is the dominant term in the denominator, this expression 

 simplifies to give: 



K.V(S) ... 



In the present case, adenine deoxyriboside is the inhibitor which is formed 

 from the substrate adenine and deoxyribose-l-POj. Now, if the net rate of 



