444 THE BIOCHEMISTRY OF B VITAMINS 



acid, the fluoride forms a fluorophosphate with the magnesium of enolase. 4 

 Iodoacetate appears to inhibit noncompetitively enzymes which contain 

 sulfhydryl groups essential for their activity. It has been postulated that 

 hydrocyanic acid, mercuric salts, sodium azide, hydroxylamine and many 

 other noncompetitive inhibitors likewise react with specific groups or ions 

 essential for the activity of the enzymes. These inactivations are not pre- 

 vented by excess substrate, as is the case in the inactivation of an enzyme 

 by a competitive type of inhibitor. 



The earliest reports of inhibitions which appear to be of a competitive 

 nature concerned inhibitions of enzymatic reactions by products of the 

 reactions. 5 Maltose and glucose inhibit maltose production from starch 

 by malt amylase. 6 In this and many other instances, such inhibitions 

 induced by the products of a reaction cannot be ascribed totally to a 

 reversal of the reaction by a mass action effect. Thus, fructose or /?-glu- 

 cose prevents the hydrolysis of sucrose by yeast saccharase, and a-glucose 

 competitively prevents the action of Aspergillus saccharase; 7 glycine as 

 well as alanine prevents the hydrolysis of glycylglycine by intestinal 

 peptidases; 8 pyruvic acid inhibits competitively the dehydrogenation of 

 lactic acid by lactic dehydrogenase; 9 and ornithine prevents the hydrol- 

 ysis of arginine by arginase. 10 In all these cases the products of the 

 enzymatic reactions appear to be able to combine with the enzyme in 

 competition with the substrate. In a number of instances compounds 

 somewhat similar to the substrate were known to prevent an enzymatic 

 reaction. Thus, 3-methylxanthine as well as guanine, uric acid or 1- or 

 7-methylguanine prevents the oxidation of xanthine by xanthine oxidase. 11 

 Some of the inhibitions were shown to be competitive; e.g., physostigmine 

 competitively prevents the hydrolysis of acetylcholine by choline es- 

 terase. 12 



The realization that substances structurally related to the substrate 

 may inhibit the action of an enzyme came with the report of Quastel and 

 Wooldridge 9 that the dehydrogenation of succinic acid by succinic de- 

 hydrogenase was competitively prevented by malonic acid and a number 

 of structurally related compounds. 



Although in this and in many other cases the competitive inhibitors 

 structurally resembled the substrate, and although the fundamental 

 theories for both competitive and noncompetitive inhibitions had been 

 previously developed, especially for isolated enzyme systems, the impor- 

 tance of inhibition of enzymatic action by an analogue of the substrate 

 as related to chemotherapy and growth inhibition was not fully realized 

 until the report of Woods and Fildes in 1940 13 - 14 that the bacteriostatic 

 action of sulfanilamide was competitively prevented by p-aminobenzoic 

 acid, a compound previously not known to have a biological function. 



