CHAPTER 1 



MALONATE 



Malonate is one of the most interesting, specific, useful, and well-known 

 enzyme inhibitors, and for these reasons will be discussed in detail in order 

 to illustrate some of the general principles delineated in the first volume. 

 It will be valuable perhaps to take up one inhibitor to the degree necessary 

 to consider many of the various problems in the application of these prin- 

 ciples, and to examine the pitfalls that may appear even in the use of an 

 inhibitor that in several ways approaches what one would want ideally. 

 Much of what will be said concerning malonate may be applied to the other 

 inhibitors. This discussion will emphasize the often overlooked fact that 

 the effect of relatively simple inhibitors in cells may constitute a very 

 complex problem and that their use in elucidating metabolic relationships in 

 tissues or whole organisms should not be undertaken lightly. It is a simple 

 matter to apply an inhibitor such as malonate but it is often very difficult 

 to use it properly and to interpret the results accurately. The treatment 

 of malonate will, furthermore, provide a foundation for the more general 

 discussion of competitive inhibitions produced by analogs in the following 

 chapter. 



EARLY HISTORICAL DEVELOPMENT 



The first report of the use of malonate in a biological system was made 

 by Heymans (1889) to the Physiological Society in Berlin. The toxicity 

 of oxalate to animals had been known for many years and Heymans be- 

 lieved that an investigation of the higher homologs of the dicarboxylate 

 series might be interesting. Although sodium oxalate was quite poisonous 

 when injected into the frog dorsal lymph sac, the sodium salts of malonate, 

 succinate, and glutarate were essentially without effect, sodium malonate 

 being nonlethal at a dose as high as about 8 g/kg. However, Pohl (1896), 

 working in Prague, found that the urinary excretion of oxalacetate was 

 increased by administering malonate to dogs and, furthermore, that only 

 a small portion of the malonate given could be recovered in the urine, 

 indicating that the dog can metabolize malonate. The first experiments 

 showing the metabolic inhibitory action of malonate were done by Thun- 



