CHAPTER 2 



MALEATE 



Maleate and fumarate are isomeric, tlie former being the cis and the 

 latter the trans form, and for this reason the differences in the actions on 

 biological systems were studied early to demonstrate the influence of 

 structure on activity. Maleic acid was discovered by Lassaigne in 1818, who 



CH— COO- -OOC— CH 



II II 



CH— COO- CH— COO- 



Maleate Fumarate 



prepared it by heating malic acid and named it paramalic acid; it was re- 

 named maleic acid by Pelouze in 1834. The first report of its toxicity was 

 made by Fodera (1894), who found that given intravenously to dogs at 

 a dose of 1.94 g/kg (neutralized) it caused rapid death, whereas the same 

 quantity of fumaric acid produced only a weak and nontoxic response. The 

 greater toxicity of maleate relative to fumarate was confirmed during the 

 next few years with whole plants and isolated plant tissues, algae, infusoria, 

 copepods, and other organisms. It has also been observed that many tissues 

 can readily metabolize fumarate but not maleate, as first reported by 

 Maassen (1895) in the penicillia, and that under certain conditions fuma- 

 rate may go to lactate whereas maleate is unable to do so. Ohta (1912) 

 believed that maleate could be transformed to acetoacetate in the perfused 

 dog liver, but it seems more likely that the observed increase in aceto- 

 acetate was due to the effect of the maleate on the metabolism of the liver. 

 Lipschitz and Gottschalk (1921) showed that fumarate brought about an 

 enzyme-catalyzed reduction of m-dinitrobenzene in ground muscle but 

 that maleate had no effect, and Dakin (1922) established that incubation 

 of fumarate with a muscle extract led to the appearance of malate, while 

 no malate arose from maleate. 



The first report of a truly inhibitory action of maleate on metabolism 

 was by Thunberg (1911 a), who demonstrated a fairly potent depression 

 of frog muscle respiration; indeed, it was the most potent inhibitor of all 

 the many organic acids examined. This study was extended by Gronvall 



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