DISCUSSION ON HYDROGEN TRANSPORT 37 



of fumarate to succinate by certain leuco dyes; it is distinct from 

 succinic dehydrogenase but could perhaps replace the latter enzyme 

 in the Szent-Gyorgyi scheme). 



While it has been proved that the four-carbon dicarboxylic acids 

 and other metabolites may act as carriers, the previous paragraph 

 indicates that we cannot conclude that fumarate-succinate actually 

 does so. Since malonate inhibits succinate oxidation, the observed 

 inhibition of respiration by malonate has been taken as evidence of 

 the carrier function of succinate-fumarate. But the inhibition of 

 respiration by malonate and the promoting effect of added fumarate 

 may be explained as inhibition and promotion of oxidative metabol- 

 ism through Krebs' cycle. 



Dr. Potter has emphasized the above points (6), and he points out 

 that carrier functions for four-carbon dicarboxylic acids and other 

 substances have been assumed on the basis of the following four 

 criteria: 1. The compound is a natural constituent of tissues. 2. It 

 can be reduced by tissues at rates compatible with the actual rate 

 of oxidation of the substrate whose oxidation it is presumed to cata- 

 lyze. 3. The reduced compound can be oxidized by the tissue prepa- 

 ration at an adequate rate. 4. The compound is able to stimulate 

 catalytically the rate of hydrogen transport in the system under 

 investigation. But it appears that a fifth requirement is necessary to 

 prove carrier function, namely, the compound must be directly re- 

 duced by one system and directly oxidized by a second system which 

 is not identical with the first. As Dr. Ball and Dr. Potter have pointed 

 out, oxalacetate is reduced by dihydrocoenzyme I and malate is 

 oxidized by coenzyme I, yielding tlie dihydrocoenzyme. That is to 

 say, hydrogen from the donator metabolite is passed to the co- 

 enzyme, producing dihydrocoenzyme, but subsequent reduction of 

 oxalacetate to malate and reoxidation of the latter merely results 

 in producing the dihydrocoenzyme again. Thus no effective trans- 

 port of hydrogen has occurred and, unless another biological mecha- 

 nism for the oxidation of malate is discovered, it seems unnecessary 

 to postulate a carrier function for malate-oxalacetate. It is conceiv- 

 able, however, that the structural relations of enzymes in tissue may 

 render the passage of hydrogen from the donators to fumarate or 

 flavoprotein easier via coenzyme-oxalacetate-malate-coenzyme than 

 directly via coenzyme in one step. 



It seems likely that in tissues there is a dynamic equilibrium be- 

 tween the oxidized and reduced forms of numerous metabolites 

 and that flavoprotein-cytochrome-cytochrome oxidase mechanisms 

 continually abstract hydrogen (or electrons) from the system, while 



