36 A SYMPOSIUM ON RESPIRATORY ENZYMES 



that added four-carbon substances removed, or prevented the for- 

 mation of, acetoacetic acid in liver and kidney brei. Krebs, working 

 vi^ith B. coli [Escherichia coli] indicated that fumarate-succinate 

 mediated the oxidation of glucose, malate, lactate, acetate, glycerol, 

 glyceraldehyde, butyrate, pyruvate, acetoacetate, Z( + )-glutamate 

 and molecular hydrogen. Apparently the oxidation of many types 

 of metabolite can be mediated by four-carbon dicarboxylic acids. 



Szent-Gyorgyi considered that the four-carbon dicarboxylic acids 

 were quite analogous to coenzymes in their catalytic role. But it 

 must be remembered that they behave also as combustible sub- 

 stances, particularly with kidney cortex slices and also to some ex- 

 tent with brei of various tissues, when they are added in excess. 

 The four-carbon dicarboxyhc acids are not the only substances that 

 can act both as catalysts and as substrates for respiration. Carrier 

 possibihties have been shown for pyruvate-lactate, as well as other 

 alpha-keto— alpha-hydroxy acids, adrenochrome, and transamination 

 reactions. It has been suggested that in B. coli formate-bicarbonate 

 plays a similar role, and in plants catechol derivatives and dihydroxy- 

 maleic acid may be important carriers. Perhaps many other sub- 

 stances may act in this way. In fact, carrier functions could be postu- 

 lated for all reversible oxidation-reduction systems, and we should 

 perhaps think of all oxidizable metabolites as capable of acting as 

 both substrates and carriers in a dynamic oxidation-reduction con- 

 tinuum. 



Addendum.'* —The Szent-Gyorgyi theoiy was first advanced at a 

 time when the succinic dehydrogenase system was the only one 

 definitely known to reduce cytochrome. Mediation by succinate- 

 fumarate of hydrogen transport between the majority of metabolites 

 and the cytochrome system thus naturally suggested itself. However, 

 the discovery of flavoproteins, which mediate oxidation of the re- 

 duced coenzymes, suggests that a flavoprotein catalyst may bring 

 about more direct oxidation of those substrates that are oxidized 

 through the action of coenzyme-deteiTnined dehydrogenases. Dr. 

 Hogness has described cytochrome c reductase, a flavoprotein from 

 yeast that causes cytochrome c reduction by dihydrocoenzyme II. It 

 seems likely that similar catalysts for the oxidation of both dihydro- 

 coenzymes I and II may occur in animal tissues. In that case there 

 would seem to be no necessity for mediation by fumarate-succinate. 

 (Another flavoprotein in yeast, fumarate reductase, has been de- 

 scribed by Fischer and coworkers. This enzyme causes the reduction 



" In the liglit of private discussions during the symposium. Dr. EUiott has 

 written an addendum to his remarks. — Ed, 



