On the Bigness of Enzymes 239 



On the above view the mechanism of the enzymatic reactions involv- 

 ing oxidoreductions are closely related to those of the hydrolytic reac- 

 tions. Here the enzyme must supply a mechanism by means of which 

 electrons can be removed from one substrate and transferred to another. 

 There is no evidence that the transfer is directly from one substrate 

 to another. These enzymes often contain iron or molybdenum, and 

 in some cases the metal is known to be an acceptor for the electrons 

 removed from the substrate. In all cases, it seems reasonable to as- 

 sume, the metal somehow facilitates the transfer of electrons from 

 substrate to enzyme. The vacant d shells found in these metals may 

 supply a set of electron levels in a manner similar to those of impurities 

 in semiconductors. 



The specificity of the protein with regard to catalase activity is in 

 accord with this view. It is not necessary that the substrate react 

 directly with the metal ion. Indeed, in cytochrome c all the six 

 coordination bonds are filled, four by the porphyrin and two by the 

 protein. 10 The substrate could interact with the enzyme at some point 

 distant from the metal atom in a manner similar to that shown in 

 Fig. 26. As the substrate approaches the enzyme, at an appropriate 

 configuration the two electrons forming the C:H bond enter the triplet 

 state, the hydrogen atom leaves as a hydronium ion, and the remaining 

 positive ion forms a bond with a free electron pair of a tertiary 

 nitrogen of the protein. Further loss of a hydrogen ion from the 

 substrate rearrangement of the electrons and evaporation from the 

 enzyme surface would yield the oxidized substrate. The electrons 

 would be transferred via the triplet state to the iron atom. 



Such a mechanism, as outlined above, would permit electrons to enter 

 the enzyme molecule at one point and to leave it at another. Transfer 

 of electrons from one protein molecule to another would not be difficult 

 if both proteins had triplet states of about the same energy. Clearly, 

 the transfer of electrons from one substrate to another could differ not 

 only in time but in space. Szent-Gyorgyi has briefly described an 

 experiment which suggests that electron flow can take place in excited 

 states of proteins. 11 



An experimental test of the hypothesis presented in this paper is 

 possible. Since molecules in a triplet state are paramagnetic, the active 

 substrate-enzyme complex should be paramagnetic. 



I am indebted to the Committee on Growth of the American Cancer 

 Society and to the Office of Naval Research for funds which supported 

 some of the experimental work which was a background for this paper. 



