28 Introduction 



covered by this method since 1938 and it seems to become increasingly evident 

 that heavy metals contribute to the action of most enzymes. Obviously the long 

 polemics directed against the first functional heavy metal that was discovered — the 

 iron of iron oxygenase — was an attack that could not have been more unjustified. 

 The chemical mechanism of the function of metals in the metallo-enzymes of 

 the second type is still unknown. One of the mysteries of enzyme chemistry is the 

 fact that of the zymohexases we have crystallized, yeast zymohexase is a metallo- 

 enzyme but muscle zymohexase is not. 



VII. Respiration {19) 



Since the active groups of the oxidizing and reducing enzymes and their chain 

 reactions have been discovered", 



[1] 0-2 — iron oxygenase -> cytochrome — flavin — * nicotinamide 

 [2] O2 -> copper oxygenase — orthoquinone -»■ nicotinamide 



the question has been discussed whether these pathways provide a complete 

 explanation for the mechanism of biological oxidation and reduction or whether 

 they are valid for only a limited number of substrata — for the initial attemps at 

 in vitro oxidation by enzymes of, for instance, fatty acids and the so-easily-com- 

 bustible acetic acid, were unsuccessful. 



Coenzyme A, which Lipmann 8 discovered in 1945, supplied the answer to this 

 question. In 1951 Lynen 9 discovered that coenzyme A acts through its SH group, 

 which forms thioesters with organic acids and thereby makes the acids capable of 

 reacting with the components of the enzyme chains. Flavoproteins dehydrogenate 

 Coat bound fatty acids 10 ; the //-hydroxy acids thus formed are dehydrogenated to 

 keto acids by pyridine proteins. The latter dehydrogenate the CoA-bound pyruvic 

 acid to acetyl CoA, whose acetic acid constituent then combines with oxalacetic 

 acid to form citric acid: 



COOH COOH 



In the citric acid cycle discovered by H. A. Krebs 11 , the equivalent of the acetic 

 acid is oxidized to carbon dioxide and water, and at the same time oxalacetic acid 

 is formed once more. The enzymes, which effect these oxidations within the 

 cycle — the oxidation of isocitric acid, ketoglutaric acid, succinic acid, and malic 

 acid — are none other than the pyridine proteins, flavoproteins, and heme proteins. 



Many similar examples could be cited today. Indeed, all the biological hydro- 

 genations and dehydrogenations that we know of are effected by reactions of 

 members of our enzymatic chains. Thus they provide the universal and complete 

 Solution to the problem of biological oxidation and reduction. 



