HEMOGLOBIN AS A CYTOCHROME OXIDASE MODEL 389 



monoxide. Hence the autoxidation of hemoglobin and the formation 

 of hem/globin can be assumed to be a reasonably good model for the 

 autoxidation of the oxidase. 



6.3.2. Hemiglobin Formation. For certain reasons which will 

 become clear later on, we discuss here not only the formation of 

 hem/globin from hemoglobin by autoxidation, but also other modes 

 of hemoglobin formation. We shall only consider the physicochemical 

 mechanism of the reaction and not its physiologic importance, which 

 will be discussed later in conjunction with the biochemistry of the 

 red cell (Chapter XI, Section 4.). 



Hemiglobin can be formed from hemoglobin in three different ways: 

 (i) by the direct action of oxidants, (2) by the coaction of hydrogen 

 donors and atmospheric oxygen, and (3) by autoxidation. 



Direct oxidation of the ferrous iron of hemoglobin. The ferrous iron of 

 hemoglobin can be oxidized directly by such reagents as ferric tartrate, ferri- 

 cyanide, bivalent copper, chlorate, nitrate, quinones, alloxan {359), and dyes 

 of high oxidation-reduction potential such as indigo sulfonates or phenol- 

 indophenol. It will be seen below, however, that even some of these reagents 

 do not simply oxidize the hemoglobin iron. 



Warburg and Kubowitz (2940) have claimed that hematins oxidize hemo- 

 globin in the red cell and in this way catalyze an increased cell respiration. 

 Their evidence is partly based on erroneous interpretation of the action of 

 phenylhydrazine, which will be discussed in Chapter XI, Section '^.3. They 

 have obtained this increase, however, also by addition of hematins. What- 

 ever is the correct interpretation of these effects, it is unlikely that it is due 

 to the oxidation of the ferrous iron of hemoglobin by the ferric hematin iron 

 since the oxidation-reduction potential of the heme-hematin system is 

 several hundred millivolts below that of the hemoglobin-hem/globin system. 



Hem/globin is formed by chlorate and nitrate, but these reactions are more 

 complicated. The hem/globin formation by chlorate is an autocatalytic 

 process {1258). Since compounds combining with hem/globin such as cyan- 

 ides, azide, cyanate, and thiocyanate inhibit the reaction, it is likely that 

 hem/globin chlorate acts as an oxidative catalyst. Myohem/globin chlorate 

 is less effective {1528). 



The oxidation of hemoglobin by nitrite and nitrite esters, e.g., amylnitrite, 

 is a still more complex process, which in spite of numerous investigations {99, 

 172,3Jf.3,1050,110It,llU-U89,lS95,20(i8) is not yet fully explained. It is 

 complicated by the formation of nitrosohemoglobin and nitrosohem/globin 

 {cf. Chapter VI, Sections '2. 2. 4. and "2.3.6.) and by the oxidation of nitric 

 oxide to higher nitrogen oxides in the presence of air. 



Brooks {3It3) and Hcubner {1254) formulate the over-all process of the 

 formation of hem/globin from oxyhemoglobin by nitrite: 



4 .\07 + 4 HhO, -^ 4 NOT + 4 HiOH + O.. 



