VARIOUS METABOLIC PATHWAYS 695 



could be secondary. There is probably some justification for attributing 

 at least part of the negative nitrogen balance during arsenical poisoning 

 to interference with protein synthesis, but other factors must certainly be 

 important. 



Few enzymes involved in nitrogen metabolism are sensitive to the arseni- 

 cals (Table 6-3). Most proteolytic enzymes are resistant, except for certain 

 cathepsins, and many of the enzymes degrading amino acids (e. g., oxidases, 

 decarboxylases, and deaminases) are inhibited only by concentrations of 

 the arsenicals far above those encountered in the tissues. It is true that the 

 oxidations of some amino acids are strongly inhibited but the sites of at- 

 tack are seldom the proximal enzymes. For exemple, it has been shown 

 many times that the oxidation of L-glutamate is readily inhibited by arsenite, 

 in some cases around 50% by 0.01-0.1 mM (Tonhazy and Pelczar, 1953; 

 Kann and Mills, 1955; Shiio, 1957; Chari-Bitron and Avi-Dor, 1959 a; 

 Das and Roy, 1961, 1962; Borst, 1962), but the site of action must be the 

 a-ketoglutarate oxidase in most cases. Similarly, the oxidation of proline 

 is inhibited by arsenite (Roche et al, 1953; Shiio, 1957), but the pathway 

 proceeds through glutamate. Possibly in some tissues the glutamate dehy- 

 drogenase is a major site of inhibition as well, and arsenite has been shown 

 to inhibit the production of ammonia by the brain (Weil-Malherbe and 

 Green, 1955 a). This ammonia probably comes from glutamate and gluta- 

 mine, but the oxygen uptake is inhibited more than the release of ammonia 

 (Takagaki et al., 1957). The adenylate deaminase of brain is unaffected 

 by 10 mM arsenite (Weil-Malherbe and Green, 1955 b). The transaminases 

 are not markedly inhibited by the arsenicals, and this is further indicated 

 by the accumulation of certain amino acids, such as alanine, aspartate, and 

 glutamate (Altenbern and Housewright, 1951). The over-all effects of 

 arsenicals on amino acids levels in cells will depend on many factors, 

 including the arsenical concentration which to some extent determines 

 the selectivity of the inhibition. It may be mentioned that essentially nothing 

 is known of the alterations which may be produced by arsenicals in the urea 

 cycle, but from the results on whole animals it appears that no important 

 inhibition is exerted here. 



Porphyrin Synthesis 



The biosynthesis of protoporphyrin involves the conversion of glycine 

 and succinyl-CoA to r3-aminolevulinate, followed by condensation to por- 

 phobilinogen, which further condenses to form the porphyrin nucleus (see 

 page 11-159). Arsenicals could interfere with porphyrin synthesis by de- 

 creasing the supply of either glycine or succinyl-CoA, or by inhibiting any 

 of the reactions leading to porphyrins. Although nothing is known of the 

 effects of the arsenicals on over-all glycine metabolism, significant depletion 

 of glycine is unlikely in view of the many pathways forming it. However, 



