338 2. ANALOGS OF ENZYME REACTION COMPONENTS 



_,,,., , Relative — AF oi bmdim 



bubstituent group 



(kcal/mole) 



—Imidazole —0.82 



—Indole 0.21 



-OH 0.25 



-H 0.61 



-COO- 0.67 



-Phenyl 1.09 



-CH3 1.40 



-SH 1.94 



The relative sensitivities to these amino acids probably vary with the 

 source of the arginase. For example, the mouse liver enzyme is inhibited 

 somewhat more strongly by L-lysine than L-ornithine, and even D-lysine 

 is a weak inhibitor (inhibitions at 1 mM are 47% for L-lysine, 42% for orni- 

 thine, and 8% for D-lysine) (Nadai, 1958). Johnstone (1958) stated that 

 there is evidence in intact ascites cells that ornithine can interfere with the 

 transport of arginine into the cells, as well as inhibit arginase intracellularly, 

 so that this additional site of inhibition must be borne in mind. 



An attempt was made by Sen (1959) to determine the effects of L-lysine in 

 vivo in order to evaluate its possible use in uremia. Bilaterally nephrec- 

 tomized dogs show an increase of blood urea at a rate of 15-16 mg/day and 

 die in 80-84 hr. When L-lysine is injected daily and intravenously at a 

 dose of 1 g, the blood urea rise only 3-4 mg/day and the animals survive 

 for 274-278 hr. Thus it would seem possible to reduce urea formation in 

 vivo with this competitive inhibitor, but the clinical benefit of this remains 

 to be tested. 



L-AMINO ACID OXIDASES 



These enzymes from snake venoms and mammalian tissues oxidize the 

 L-isomers of the monoamino-monocarboxylate amino acids, the substrate 

 used often being L-leucine. The snake venom enzyme was shown by Zeller 

 and Maritz (1944) to be inhibited by various aromatic sulfonates. Some of 

 the results are shown in Table 2-14, from which it may be seen that 

 p-nitrodiphenyl sulfonate is the most potent inhibitor studied. The inhi- 

 bitions seem to be competitive and a complex between the sulfonate group 

 and an enzyme amino group was postulated. Benzoate is a rather weak 

 inhibitor of rat kidney L-amino acid oxidase, 10 mM inhibiting 28% 

 (Blanchard et al., 1944). However, the ammonium ion is a surprisingly good 

 inhibitor, 12 mM producing 69% depression of activity. 



