Mechanistic and metabolic inferences from the binding of substrate analogues and products to arginase

Arginase is a binuclear Mn2+ metalloenzyme that catalyzes the hydrolysis of L-arginine to L-ornithine and urea. X-ray crystal structures of arginase c omplexed to substrate analogues N-omega-hydroxy-L-arginine and N-omega-hydr oxy-nor-L-arginine, as well as the products L-ornithine and urea, complete a set of structural "snapshots" along the reaction coordinate of arginase c atalysis when interpreted along with the X-ray crystal structure of the arg inase-transition-state analogue complex described in Kim et;II. [Kim, N. N. , Cox, J. D., Baggie, R. F., Emig, F. A., Mistry, S., Harper, S. L., Speich er, D. W., Morris, Jr., S. M., Ash, D. E., Traish, A. M., and Christianson, D. W. (2001) Biochemistry 40, 2678-2688]. Taken together, these structures render important insight on the structural determinants of tight binding i nhibitors. Furthermore, we demonstrate for the first time the structural me chanistic link between arginase and NO synthase through their respective co mplexes with N-omega-hydroxy-L-arginine. That N-omega-hydroxy-L-arginine is a catalytic intermediate for NO synthase and an inhibitor of arginase refl ects the reciprocal metabolic relationship between these two critical enzym es of L-arginine catabolism.