Cox J D, Cama E, Colleluori D M, Pethe S, Boucher J L, Mansuy D, Ash D E, Christianson D W
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323, USA.
Biochemistry. 2001 Mar 6;40(9):2689-701. doi: 10.1021/bi002318+.
Arginase is a binuclear Mn(2+) metalloenzyme that catalyzes the hydrolysis of L-arginine to L-ornithine and urea. X-ray crystal structures of arginase complexed to substrate analogues N(omega)-hydroxy-L-arginine and N(omega)-hydroxy-nor-L-arginine, as well as the products L-ornithine and urea, complete a set of structural "snapshots" along the reaction coordinate of arginase catalysis when interpreted along with the X-ray crystal structure of the arginase-transition-state analogue complex described in Kim et al. [Kim, N. N., Cox, J. D., Baggio, R. F., Emig, F. A., Mistry, S., Harper, S. L., Speicher, 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 inhibitors. Furthermore, we demonstrate for the first time the structural mechanistic link between arginase and NO synthase through their respective complexes with N(omega)-hydroxy-L-arginine. That N(omega)-hydroxy-L-arginine is a catalytic intermediate for NO synthase and an inhibitor of arginase reflects the reciprocal metabolic relationship between these two critical enzymes of L-arginine catabolism.
精氨酸酶是一种双核锰（II）金属酶，可催化L-精氨酸水解生成L-鸟氨酸和尿素。当与Kim等人[Kim, N. N., Cox, J. D., Baggio, R. F., Emig, F. A., Mistry, S., Harper, S. L., Speicher, D. W., Morris, Jr., S. M., Ash, D. E., Traish, A. M., and Christianson, D. W. (2001) Biochemistry 40, 2678 - 2688]所描述的精氨酸酶-过渡态类似物复合物的X射线晶体结构一起解读时，精氨酸酶与底物类似物N（ω）-羟基-L-精氨酸和N（ω）-羟基-去甲-L-精氨酸以及产物L-鸟氨酸和尿素的X射线晶体结构，完成了一组沿着精氨酸酶催化反应坐标的结构“快照”。综合起来，这些结构为紧密结合抑制剂的结构决定因素提供了重要见解。此外，我们首次通过它们与N（ω）-羟基-L-精氨酸的各自复合物证明了精氨酸酶和一氧化氮合酶之间的结构机制联系。N（ω）-羟基-L-精氨酸是一氧化氮合酶的催化中间体和精氨酸酶的抑制剂，这反映了L-精氨酸分解代谢中这两种关键酶之间的相互代谢关系。
