Nature 383, 554 - 557 (10 October 1996); doi:10.1038/383554a0

Structure of a unique binuclear manganese cluster in arginase

Zoltan F. Kanyo^*, Laura R. Scolnick^*, David E. Ash^† & David W. Christianson^*

^* Department of Chemistry, 231S. 34th Street, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323, USA
^† Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA

EACH individual excretes roughly 10 kg of urea per year, as a result of the hydrolysis of arginine in the final cytosolic step of the urea cycle¹. This reaction allows the disposal of nitrogenous waste from protein catabolism, and is catalysed by the liver arginase enzyme². In other tissues that lack a complete urea cycle, arginase regulates cellular arginine and ornithine concentrations for biosynthetic reactions³, including nitric oxide synthesis: in the macrophage, arginase activity is reciprocally coordinated with that of NO synthase to modulate NO-dependent cytotoxicity^4–9. The bioinorganic chemistry of arginase is particularly rich because this enzyme is one of very few that specifically requires a spin-coupled Mn²⁺ –Mn²⁺ cluster for catalytic activity in vitro and in vivo ¹⁰. The 2.1 Å-resolution crystal structure of trimeric¹¹ rat liver arginase reveals that this unique metal cluster resides at the bottom of an active-site cleft that is 15 Å deep. Analysis of the structure indicates that arginine hydrolysis is achieved by a metal-activated solvent molecule which symmetrically bridges the two Mn²⁺ ions.

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