Structure of a unique binuclear manganese cluster in arginase

• Published in: Nature (London) 1996-10, Vol.383 (6600), p.554-557
• Main Authors: Kanyo, Zoltan F., Scolnick, Laura R., Ash, David E., Christianson, David W.
• Format: Article
• Language: English
• Subjects: Animals; Arginase - chemistry; Arginase - metabolism; Arginine - metabolism; Binding Sites; Body fluids; Crystallography, X-Ray; Crystals; Cytotoxicity; Humanities and Social Sciences; Hydrolysis; Ions; letter; Liver - enzymology; Manganese; Manganese - chemistry; Metalloproteins - chemistry; Models, Molecular; Molecular biology; multidisciplinary; Nitric oxide; Protein Conformation; Protein Structure, Secondary; Rats; Science; Science (multidisciplinary); Solvents; Urea
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/383554a0

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 cycle 1 . This reaction allows the disposal of nitrogenous waste from protein catabolism, and is catalysed by the liver arginase enzyme 2 . In other tissues that lack a complete urea cycle, arginase regulates cellular arginine and ornithine concentrations for biosynthetic reactions 3 , 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 Mn 2+ –Mn 2+ cluster for catalytic activity in vitro and in vivo 10 . The 2.1 Å-resolution crystal structure of trimeric 11 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 Mn 2+ ions.