1r1o
From Proteopedia
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Amino Acid Sulfonamides as Transition-State Analogue Inhibitors of Arginase
Overview
Arginase is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of L-arginine to form L-ornithine plus urea. Chiral L-amino acids bearing sulfonamide side chains have been synthesized in which the tetrahedral sulfonamide groups are designed to target bridging coordination interactions with the binuclear manganese cluster in the arginase active site. Syntheses of the amino acid sulfonamides have been accomplished by the amination of sulfonyl halide derivatives of (S)-(tert-butoxy)-[(tert-butoxycarbonyl)amino]oxoalkanoic acids. Amino acid sulfonamides with side chains comparable in length to that of L-arginine exhibit inhibition in the micromolar range, and the X-ray crystal structure of arginase I complexed with one of these inhibitors, S-(2-sulfonamidoethyl)-L-cysteine, has been determined at 2.8 A resolution. In the enzyme-inhibitor complex, the sulfonamide group displaces the metal-bridging hydroxide ion of the native enzyme and bridges the binuclear manganese cluster with an ionized NH(-) group. The binding mode of the sulfonamide inhibitor may mimic the binding of the tetrahedral intermediate and its flanking transition states in catalysis. It is notable that the ionized sulfonamide group is an excellent bridging ligand in this enzyme-inhibitor complex; accordingly, the sulfonamide functionality can be considered in the design of inhibitors targeting other binuclear metalloenzymes.
About this Structure
1R1O is a Single protein structure of sequence from Rattus norvegicus with and as ligands. Active as Arginase, with EC number 3.5.3.1 Full crystallographic information is available from OCA.
Reference
Design of amino acid sulfonamides as transition-state analogue inhibitors of arginase., Cama E, Shin H, Christianson DW, J Am Chem Soc. 2003 Oct 29;125(43):13052-7. PMID:14570477
Page seeded by OCA on Thu Feb 21 14:46:05 2008
