1R1O

Amino Acid Sulfonamides as Transition-State Analogue Inhibitors of Arginase

Summary for 1R1O

• Entry DOI: 10.2210/pdb1r1o/pdb
• Related: 1D3V 1HQ5
• Descriptor: Arginase 1, MANGANESE (II) ION, S-[2-(AMINOSULFONYL)ETHYL]-D-CYSTEINE, ... (4 entities in total)
• Functional Keywords: arginase, hydrolase, sulfonamides, transition-state analogue
• Biological source: Rattus norvegicus (Norway rat)
• Cellular location: Cytoplasm: P07824
• Total number of polymer chains: 3
• Total formula weight: 106071.79

Authors

Cama, E.,Shin, H.,Christianson, D.W. (deposition date: 2003-09-24, release date: 2003-10-28, Last modification date: 2024-02-14)

Primary citation

Cama, E.,Shin, H.,Christianson, D.W.
Design of Amino Acid Sulfonamides as Transition-State Analogue Inhibitors of Arginase
J.Am.Chem.Soc., 125:13052-13057, 2003

PubMed Abstract: 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.

PubMed: 14570477
DOI: 10.1021/ja036365b

Experimental method

X-RAY DIFFRACTION (2.8 Å)