Arginase is a trimeric manganese metalloenzyme that catalyzes the hydrolysis of the guanidinium side chain of L-arginine to form L-ornithine and urea. Our crystal structure of the enzyme from rat liver revealed the architecture of the binuclear manganese cluster and suggested a metal-activated hydroxide mechanism for catalysis. Our subsequently determined structures of rat, human, and parasitic arginases complexed with boronic acid analogues of L-arginine revealed the binding of tetrahedral boronate anions that mimic the tetrahedral intermediate and its flanking transition states in catalysis. Recent studies indicate that boronic acid analogues of L-arginine can be further derivatized as α,α-disubstituted amino acids to enhance inhibitory potency. Given that upregulated arginase activity comprises a mechanism of immune evasion, arginase may serve as a possible target for cancer chemotherapy.<br/>

Structure, mechanism, and inhibition of arginase, a binuclear manganese metalloenzyme implicated in immune evasion<br />

250th National Meeting (2015)

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