Nitro as a novel zinc-binding group in the inhibition of carboxypeptidase A

2-Substituted 3-nitropropanoic acids were designed and synthesized as inhibitors against carboxypeptidase A (CPA). (R)-2-Benzyl- 3-nitropropanoic acid showed a potent inhibition against CPA (Ki = 0.15 μM). X-ray crystallography discloses that the nitro group well mimics the transition state occurred in the hydrolysis catalyzed by CPA, that is, an O,O′-bidentate coordination to the zinc ion and the two respective hydrogen bonds with Glu-270 and Arg-127. Because the nitro group is a planar species, we proposed (R)-2-benzyl-3-nitropropanoic acid as a pseudo-transition-state analog inhibitor against CPA.

X-ray crystallography of carboxypeptidase A-(R)-2-benzyl-3-nitropropanoic acid complex disclosed that the nitro group chelate the zinc ion in the active site of CPA in an O,O′-bidentate fashion.Figure optionsDownload as PowerPoint slide