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 (K(i)=0.15 microM). 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.
Wang
Si-Hong
SH
Department of Chemistry, Yanbian University, Yanji, Jilin 133002, China.
Wang
Shou-Feng
SF
Xuan
Wei
W
Zeng
Zong-Hao
ZH
Jin
Jing-Yi
JY
Ma
Jie
J
Tian
Guan Rong
GR
D043422:Carboxypeptidases A / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D002384:Catalysis; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D009584:Nitrogen / Q000737:chemistry*; D013329:Structure-Activity Relationship; D015032:Zinc / Q000737:chemistry*
D004791:Enzyme Inhibitors; D043422:Carboxypeptidases A; D015032:Zinc; D009584:Nitrogen