Citation: Shou Feng Wang, Jing-Yi Jin, Zong Hao Zeng, Guan Rong Tian. Optical 2-benzyl-5-hydroxy-4-oxopentanoic acids against carboxypeptidase A:Synthesis,Kinetic evaluation and X-ray crystallographic study[J]. Chinese Chemical Letters, ;2010, 21(2): 159-162. doi: 10.1016/j.cclet.2009.09.005 shu

Optical 2-benzyl-5-hydroxy-4-oxopentanoic acids against carboxypeptidase A:Synthesis,Kinetic evaluation and X-ray crystallographic study

a Key Laboratory of Organism Functional Factors of Changbai Mountains of Ministry of Education, Yanbian University, Yanji 133002, China;
b Institute of Biophysics, Chinese Academy of Science, Beijing 100871, China

Received Date: 17 June 2009

2-Benzy1-5-hydroxy-4-oxopentanoic acid 1 and its enantiomers were designed,synthesized and assayed for inhibitory activity against carboxypeptidase A(CPA,EC 3.4.17.1).To verify the role of the terminal hydroxyl group in 1 binding to CPA,2-benzyl-5benzyloxy-4-oxopentanoic acid 2 was also synthesized and evaluated.The inhibition constants show that both L-1 and D-1 were shown to have strong binding affinity with L-1 being more potent than its enantiomer by 165-fold.On the other hand,the inhibition constant of 2 increases 4-fold comparing with that of 1.In order to explore the exact binding mode of the hydroxyacteyl group of 1 to the active site zinc ion of CPA, we have solved the crystal structure of CPA complexed with L-1 up to 1.85 Å resolution. In CPA L-1 complex,the phenyl ring is fitted in the substrate recognition pocket at the S'₁ subsite,and the carboxylate forms bifurcated hydrogen bonds with the guanidinium moiety of Arg-145 and Arg-127 and a hydrogen bond with the phenolic hydroxyl of the downpositioned Tyr-248.The carbonyl oxygen of L-1 does coordinate to the active site zinc ion of CPA as expectedly.Unexpectedly,the terminal hydroxyl group of L-1 is engaged in hydrogen bonding with carbonyl oxygen of Ser-197 instead of coordinating to the active site zinc ion.
- 2-Benzyl-5-hydroxy-4-oxopentanoic acid,
- Carboxypeptidase A,
- X-ray crystallographic study
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