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J. Biol. Chem., Vol. 281, Issue 48, 36929-36936, December 1, 2006

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A Catalytic Mechanism Revealed by the Crystal Structures of the Imidazolonepropionase from Bacillus subtilis^*

Yamei Yu¹, Yu-He Liang¹, Erik Brostromer, Jun-Min Quan, Santosh Panjikar^¶, Yu-Hui Dong^||, and Xiao-Dong Su²³

From the The National Laboratory of Protein Engineering and Plant Genetic Engineering, College of Life Sciences, Peking University, Beijing 100871, China, Laboratory of Chemical Genomics, Shenzhen Graduate School of Peking University, Shenzhen 513055, China, ^¶European Molecular Biology Laboratory Hamburg Outstation, c/o Deutsches Elektronen-Synchrotron, Notkestrasse 85, D-22603 Hamburg, Germany, and ^||Beijing Synchrotron Radiation Facility, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049, China

Imidazolonepropionase (EC 3.5.2.7 [EC] ) catalyzes the third step in the universal histidine degradation pathway, hydrolyzing the carbon-nitrogen bonds in 4-imidazolone-5-propionic acid to yield N-formimino-L-glutamic acid. Here we report the crystal structures of the Bacillus subtilis imidazolonepropionase and its complex at 2.0-Å resolution with substrate analog imidazole-4-acetic acid sodium (I4AA). The structure of the native enzyme contains two domains, a TIM (triose-phosphate isomerase) barrel domain with two insertions and a small -sandwich domain. The TIM barrel domain is quite similar to the members of the / barrel metallo-dependent hydrolase superfamily, especially to Escherichia coli cytosine deaminase. A metal ion was found in the central cavity of the TIM barrel and was tightly coordinated to residues His-80, His-82, His-249, Asp-324, and a water molecule. X-ray fluorescence scan analysis confirmed that the bound metal ion was a zinc ion. An acetate ion, 6 Å away from the zinc ion, was also found in the potential active site. In the complex structure with I4AA, a substrate analog, I4AA replaced the acetate ion and contacted with Arg-89, Try-102, Tyr-152, His-185, and Glu-252, further defining and confirming the active site. The detailed structural studies allowed us to propose a zinc-activated nucleophilic attack mechanism for the hydrolysis reaction catalyzed by the enzyme.

Received for publication, August 11, 2006 , and in revised form, September 12, 2006.

The atomic coordinates and structure factors (codes 2BB0 and 2G3F) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported in part by the National High Technology and Development Program of China (863, Program 2002BA711A13) and Grants 985 and 211 from the Peking University. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² Recipient of a National Science Fund for Distinguished Young Scholars of National Natural Science Foundation of China (30325012).

³ To whom correspondence should be addressed. Tel.: 86-10-62759743; Fax: 86-10-62765669; E-mail: su-xd{at}pku.edu.cn.

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