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J. Biol. Chem., Vol. 281, Issue 11, 7605-7613, March 17, 2006

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Crystal Structure of a Bifunctional Deaminase and Reductase from Bacillus subtilis Involved in Riboflavin Biosynthesis^*

Sheng-Chia Chen¹, Yuan-Chih Chang¹, Chao-Hsiung Lin^¶, Chun-Hung Lin^||, and Shwu-Huey Liaw^¶**2

From the Structural Biology Program, Institute of Biochemistry, and ^||Faculty of Life Science, National Yang-Ming University, Taipei 11221, Taiwan, ^¶Institute of Biological Chemistry, Academia Sinica, Taipei 11529, Taiwan, and ^**Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei 11217, Taiwan

Bacterial RibG is an attractive candidate for development of antimicrobial drugs because of its involvement in the riboflavin biosynthesis. The crystal structure of Bacillus subtilis RibG at 2.41-Šresolution displayed a tetrameric ring-like structure with an extensive interface of 2400 Ų/monomer. The N-terminal deaminase domain belongs to the cytidine deaminase superfamily. A structure-based sequence alignment of a variety of nucleotide deaminases reveals not only the unique signatures in each family member for gene annotation but also putative substrate-interacting residues for RNA-editing deaminases. The strong structural conservation between the C-terminal reductase domain and the pharmaceutically important dihydrofolate reductase suggests that the two reductases involved in the riboflavin and folate biosyntheses evolved from a single ancestral gene. Together with the binding of the essential cofactors, zinc ion and NADPH, the structural comparison assists substrate modeling into the active-site cavities allowing identification of specific substrate recognition. Finally, the present structure reveals that the deaminase and the reductase are separate functional domains and that domain fusion is crucial for the enzyme activities through formation of a stable tetrameric structure.

Received for publication, September 19, 2005 , and in revised form, November 3, 2005.

The atomic coordinates and structure factors (codes 2B3Z and 2D5N) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This study was supported by National Science Council Grant NSC94-2311-B010-017. 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 These authors contributed equally to this work.

² To whom correspondence should be addressed: Faculty of Life Science, National Yang-Ming University, Taipei, Taiwan 11221. Tel.: 886-2-2826-7278; Fax: 886-2-2820-2449; E-mail: shliaw{at}ym.edu.tw.

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