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J. Biol. Chem., Vol. 278, Issue 38, 36897-36904, September 19, 2003

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Crystal Structure of the Monomeric Isocitrate Dehydrogenase in the Presence of NADP⁺

INSIGHT INTO THE COFACTOR RECOGNITION, CATALYSIS, AND EVOLUTION^*

Yoshiaki Yasutake, Seiya Watanabe , Min Yao, Yasuhiro Takada, Noriyuki Fukunaga and Isao Tanaka 

From the Division of Biological Sciences, Graduate School of Science, Hokkaido University, Kita-10, Nishi-8, Kita-ku, Sapporo, Hokkaido 060-0810, Japan

NADP⁺-dependent monomeric isocitrate dehydrogenase (IDH) from the nitrogen-fixing bacterium Azotobacter vinelandii (AvIDH) is one of members of the -decarboxylating dehydrogenase family and catalyzes the dehydration and decarboxylation of isocitrate to yield 2-oxoglutrate and CO₂ in the Krebs cycle. We solved the crystal structure of the AvIDH in complex with cofactor NADP⁺ (AvIDH-NADP⁺ complex). The final refined model shows the closed form that has never been detected in any previously solved structures of -decarboxylating dehydrogenases. The structure also reveals all of the residues that interact with NADP⁺. The structure-based sequence alignment reveals that these residues were not conserved in any other dimeric NADP⁺-dependent IDHs. Therefore the NADP⁺ specificity of the monomeric and dimeric IDHs was independently acquired through the evolutional process. The AvIDH was known to show an exceptionally high turnover rate. The structure of the AvIDH-NADP⁺ complex indicates that one loop, which is not present in the Escherichia coli IDHs, reliably stabilizes the conformation of the nicotinamide mononucleotide of the bound NADP⁺ by forming a few hydrogen bonds, and such interactions are considered to be important for the monomeric enzyme to initiate the hydride transfer reaction immediately. Finally, the structure of the AvIDH is compared with that of other dimeric NADP-IDHs. Several structural features demonstrate that the monomeric IDHs are structurally more related to the eukaryotic dimeric IDHs than to the bacterial dimeric IDHs.

Received for publication, April 18, 2003 , and in revised form, July 9, 2003.

The atomic coordinates and structure factors (code 1j1w) 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 a grant-in-aid for Scientific Research and a research grant from the National Project on Protein Structural and Functional Analyses from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. 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.

Present address: Institute of Advanced Energy, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan.

To whom correspondence should be addressed. Tel.: 81-11-706-3221; Fax: 81-11-706-4905; E-mail: tanaka{at}castor.sci.hokudai.ac.jp.

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