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J. Biol. Chem., Vol. 281, Issue 28, 19740-19747, July 14, 2006

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Crystal Structures of N-Acetylglucosamine-phosphate Mutase, a Member of the -D-Phosphohexomutase Superfamily, and Its Substrate and Product Complexes^*

Yuichi Nishitani, Daisuke Maruyama, Tsuyoshi Nonaka, Akiko Kita, Takaaki A. Fukami, Toshiyuki Mio, Hisafumi Yamada-Okabe, Toshiko Yamada-Okabe^¶, and Kunio Miki^||1

From the Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan, Kamakura Research Laboratory, Chugai Pharmaceutical Company Ltd., 200 Kajiwara, Kamakura, Kanagawa, 247-8530 Japan, ^¶Department of Hygiene, School of Medicine, Yokohama City University, 3-9, Fukuura, Kanazawa, Yokohama 236-0004, Japan, and ^||RIKEN SPring-8 Center at Harima Institute, Koto 1-1-1, Sayo, Hyogo 679-5148, Japan

N-Acetylglucosamine-phosphate mutase (AGM1) is an essential enzyme in the synthetic process of UDP-N-acetylglucosamine (UDP-GlcNAc). UDP-GlcNAc is a UDP sugar that serves as a biosynthetic precursor of glycoproteins, mucopolysaccharides, and the cell wall of bacteria. Thus, a specific inhibitor of AGM1 from pathogenetic fungi could be a new candidate for an antifungal reagent that inhibits cell wall synthesis. AGM1 catalyzes the conversion of N-acetylglucosamine 6-phosphate (GlcNAc-6-P) into N-acetylglucosamine 1-phosphate (GlcNAc-1-P). This enzyme is a member of the -D-phosphohexomutase superfamily, which catalyzes the intramolecular phosphoryl transfer of sugar substrates. Here we report the crystal structures of AGM1 from Candida albicans for the first time, both in the apoform and in the complex forms with the substrate and the product, and discuss its catalytic mechanism. The structure of AGM1 consists of four domains, of which three domains have essentially the same fold. The overall structure is similar to those of phosphohexomutases; however, there are two additional -strands in domain 4, and a circular permutation occurs in domain 1. The catalytic cleft is formed by four loops from each domain. The N-acetyl group of the substrate is recognized by Val-370 and Asn-389 in domain 3, from which the substrate specificity arises. By comparing the substrate and product complexes, it is suggested that the substrate rotates about 180° on the axis linking C-4 and the midpoint of the C-5—O-5 bond in the reaction.

Received for publication, January 26, 2006 , and in revised form, April 4, 2006.

The atomic coordinates and structure factors (codes 2DKA, 2DKC, 2DKD) 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 by a grant of 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.

¹ To whom correspondence should be addressed: Dept. of Chemistry, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan. Tel.: 81-75-753-4029; Fax: 81-75-753-4032; E-mail: miki{at}kuchem.kyoto-u.ac.jp.

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