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J. Biol. Chem., Vol. 282, Issue 26, 19227-19236, June 29, 2007

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The X-ray Structure of dTDP-4-Keto-6-deoxy-D-glucose-3,4-ketoisomerase^*

From the Department of Biochemistry, University of Wisconsin, Madison, Wisconsin 53706-1544

The repeating unit of the glycan chain in the S-layer of the bacterium Aneurinibacillus thermoaerophilus L420-91^T is composed of four -D-rhamnose molecules and two 3-acetamido-3,6-dideoxy--D-galactose moieties (abbreviated as Fucp3NAc). Formation of the glycan layer requires nucleotide-activated sugars as the donor molecules. Whereas the enzymes involved in the synthesis of GDP-rhamnose have been well characterized, less is known regarding the structures and enzymatic mechanisms of the enzymes required for the production of dTDP-Fucp3NAc. One of the enzymes involved in the biosynthesis of dTDP-Fucp3NAc is a 3,4-ketoisomerase, hereafter referred to as FdtA. Here we describe the first three-dimensional structure of this sugar isomerase complexed with dTDP and solved to 1.5 Å resolution. The FdtA dimer assumes an almost jellyfish-like appearance with the sole -helices representing the tentacles. Formation of the FdtA dimer represents a classical example of domain swapping whereby -strands 2 and 3 from one subunit form part of a -sheet in the second subunit. The active site architecture of FdtA is characterized by a cluster of three histidine residues, two of which, His⁴⁹ and His⁵¹, appear to be strictly conserved in the amino acid sequences deposited to date. Site-directed mutagenesis experiments, enzymatic assays, and x-ray crystallographic analyses suggest that His⁴⁹ functions as an active site base.

Received for publication, March 23, 2007 , and in revised form, April 10, 2007.

The atomic coordinates and structure factors (code 2PA7, 2PAE, 2PAK, and 2PAM) 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 Grant DK47814 from the National Institutes of Health (to H. M. H.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S3.

¹ Recipient of a predoctoral fellowship from the National Science Foundation.

² To whom correspondence should be addressed. E-mail: Hazel_Holden{at}biochem.wisc.edu.

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