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J. Biol. Chem., Vol. 281, Issue 41, 31031-31040, October 13, 2006

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Examination of Key Intermediates in the Catalytic Cycle of Aspartate--semialdehyde Dehydrogenase from a Gram-positive Infectious Bacteria^*

From the Department of Chemistry, University of Toledo, Toledo, Ohio 43606

Aspartate--semialdehyde dehydrogenase (ASADH) catalyzes a critical branch point transformation in amino acid bio-synthesis. The products of the aspartate pathway are essential in microorganisms, and this entire pathway is absent in mammals, making this enzyme an attractive target for antibiotic development. The first structure of an ASADH from a Gram-positive bacterium, Streptococcus pneumoniae, has now been determined. The overall structure of the apoenzyme has a similar fold to those of the Gram-negative and archaeal ASADHs but contains some interesting structural variations that can be exploited for inhibitor design. Binding of the coenzyme NADP, as well as a truncated nucleotide analogue, into an alternative conformation from that observed in Gram-negative ASADHs causes an enzyme domain closure that precedes catalysis. The covalent acyl-enzyme intermediate was trapped by soaking the substrate into crystals of the coenzyme complex, and the structure of this elusive intermediate provides detailed insights into the catalytic mechanism.

Received for publication, June 21, 2006 , and in revised form, July 25, 2006.

The atomic coordinates and structure factors (code 2GZ1, 2GYY, 2GZ2, and 2GZ3) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* 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, University of Toledo, 2801 W. Bancroft St., Toledo, OH 43606. Tel.: 419-530-1582; Fax: 419-530-1583; E-mail: ron.viola{at}utoledo.edu.

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