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Originally published In Press as doi:10.1074/jbc.M011102200 on January 12, 2001

J. Biol. Chem., Vol. 276, Issue 18, 15125-15130, May 4, 2001
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Vitamin C Inhibits the Enzymatic Activity of Streptococcus pneumoniae Hyaluronate Lyase*

Songlin LiDagger , Kenneth B. Taylor§, Stephen J. KellyDagger , and Mark J. JedrzejasDagger

From the Dagger  Department of Microbiology and the § Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, Alabama 35294

Enzyme activity measurement showed that L-ascorbic acid (vitamin C (Vc)) competitively inhibits the hyaluronan degradation by Streptococcus pneumoniae hyaluronate lyase. The complex crystal structure of this enzyme with Vc was determined at 2.0 Å resolution. One Vc molecule was found to bind to the active site of the enzyme. The Vc carboxyl group provides the negative charges that lead the molecule into the highly positively charged cleft of the enzyme. The Vc ring system forms hydrophobic interactions with the side chain of Trp-292, which is one of the aromatic patch residues of this enzyme responsible for the selection of the cleavage sites on the substrate chain. The binding of Vc inhibits the substrate binding at hyaluronan 1, 2, and 3 (HA1, HA2, and HA3) catalytic positions. The high concentration of Vc in human tissues probably provides a low level of natural resistance to the pneumococcal invasion. This is the first time that Vc the direct inhibition on the bacterial "spreading factor" was reported, and Vc is also the first chemical that has been shown experimentally to have an inhibitory effect on bacterial hyaluronate lyase. These studies also highlight the possible structural requirement for the design of a stronger inhibitor of bacterial hyaluronate lyase.

* This work was supported by National Institutes of Health Grant AI 44079 (to M. J. J.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The atomic coordinates and the structure factors (code 1f9g) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

To whom correspondence should be addressed: Dept. of Microbiology, 933 19th St. South, 545 CHSB-19, UAB, Birmingham, AL 35294-2041. Tel.: 205-975-7627; Fax: 205-975-5424; E-mail: jedrzejas@uab.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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