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J. Biol. Chem., Vol. 276, Issue 18, 15125-15130, May 4, 2001
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From the 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.
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/).
Vitamin C Inhibits the Enzymatic Activity of
Streptococcus pneumoniae Hyaluronate Lyase*
,, and¶
Department of Microbiology and the
§ Department of Biochemistry and Molecular Genetics,
University of Alabama at Birmingham, Birmingham, Alabama 35294
*
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.
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