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J. Biol. Chem., Vol. 279, Issue 44, 45909-45918, October 29, 2004

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Analysis of a Novel Prophage-encoded Group A Streptococcus Extracellular Phospholipase A₂^*

Michal J. Nagiec, Benfang Lei¶, Sarah K. Parker||, Michael L. Vasil||, Masakado Matsumoto**, Robin M. Ireland, Stephen B. Beres, Nancy P. Hoe, and James M. Musser

From the Center for Human Bacterial Pathogenesis Research, Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, the Laboratory of Human Bacterial Pathogenesis, Rocky Mountain Laboratories, NIAID, National Institutes of Health, Hamilton, Montana 59840, and the ^||Department of Microbiology, University of Colorado Health Sciences Center, Denver, Colorado 80262

Group A Streptococcus (GAS) is an important human pathogen that causes many types of infections, including pharyngitis and severe invasive diseases. We recently sequenced the genome of a serotype M3 strain and identified a prophage-encoded secreted phospholipase A₂ designated SlaA. To study SlaA structure-activity relationships, 20 site-specific mutants were constructed by alanine-replacement mutagenesis and purified to apparent homogeneity. Enzymatic activity was greatly reduced by alanine replacement of amino acid residues previously described as crucial in the catalytic mechanism of secreted phospholipase A₂. Similarly, substitution of five residues in an inferred Ca²⁺-binding loop and three residues in the inferred active site region resulted in loss of activity of 76.5% or greater relative to the wild-type enzyme. Analysis of enzyme substrate specificity confirmed SlaA as a phospholipase A₂, with activity against multiple phospholipid head groups and acyl chains located at the sn-2 position. PCR analysis of 1,189 GAS strains representing 48 M protein serotypes commonly causing human infections identified the slaA gene in 129 strains of nine serotypes (M1, M2, M3, M4, M6, M22, M28, M75, and st3757). Expression of SlaA by strains of these serotypes was confirmed by Western immunoblot. SlaA production increased rapidly and substantially on co-culture with Detroit 562 human pharyngeal epithelial cells. Together, these data provide new information about a novel extracellular enzyme that participates in GAS-human interactions.

Received for publication, May 17, 2004 , and in revised form, August 2, 2004.

^* 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.

^¶ Current address: Veterinary Molecular Biology, Montana State University, Bozeman, Montana 59717.

^** Current address: Dept. of Microbiology, Aichi Prefectural Institute of Public Health, Nagoya 462-8576, Japan.

To whom correspondence should be addressed: Dept. of Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Tel.: 713-798-3823; Fax: 713-798-5838; E-mail: musser{at}bcm.tmc.edu.

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