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Identified virulence factors of Staphylococcus: Exoenzyme


Aureolysin  

Related genes: aur;
Keywords: Exoenzyme; Protease; Zinc metalloproteinase;
Characteristics:
The aur gene encoding aureolysin is present in two allelic forms: type I and type II.
Low substrate specificity: cleaving peptide bonds on the N-terminal side of bulky, aliphatic, hydrophobic residues.
Structure features:
A β-pleated N-terminal domain and an α-helical C-terminal domain, a typical fold for the thermolysin family of metalloproteinases.
PDB code: 1BQB.
Functions:
Processing the precursor of V8 protease into an active form.
Modifying the bacterial cell surface proteins by specific inactivation of ClfB through cleavage of the N-terminal domain, thus may promote the detachment of bacterial cells from colonized sites and facilitate the spread of infection.
In vitro, aureolysin has been shown to cleave the human plasma proteinase inhibitors.
References:
Potempa J, et al., 1991. Proteolytic inactivation of α-1-anti-chymotrypsin. Sites of cleavage and generation of chemotactic activity. J. Biol. Chem. 266(32):21482-21487.
Banbula A, et al., 1998. Amino-acid sequence and three-dimensional structure of the Staphylococcus aureus metalloproteinase at 1.72 A resolution. Structure 6(9):1185-1193.
Sabat A, et al., 2000. Two allelic forms of the aureolysin gene (aur) within Staphylococcus aureus. Infect. Immun. 68(2):973-976.
McAleese FM, et al., 2001. Loss of clumping factor B fibrinogen binding activity by Staphylococcus aureus involves cessation of transcription, shedding and cleavage by metalloprotease. J. Biol. Chem. 276(32):29969-29978.
Dubin G., 2002. Extracellular proteases of Staphylococcus spp. Biol. Chem. 383:1075-1086.


Hyaluronate lyase  

Related genes: hysA;
Keywords: Exoenzyme; Spreading factor;
Functions:
Degradation of hyaluronic acid, contribute to local dissolution of the extracellular matrix.
Mechanism:
Cleaves the 1,4-glycosidic linkage between N-acetyl-b-D-glucosamine and D-glucuronic acid residues in hyaluronan and catalyzes the release of unsaturated polysaccharides, with the disaccharide unit 2-acetamido-2-deoxy-3- O-(β-D-gluco-4-enepyranosyluronic acid)-D-glucose being the main end product.
References:
Farrell AM, et al., 1995. Cloning, nucleotide sequence determination and expression of the Staphylococcus aureus hyaluronate lyase gene. FMES Microbiol. Lett. 130(1):81-85.
Makris G, et al., 2004. The hyaluronate lyase of Staphylococcus aureus - a virulence factor? Microbiology. 150:2005-2013.


Lipase  

Related genes: geh;
Keywords: Exoenzyme; Lipase;
Characteristics:
Organized as pre-pro-enzymes: the pre-region represents the signal peptide.
Secreted in the pro-lipase form. The pro-region protects the proteins from proteolytic degradation and acts as an intramolecular chaperone to facilitate translocation of the lipase.
Functions:
Responsible for the release of considerate amounts of fatty acids, particularly octadecenoic acid in human plasma.
Might contribute to virulence by enabling the bacteria to persist in the fatty secretions of the human or mammalian skin.
The recent finding that the lipase GehD of S. epidermidis can bind to collagen might constitute a novel role for lipase in virulence.
References:
Longshaw CM, et al., 2000. Identification of a second lipase gene, gehD, in Staphylococcus epidermidis: comparison of sequence with those of other staphylococcal lipases. Microbiology. 146:1419-1427.
Rosenstein R, Gotz F, 2000. Staphylococcal lipases: biochemical and molecular characterization. Biochimie. 82(11):1005-1014.
Bowden MG, et al., 2002. Is the GehD lipase from Staphylococcus epidermidis a collagen binding adhesin? J. Biol. Chem. 277(45):43017-43023.


Staphopain  

Related genes: sspB; sspC;
Keywords: Exoenzyme; Protease; Cysteine protease;
Characteristics:
Staphopains A (encoded by scpA) and B (encoded by sspB) are the major secreted cysteine proteases of S. aureus.
A novel type of cysteine proteinase inhibitor, referred as staphostatins (ScpC, SspC), has been recently identified. They specifically inhibit cysteine proteinases (staphopains).
Structure features:
PDB code: 1PXV.
Functions:
Broad substrate specificity, unclear role in pathogenesis.
References:
Massimi I, et al., 2002. Identification of a novel maturation mechanism and restricted substrate specificity for the SspB cysteine protease of Staphylococcus aureus. J. Biol. Chem. 277(44):41770-41777.
Dubin G., 2002. Extracellular proteases of Staphylococcus spp. Biol. Chem. 383:1075-1086.
Filipek R, et al., 2003. The Staphostatin-staphopain complex: a forward binding inhibitor in complex with its target cysteine protease. J. Biol. Chem. 278(42):40959-40966.
Rzychon M, et al., 2003. Staphostatins: an expanding new group of proteinase inhibitors with a unique specificity for the regulation of staphopains, Staphylococcus spp. cysteine proteinases. Mol. Microbiol. 49(4):1051-1066.


Staphylocoagulase  

Related genes: coa;
Keywords: Exoenzyme;
Functions:
Promotes the pathogenesis of S. aureus abscess formation and lethal bacteremia.
Mechanism:
Binds prothrombin and alters the enzyme's active site through insertion of its N-terminal residues into the activation pocket, thereby providing for the cleavage of fibrinogen to fibrin.
References:
Friedrich R, et al., 2003. Staphylocoagulase is a prototype for the mechanism of cofactor-induced zymogen activation. Nature 425(6957):535-539.
McAdow M, et al., 2012. Coagulases as determinants of protective immune responses against Staphylococcus aureus. Infect Immun. 80(10):3389-3398.


V8 protease  

Related genes: sspA;
Keywords: Exoenzyme; Protease; Serine protease;
Characteristics:
A member of the glutamyl endopeptidase family of enzymes.
Narrow substrate specificity: cleaving peptide bonds exclusively on the carbonyl side of aspartate and glutamate residues.
Synthesized as a preproenzyme, the zymogen undergoes proteolytic activation via cleavage by the staphylococcal extracellular metalloprotease.
The ssp gene encoding V8 protease is designated as sspA, and is followed by sspB, which encodes a cysteine protease, and sspC, which encodes a protein of unknown function.
Structure features:
Possesses no disulfide bridges.
Unusual C-terminal structure of tandemly repeated Pro-Asn/Asp-Asn tripeptides.
PDB code: 1QY6.
Functions:
A pleiotropic effect on the profile of secreted proteins, including autolytic activity and proteolytic maturation of SspB.
Degrading the bacterial cell surface fibronectin-binding protein (FnBP).
References:
McGavin MJ, et al., 1997. Modification of the Staphylococcus aureus fibronectin binding phenotype by V8 protease. Infect. Immun. 65(7):2621-2628.
Coulter SN, et al., 1998. Staphylococcus aureus genetic loci impacting growth and survival in multiple infection environments. Mol. Microbiol. 30(2):393-404.
Rice K, et al., 2001. Description of staphylococcus serine protease (ssp) operon in Staphylococcus aureus and nonpolar inactivation of sspA-encoded serine protease. Infect. Immun. 69(1):159-169.
Massimi I, et al., 2002. Identification of a novel maturation mechanism and restricted substrate specificity for the SspB cysteine protease of Staphylococcus aureus. J. Biol. Chem. 277(44):41770-41777.
Dubin G., 2002. Extracellular proteases of Staphylococcus spp. Biol. Chem. 383:1075-1086.
Prasad L, et al., 2004. The structure of a universally employed enzyme: V8 protease from Staphylococcus aureus. Acta Crystallogr. D Biol. Crystallogr. 60:256-259.


vWbp (von Willebrand factor-binding protein)  

Related genes: vWbp;
Keywords: Exoenzyme;
Functions:
A coagulase to enable the bacteria to disseminate as thromboembolic lesions and to resist opsonophagocytic clearance by host immune cells.
References:
Bjerketop J, et al., 2004. The von Willebrand factor-binding protein (vWbp) of Staphylococcus aureus is a coagulase. FEMS Microbiol. Lett. 234(2):309-314.
McAdow M, et al., 2012. Staphylococcus aureus secretes coagulase and von Willebrand factor binding protein to modify the coagulation cascade and establish host infections. J. Innate Immun. 4(2):141-148.








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