title: Multivalency and the mode of action of bacterial sialidases.
abstract: Although complex modular proteins are encountered frequently in a variety of biological systems, their occurrence in biocatalysis has not been widely appreciated. Here, we describe that bacterial sialidases, which have both a catalytic and carbohydrate-binding domain, can hydrolyze polyvalent substrates with much greater catalytic efficiency than their monovalent counterparts. The enhancement of catalytic efficiency was due to a much smaller Michaelis constant and rationalized by a model in which the catalytic and lectin domains interact simultaneously with the polyvalent substrate, leading to an enhancement of affinity. Inhibition studies have shown that galactosides released by the action of the sialidase can act as the ligand for the lectin domain. This knowledge has been exploited in the design of a potent polyvalent inhibitor of the sialidase of Vibrio cholerae, which displayed exquisite selectivities for sialidases that have a lectin domain.
authors.affiliation: Complex Carbohydrate Research Center, The University of Georgia, 220 Riverbend Road, Athens, Georgia 30602, USA.
authors.forename: Smita
authors.initials: S
authors.lastname: Thobhani
authors.forename: Brian
authors.initials: B
authors.lastname: Ember
authors.forename: Aloysius
authors.initials: A
authors.lastname: Siriwardena
authors.forename: Geert-Jan
authors.initials: GJ
authors.lastname: Boons
mesh_terms: D000606:Amino Sugars / Q000737:chemistry / Q000378:metabolism; D002384:Catalysis; D003016:Clostridium perfringens / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005697:Galactosides / Q000737:chemistry / Q000494:pharmacology; D006868:Hydrolysis; D007700:Kinetics; D037102:Lectins / Q000737:chemistry / Q000378:metabolism; D009439:Neuraminidase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D012486:Salmonella typhimurium / Q000201:enzymology*; D014312:Trisaccharides / Q000737:chemistry / Q000378:metabolism; D014734:Vibrio cholerae / Q000201:enzymology*
chemical_list: D000606:Amino Sugars; D004791:Enzyme Inhibitors; D005697:Galactosides; D037102:Lectins; D014312:Trisaccharides; C032269:sialyl-N-acetyllactosamine; D009439:Neuraminidase