Distinguishing mammalian sialidases by inhibition kinetics with novel derivatives of 5-acetamido-2,6-anhydro-3,5-dideoxy-D-glycero-D-galacto-non-2-enonic acid, an unsaturated derivative of N-acetylneuraminic acid.
Kinetic analysis of mammalian sialidases was carried out using analogs of the potent sialidase inhibitor, 5-acetamido-2,6-anhydro-3,5-dideoxy-D-glycero-D-galacto-non-2-enonic+ ++ acid (1). Substitutents at C-9 in place of the terminal hydroxyl group included a, 4-azido-2-nitrophenylthio group to give 5-acetamido-2,6-anhydro-9-S-(4-azido-2-nitrophenyl)-3,5, 9-trideoxy-9-thio-D-glycero-D-galacto-non-2-enonic acid (2), and an azide group to give 5-acetamido-2,6-anhydro-9-azido-3,5,9-trideoxy-D-glycero-D-galacto-non-2 -enonic acid (3). Competitive inhibition kinetics were observed when 1,2, and 3 were tested with the lysosomal sialidase (cultured fibroblasts) and the plasma membrane sialidase (adenovirus DNA-transformed, human embryonic kidney cells), giving a Ki of about 10 microM for both enzymes with all three compounds. In contrast, only 1 was a potent inhibitor of the microsomal sialidase (rat muscle).
Warner
T G
TG
University of Tennessee, Department of Pediatrics, Memphis 38163.
Louie
A
A
Potier
M
M
Ribeiro
A
A
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002461:Cell Line, Transformed; D002462:Cell Membrane / Q000201:enzymology; D002471:Cell Transformation, Neoplastic; D005347:Fibroblasts / Q000201:enzymology; D006801:Humans; D007700:Kinetics; D008247:Lysosomes / Q000201:enzymology; D008861:Microsomes / Q000201:enzymology; D009132:Muscles / Q000201:enzymology; D019158:N-Acetylneuraminic Acid / Q000031:analogs & derivatives*; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D051381:Rats; D012794:Sialic Acids / Q000138:chemical synthesis / Q000494:pharmacology*
D012794:Sialic Acids; C036137:2-deoxy-2,3-dehydro-N-acetylneuraminic acid; D009439:Neuraminidase; D019158:N-Acetylneuraminic Acid