Biological activities of cyclophellitol.
Cyclophellitol [1S,2R,3S,4R,5R,6R)-5-hydroxymethyl-7-oxabicyclo[4,1,0] heptane-2,3,4-triol) was tested against 9 glycosidases and found to be a specific inhibitor of almond beta-glucosidase. Cyclophellitol inhibited almond beta-glucosidase activity by 50% at 0.8 micrograms/ml and was a competitive inhibitor of almond beta-glucosidase as revealed by Lineweaver-Burk plot. Cyclophellitol was inactive against yeast alpha-glucosidase, beta-galactosidase, beta-glucuronidase, alpha-L-fucosidase, end-beta-N-acetyl glucosaminidase, alpha-mannosidase, and cellulase. It was weakly active toward fungal beta-xylosidase. Cyclophellitol-treated almond beta-glucosidase was equally suppressed after dialysis; thus cyclophellitol is likely to bind to almond beta-glucosidase irreversibly. The inhibitor was found by fluorimetric assay to be active against beta-glucosidase but inactive toward alpha-glucosidase in Molt-4 microsomal fraction. It also inhibited Molt-4 beta-glucocerebrosidase completely at 2 micrograms/ml when the enzyme was assayed with a synthetic labeled substrate, and the inhibitory activity was more than one hundred times higher than that of nojirimycin, castanospermine, or of deoxynojirimycin. Mice administered 1 mg of cyclophellitol daily for 5 days began to exhibit severe abnormalities of nervous system similar to those found in Gaucher's mouse.
Atsumi
S
S
Institute of Microbial Chemistry, Tokyo, Japan.
Iinuma
H
H
Nosaka
C
C
Umezawa
K
K
D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001667:Binding, Competitive; D001835:Body Weight / Q000187:drug effects; D002460:Cell Line; D003511:Cyclohexanols / Q000494:pharmacology* / Q000633:toxicity; D005260:Female; D005944:Glucosamine / Q000031:analogs & derivatives / Q000494:pharmacology; D005962:Glucosylceramidase / Q000037:antagonists & inhibitors; D007212:Indolizines / Q000494:pharmacology; D051379:Mice; D008861:Microsomes / Q000201:enzymology; D014407:Tumor Cells, Cultured; D001617:beta-Glucosidase / Q000037:antagonists & inhibitors*; D054836:Indolizidines
D017485:1-Deoxynojirimycin; D000900:Anti-Bacterial Agents; D003511:Cyclohexanols; D005944:Glucosamine; D005962:Glucosylceramidase; D007212:Indolizines; D001617:beta-Glucosidase; C063285:cyclophellitol; C037806:castanospermine; D054836:Indolizidines; C013626:nojirimycin