Ceramide-like synthetic amides that inhibit cerebroside galactosidase.
Amides resembling ceramide (fatty acyl sphingosine) were synthesized and tested for their effects on rat brain cerebrosidase (galactosyl ceramide beta-galactosidase). The best inhibitor was N-decanoyl dl-erythro-3-phenyl-2-aminopro-panediol, which exhibited a K(i) of 0.4 mm. A Lineweaver-Burk plot indicated that the amide acted as a noncompetitive inhibitor, presumably by attachment to a site other than the substrate-active site. Preincubation did not affect the degree of inhibition, and inhibition was independent of incubation duration; these observations suggest that the inhibitor does not combine with the enzyme irreversibly. Structural variations produced decreased inhibitory activity: loss of one of the hydroxyl groups, replacement of the aromatic side chain with an aliphatic or substituted phenyl group, or isomeric inversion of the 3-hydroxyl group. It appears that the best activity is obtained with a substance most closely resembling natural ceramide. The cerebrosidases of rat spleen, kidney, and liver are also inhibited by the same amide.
D000215:Acylation; D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology*; D000605:Amino Alcohols; D000818:Animals; D001921:Brain / Q000201:enzymology*; D002518:Ceramides / Q000494:pharmacology*; D002554:Cerebrosides; D005227:Fatty Acids; D005696:Galactosidases / Q000037:antagonists & inhibitors*; D007668:Kidney / Q000201:enzymology; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D011817:Rabbits; D051381:Rats; D013154:Spleen / Q000201:enzymology; D013329:Structure-Activity Relationship; D014316:Tritium
D000577:Amides; D000605:Amino Alcohols; D002518:Ceramides; D002554:Cerebrosides; D005227:Fatty Acids; D014316:Tritium; D005696:Galactosidases