Synthetic derivatives of N3-fumaroyl-L-2,3-diaminopropanoic acid inactivate glucosamine synthetase from Candida albicans.
Synthetic derivatives of N3-fumaroyl-L-2,3-diaminopropanoic acid constitute the novel group of glutamine analogs. They are powerful, competitive inhibitors of the glucosamine synthetase (2-amino-2-deoxy-D-glucose-6-phosphate ketol-isomerase (amino-transferring), EC 5.3.1.19) from Candida albicans with respect to glutamine and uncompetitive with respect to D-fructose 6-phosphate. Some of the compounds tested irreversibly inactivate glucosamine synthetase with Kinact values of 10(-4) to 10(-6) M. The addition of glutamine protects enzyme from the inactivation, while the absence of D-fructose 6-phosphate lowers the rate of inactivation. An ordered, sequential mechanism is suggested for binding of the inhibitors to the glutamine-binding site. A number of tested compounds act as active-site-directed, irreversible inhibitors. It is suggested that derivatives of N3-fumaroyl-L-2,3-diaminopropanoic acid should be classified as mechanism-based enzyme inactivators. Structural requirements for an effective inactivator containing N3-fumaroyl-L-2,3-diaminopropanoic acid moiety are discussed.
D000409:Alanine / Q000031:analogs & derivatives*; D002176:Candida albicans / Q000201:enzymology*; D002238:Carbohydrate Epimerases / Q000037:antagonists & inhibitors*; D005650:Fumarates / Q000494:pharmacology*; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D007700:Kinetics; D013329:Structure-Activity Relationship; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology
D005650:Fumarates; D015091:beta-Alanine; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing); D002238:Carbohydrate Epimerases; D000409:Alanine