Synthetic derivatives of [formula omitted] acid inactivate glucosamine synthetase from Candida albicans

• Published in: Biochimica et biophysica acta, Protein structure and molecular enzymology Vol. 828; no. 3; pp. 247 - 254
• Main Authors: Milewski, Sławomir, Chmara, Henryk, Andruszkiewicz, Ryszard, Borowski, Edward
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.04.1985
• Subjects: C. albicans; Enzyme inhibition; Glucosamine synthetase; Glutamine analog; CRDP; FMDB; MMDP; FCDP; DON, 6-diazo-5-oxo- l-norleucine; GlcN-6- P; AADP; FMDP; C. albicans; Glucosamine synthetase; Enzyme inhibition; Glutamine analog; Fru-6- P
• ISSN: 0167-4838; 1879-2588
• DOI: 10.1016/0167-4838(85)90304-8

Synthetic derivatives of N 3- 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-phoshate ketol-isomerase (amino-transferring), EC 5.3.1.9) from Candida albicans with respect to glutamine and uncompetitive with respect to d-fructose 6-phosphate. Some of the compounds tested irreversibly inactive glucosamine synthetase with K inact 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 N 3- fumaroyl- l-2,3- diaminopropanoic acid should be classified as mechanism-based enzyme inactivators. Structural requirements for an effective inactivator containing N 3- fumaroyl- l-2,3-diaminopropanoic acid moiety are discussed.