Kifunensine, produced by the actinomycete Kitasatosporia kifunense 9482, is an
alkaloid that corresponds to a cyclic
oxamide derivative of 1-amino mannojirimycin. This compound was reported to be a weak inhibitor of jack bean
alpha-mannosidase (IC50 of 1.2 x 10(-4) M) (Kayakiri, H., Takese, S., Shibata, T., Okamoto, M., Terano, H., Hashimoto, M., Tada, T., and Koda, S. (1989) J. Org. Chem. 54, 4015-4016). We also found that
kifunensine was a poor inhibitor of jack bean and mung bean aryl-alpha-
mannosidases, but it was a very potent inhibitor of the plant
glycoprotein processing
enzyme,
mannosidase I (IC50 of 2-5 x 10(-8) M), when [3H]
mannose-labeled
Man9GlcNAc was used as substrate. However,
kifunensine was inactive toward the plant
mannosidase II. Studies with rat liver microsomes also indicated that
kifunensine inhibited the Golgi
mannosidase I, but probably does not inhibit the endoplasmic reticulum
mannosidase.
Kifunensine was tested in cell culture by examining its ability to inhibit processing of the
influenza viral
glycoproteins in Madin-Darby canine kidney cells. Thus, when
kifunensine was placed in the incubation medium at concentrations of 1 microgram/ml or higher, it caused a complete shift in the structure of the N-linked
oligosaccharides from complex chains to Man9(
GlcNAc)2 structures, in keeping with its inhibition of
mannosidase I. On the other hand, even at 50 micrograms/ml, deoxymannojirimyucin did not prevent the formation of all complex chains. Thus
kifunensine appears to be one of the most effective
glycoprotein processing inhibitors observed thus far, and knowledge of its structure may lead to the development of potent inhibitors for other processing
enzymes.