Mannostatin A, a new glycoprotein-processing inhibitor

Abstract

Mannostatin A is a metabolite produced by the microorganism Streptoverticillium verticillus and reported to be a potent competitive inhibitor of rat epididymal alpha-mannosidase. When tested against a number of other arylglycosidases, mannostatin A was inactive toward alpha- and beta-glucosidase and galactosidase as well as beta-mannosidase, but it was a potent inhibitor of jack bean, mung bean, and rat liver lysosomal alpha-mannosidases, with estimated IC50's of 70 nM, 450 nM, and 160 nM, respectively. The type of inhibition was competitive in nature. This compound also proved to be an effective competitive inhibitor of the glycoprotein-processing enzyme mannosidase II (IC50 of about 10-15 nM with p-nitrophenyl alpha-D-mannopyranoside as substrate, and about 90 nM with [3H]mannose-labeled GlcNAc-Man5GlcNAc as substrate). However, it was virtually inactive toward mannosidase I. The N-acetylated derivative of mannostatin A had no inhibitory activity. In cell culture studies, mannostatin A also proved to be a potent inhibitor of glycoprotein processing. Thus, in influenza virus infected Madin Darby canine kidney (MDCK) cells, mannostatin A blocked the normal formation of complex types of oligosaccharides on the viral glycoproteins and caused the accumulation of hybrid types of oligosaccharides. This observation is in keeping with other data which indicate that the site of action of mannostatin A is mannosidase II. Thus, mannostatin A represents the first nonalkaloidal processing inhibitor and adds to the growing list of chemical structures that can have important biological activity.

Synthesis and Oxidation of N‐Aminoglyconolactams: A Synthesis of Mannostatin A

“…t-BuOCl provided the tetrazene 6 (63%) instead of the expected 1,2-diacyl-diazene [50] or of a cyclopentane derivative. It is known that tetrazenes are formed upon oxidation of hydrazines 7 ) with PhSeO 2 H [61], KBrO 3 ¥ HCl [62], KMnO 4 [63], Br 2 [64], MnO 2 [60], and other oxidants [55] [65]. Tetrazenes are considered to result from the dimerization of diazenes (N-aminonitrenes); 6 may, however, result from dimerization of an intermediate N-chlorohydrazide (X-philic substitution followed by elimination).…”

3,4-Dihydroxypyrrolidine as Glycosidase Inhibitor

“…Therefore, structure-activity relationships might be obtained. Inhibitors of the family include deoxymannojirimycin (6) [45][46][47][48], (+)-mannostatin A (7) [49,50], swainsonin (8), [51,52] an aminocycropentitol 9 [53], and a pyrrolidine 10 ( Fig. 3) [38,54,55].…”

Glycoprotein Processing Inhibitors

“…Another inhibitor of mannosidase 11, called mannostatin, was isolated from the fungus, Streptoverticillium verticillus [97]. This compound is quite unusual because it has an exocyclic nitrogen rather than a nitrogen in the ring.…”

“…Mannostatin does have a five-membered ring structure but without a bridge nitrogen, and a thiomethyl group, both of which are also uncommon in glycosidase inhibitors. Nevertheless, mannostatin is a fairly good mannosidase 11 inhibitor (I& = 100 nM), and causes the formation of hybrid chains in cell cultures, or in enveloped viruses [97]. Of interest is the observation that acetylation of the amino group of mannostatin resulted in loss of inhibitory activity.…”