Mannostatin A, a new glycoprotein-processing inhibitor.
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.
Tropea
J E
JE
Department of Biochemistry, University of Texas Health Science Center, San Antonio 78284.
Kaushal
G P
GP
Pastuszak
I
I
Mitchell
M
M
Aoyagi
T
T
Molyneux
R J
RJ
Elbein
A D
AD
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D002240:Carbohydrate Sequence; D002460:Cell Line; D003517:Cyclopentanes / Q000494:pharmacology*; D004285:Dogs; D006023:Glycoproteins / Q000096:biosynthesis; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors; D006031:Glycosylation / Q000187:drug effects; D008361:Mannosidases / Q000037:antagonists & inhibitors*; D008969:Molecular Sequence Data; D009844:Oligosaccharides / Q000032:analysis; D009975:Orthomyxoviridae / Q000187:drug effects; D010940:Plant Proteins / Q000037:antagonists & inhibitors; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D051381:Rats; D013306:Streptomycetaceae / Q000378:metabolism; D014764:Viral Proteins / Q000096:biosynthesis; D043323:alpha-Mannosidase
D000998:Antiviral Agents; D003517:Cyclopentanes; D006023:Glycoproteins; D009844:Oligosaccharides; D010940:Plant Proteins; D014764:Viral Proteins; C060107:mannostatin A; D006026:Glycoside Hydrolases; D008361:Mannosidases; C038829:mannosyl-oligosaccharide 1,3 - 1,6-alpha-mannosidase; D043323:alpha-Mannosidase