A unique alpha-1,3 mannosyltransferase of the pathogenic fungus Cryptococcus neoformans.
The major virulence factor of the pathogenic fungus Cryptococcus neoformans is an extensive polysaccharide capsule which surrounds the cell. Almost 90% of the capsule is composed of a partially acetylated linear alpha-1,3-linked mannan substituted with D-xylose and D-glucuronic acid. A novel mannosyltransferase with specificity appropriate for a role in the synthesis of this glucuronoxylomannan is active in cryptococcal membranes. This membrane-associated activity transfers mannose in vitro from GDP-mannose to an alpha-1, 3-dimannoside acceptor, forming a second alpha-1,3 linkage. Product formation by the transferase is dependent on protein, time, temperature, divalent cations, and each substrate. It is not affected by amphomycin or tunicamycin but is inhibited by GDP and mannose-1-phosphate. The described activity is not detectable in the model yeast Saccharomyces cerevisiae, consistent with the absence of a similar polysaccharide structure in that organism. A second mannosyltransferase from C. neoformans membranes adds mannose in alpha-1,2 linkage to the same dimannoside acceptor. The two activities differ in pH optimum and cation preference. While the alpha-1,2 transferase does not have specificity appropriate for a role in glucuronoxylomannan synthesis, it may participate in production of mannoprotein components of the capsule. This study suggests two new targets for antifungal drug discovery.
Doering
T L
TL
Department of Pharmacology, Cornell University Medical College, New York, New York, USA. doering@borcim.wustl.edu
D002240:Carbohydrate Sequence; D003455:Cryptococcus neoformans / Q000201:enzymology* / Q000472:pathogenicity; D008364:Mannosyltransferases / Q000378:metabolism*; D008969:Molecular Sequence Data; D011134:Polysaccharides / Q000096:biosynthesis*
D011134:Polysaccharides; C027478:glucuronoxylomannan; D008364:Mannosyltransferases; C121563:alpha 1,3-mannosyltransferase