Synthesis of a Complex Glycolipid from Malassezia Pachydermitis Permits Identification of Ability to Signal through Human Mincle

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Mini symposium: Glycobiology at the LUMC and beyond

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Synthesis of a Complex Glycolipid from Malassezia Pachydermitis Permits Identification of Ability to Signal through Human Mincle

Phillip van der Peet 1 , Spencer Williams 1 , Christian Gunawan 1 , Miyuki Watanabe 2 , Sho Yamasaki 2,3

1 School of Chemistry and Bio21 Institute, University of Melbourne, Parkville, Australia, 2 Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, 3 Department of Molecular Immunology, Immunology Frontier Research Center, Osaka University

Malassezia pachydermitis is a commensal fungus that causes skin diseases and otitis in humans and carnivorous pets and can result in serious infections in susceptible humans. Yamasaki and co-workers isolated a unique glycolipid, 44-2, from M. pachydermitis composed of a mannitol core bearing three β-mannosylated hydroxystearate chains. Glycolipid 44-2 was shown to be a potent stimulator of murine macrophage-inducible C-type lectin (Mincle) receptor,[1] a pattern recognition receptor of the innate immune system that senses lipidic species and signals the presence of bacteria and fungi. Glycolipid 44-2 contains three β-mannosyl linkages to 10-hydroxystearic acid moieties, which are in turn esterified to L-mannitol. We report the concise synthesis of this complex lipid through a highly convergent approach utilising a single glucosyl trichloroacetimidate donor to generate all four β-glycosidic linkages. Inversion of glucose at C2 was used to access the synthetically challenging β-mannosyl configuration. The chiral 10-hydroxystearic acid chains were generated by cuprate coupling to an enantiopure epoxide obtained by Jacobsen’s hydrolytic kinetic resolution of the racemate. Synthetic 44-2 was shown to be a potent agonist of signalling through human Mincle, and represents the first such fungal metabolite to do so.

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