A Family of Dual-Activity Glycosyltransferase-Phosphorylases Mediates Mannogen Turnover and Virulence in Leishmania Parasites

• Published in: Cell host & microbe Vol. 26; no. 3; pp. 385 - 399.e9
• Main Authors: Sernee, M. Fleur, Ralton, Julie E., Nero, Tracy L., Sobala, Lukasz F., Kloehn, Joachim, Vieira-Lara, Marcel A., Cobbold, Simon A., Stanton, Lauren, Pires, Douglas E.V., Hanssen, Eric, Males, Alexandra, Ward, Tom, Bastidas, Laurence M., van der Peet, Phillip L., Parker, Michael W., Ascher, David B., Williams, Spencer J., Davies, Gideon J., McConville, Malcolm J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11-09-2019
• Subjects: carbohydrate reserve; central carbon metabolism; Crystallography, X-Ray; Gene Transfer, Horizontal; glycan phosphorylase; glycosyltransferase; Glycosyltransferases - chemistry; Glycosyltransferases - classification; Glycosyltransferases - genetics; Glycosyltransferases - metabolism; GT108; horizontal gene transfer; Leishmania - enzymology; mannan; Mannans; Mannosyltransferases - chemistry; Mannosyltransferases - genetics; Mannosyltransferases - metabolism; Models, Molecular; Oligosaccharides; parasite pathogenesis; Phosphorylases - chemistry; Phosphorylases - classification; Phosphorylases - genetics; Phosphorylases - metabolism; Protein Conformation; Thermotolerance; Virulence; X-ray crystallography; central carbon metabolism; X-ray crystallography; parasite pathogenesis; GT108; glycan phosphorylase; carbohydrate reserve; glycosyltransferase; mannan; horizontal gene transfer
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2019.08.009

Parasitic protists belonging to the genus Leishmania synthesize the non-canonical carbohydrate reserve, mannogen, which is composed of β-1,2-mannan oligosaccharides. Here, we identify a class of dual-activity mannosyltransferase/phosphorylases (MTPs) that catalyze both the sugar nucleotide-dependent biosynthesis and phosphorolytic turnover of mannogen. Structural and phylogenic analysis shows that while the MTPs are structurally related to bacterial mannan phosphorylases, they constitute a distinct family of glycosyltransferases (GT108) that have likely been acquired by horizontal gene transfer from gram-positive bacteria. The seven MTPs catalyze the constitutive synthesis and turnover of mannogen. This metabolic rheostat protects obligate intracellular parasite stages from nutrient excess, and is essential for thermotolerance and parasite infectivity in the mammalian host. Our results suggest that the acquisition and expansion of the MTP family in Leishmania increased the metabolic flexibility of these protists and contributed to their capacity to colonize new host niches.
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•Leishmania have replaced canonical carbohydrate reserves with mannogen•Mannogen cycling is regulated by dual-activity sugar transferase/phosphorylases•Enzyme evolution required horizontal gene transfer and enzyme substrate diversification•Mannogen cycling protects against glucose toxicity and is essential for virulence
Sernee et al. show that metabolism of the Leishmania carbohydrate reserve, mannogen, is mediated by a single family of enzymes acquired by horizontal gene transfer. The evolution of this pathway may have allowed these parasites to expand their host range and colonize intracellular niches in their vertebrate hosts.