A family of dual-activity glycosyltransferase-phosphorylases mediates mannogen turnover and virulence in Leishmania parasites

DOI: 10.1016/j.chom.2019.08.009

Authors: M. Fleur Sernee (University of Melbourne) , Julie E. Ralton (University of Melbourne) , Tracy L. Nero (University of Melbourne; St. Vincent’s Institute of Medical Research) , Lukasz F. Sobala (University of York) , Joachim Kloehn (University of Melbourne) , Marcel A. Vieira-Lara (University of Melbourne) , Simon A. Cobbold (University of Melbourne) , Lauren Stanton (University of Melbourne) , Douglas E. V. Pires (University of Melbourne) , Eric Hanssen (University of Melbourne) , Alexandra Males (University of York) , Tom Ward (University of York) , Laurence M. Bastidas (University of York) , Phillip L. Van Der Peet (University of Melbourne) , Michael W. Parker (University of Melbourne; St. Vincent’s Institute of Medical Research) , David B. Ascher (University of Melbourne) , Spencer J. Williams (University of Melbourne) , Gideon J. Davies (University of York) , Malcolm J. Mcconville (University of Melbourne)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Cell Host & Microbe , VOL 26 , PAGES 385 - 399.e9

State: Published (Approved)
Published: September 2019
Diamond Proposal Number(s): 13587 , 18598

Abstract: 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.

Journal Keywords: parasite pathogenesis; carbohydrate reserve; glycan phosphorylase; glycosyltransferase; mannan; central carbon metabolism; horizontal gene transfer; X-ray crystallography; GT108

Diamond Keywords: Leishmaniasis; Enzymes

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Added On: 24/09/2019 09:35

Documents:
lkjeheh44.pdf

Discipline Tags:

Infectious Diseases Disease in the Developing World Health & Wellbeing Biochemistry Catalysis Chemistry Drug Discovery Life Sciences & Biotech Parasitology

Technical Tags:

Diffraction Macromolecular Crystallography (MX)