Mechanism of high-mannose N-glycan breakdown and metabolism by Bifidobacterium longum

Bifidobacteria are early colonizers of the human gut and play central roles in human health and metabolism. To thrive in this competitive niche, these bacteria evolved the capacity to use complex carbohydrates, including mammalian N -glycans. Herein, we elucidated pivotal biochemical steps involved...

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Published in:	Nature chemical biology Vol. 19; no. 2; pp. 218 - 229
Main Authors:	Cordeiro, Rosa L., Santos, Camila R., Domingues, Mariane N., Lima, Tatiani B., Pirolla, Renan A. S., Morais, Mariana A. B., Colombari, Felippe M., Miyamoto, Renan Y., Persinoti, Gabriela F., Borges, Antonio C., de Farias, Marcelo A., Stoffel, Fabiane, Li, Chao, Gozzo, Fabio C., van Heel, Marin, Guerin, Marcelo E., Sundberg, Eric J., Wang, Lai-Xi, Portugal, Rodrigo V., Giuseppe, Priscila O., Murakami, Mario T.
Format:	Journal Article
Language:	English
Published:	New York Nature Publishing Group US 01-02-2023 Nature Publishing Group
Subjects:	631/326/41 631/45/603 631/57/2265 631/92/221 Animals Bifidobacterium - metabolism Bifidobacterium longum Bifidobacterium longum - metabolism Biochemical Engineering Biochemistry Bioorganic Chemistry Carbohydrates Carbon Carbon sources Cell Biology Chemistry Chemistry and Materials Science Chemistry/Food Science Cryoelectron Microscopy Digestive system Electron microscopy Energy sources Gastrointestinal tract Glucosidase Glycan Glycosidases Glycoside hydrolase Glycoside Hydrolases - chemistry Humans Mammals Mannose Mannose - metabolism Mannosidase Mannosidases - metabolism Metabolism Molecular modelling N-Acetylglucosaminidase N-glycans Phosphorylation Polysaccharides Polysaccharides - chemistry Selectivity Substrates α-Glucosidase
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Summary:	Bifidobacteria are early colonizers of the human gut and play central roles in human health and metabolism. To thrive in this competitive niche, these bacteria evolved the capacity to use complex carbohydrates, including mammalian N -glycans. Herein, we elucidated pivotal biochemical steps involved in high-mannose N -glycan utilization by Bifidobacterium longum . After N -glycan release by an endo-β- N -acetylglucosaminidase, the mannosyl arms are trimmed by the cooperative action of three functionally distinct glycoside hydrolase 38 (GH38) α-mannosidases and a specific GH125 α-1,6-mannosidase. High-resolution cryo-electron microscopy structures revealed that bifidobacterial GH38 α-mannosidases form homotetramers, with the N-terminal jelly roll domain contributing to substrate selectivity. Additionally, an α-glucosidase enables the processing of monoglucosylated N -glycans. Notably, the main degradation product, mannose, is isomerized into fructose before phosphorylation, an unconventional metabolic route connecting it to the bifid shunt pathway. These findings shed light on key molecular mechanisms used by bifidobacteria to use high-mannose N -glycans, a perennial carbon and energy source in the intestinal lumen. The human gut Bifidobacterium longum can use host N -glycans as carbon and energy sources via a specific and cooperative multienzymatic system.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 R.L.C., C.R.S., P.O.G. and M.T.M. designed the study and wrote the original draft. R.L.C., C.R.S., M.E.G., E.J.S., P.O.G. and M.T.M. revised and contributed to the final version of the paper. R.L.C. and G.F.P. performed the bioinformatics analyses. M.A.B.M. and F.M.C. performed the molecular dynamic simulations. T.B.L., R.A.S.P. and F.C.G. performed the MS analyses. R.L.C., M.N.D., R.Y.M. and F.S. expressed and purified the enzymes and performed the enzymatic assays. C.L. and L.-X.W. produced the carbohydrates Man9GlcNAc2-Asn and Man5GlcNAc2-Asn. R.L.C., M.N.D., M.E.G., E.J.S., P.O.G. and M.T.M. analyzed the functional data. A.C.B., M.A.d.F., M.v.H. and R.V.P. prepared grids and collected and processed the cryo-EM data. R.L.C. and C.R.S. modeled and refined the atomic models. R.L.C., C.R.S., P.O.G. and M.T.M. performed the structural analyses. All authors analyzed the results and approved the final version of the manuscript. Author contributions
ISSN:	1552-4450 1552-4469
DOI:	10.1038/s41589-022-01202-4