Human gut microbes express functionally distinct endoglycosidases to metabolize the same N-glycan substrate

Diego E. Sastre (), Nazneen Sultana, Marcos V. A. S. Navarro, Maros Huliciak, Jonathan Du, Javier O. Cifuente, Maria Flowers, Xu Liu, Pete Lollar, Beatriz Trastoy, Marcelo E. Guerin and Eric J. Sundberg ()
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Diego E. Sastre: Emory University School of Medicine
Nazneen Sultana: Emory University School of Medicine
Marcos V. A. S. Navarro: University of São Paulo
Maros Huliciak: Emory University School of Medicine
Jonathan Du: Emory University School of Medicine
Javier O. Cifuente: University of the Basque Country
Maria Flowers: Emory University School of Medicine
Xu Liu: Emory University School of Medicine
Pete Lollar: Emory University School of Medicine
Beatriz Trastoy: Biobizkaia Health Research Institute
Marcelo E. Guerin: Tower R
Eric J. Sundberg: Emory University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Bacteroidales (syn. Bacteroidetes) are prominent members of the human gastrointestinal ecosystem mainly due to their efficient glycan-degrading machinery, organized into gene clusters known as polysaccharide utilization loci (PULs). A single PUL was reported for catabolism of high-mannose (HM) N-glycan glyco-polypeptides in the gut symbiont Bacteroides thetaiotaomicron, encoding a surface endo-β-N-acetylglucosaminidase (ENGase), BT3987. Here, we discover an ENGase from the GH18 family in B. thetaiotaomicron, BT1285, encoded in a distinct PUL with its own repertoire of proteins for catabolism of the same HM N-glycan substrate as that of BT3987. We employ X-ray crystallography, electron microscopy, mass spectrometry-based activity measurements, alanine scanning mutagenesis and a broad range of biophysical methods to comprehensively define the molecular mechanism by which BT1285 recognizes and hydrolyzes HM N-glycans, revealing that the stabilities and activities of BT1285 and BT3987 were optimal in markedly different conditions. BT1285 exhibits significantly higher affinity and faster hydrolysis of poorly accessible HM N-glycans than does BT3987. We also find that two HM-processing endoglycosidases from the human gut-resident Alistipes finegoldii display condition-specific functional properties. Altogether, our data suggest that human gut microbes employ evolutionary strategies to express distinct ENGases in order to optimally metabolize the same N-glycan substrate in the gastroinstestinal tract.

Date: 2024
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DOI: 10.1038/s41467-024-48802-3

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