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Title: Molecular basis for catabolism of the abundant metabolite trans-4-hydroxy-L-proline by a microbial glycyl radical enzyme

Abstract

The glycyl radical enzyme (GRE) superfamily utilizes a glycyl radical cofactor to catalyze difficult chemical reactions in a variety of anaerobic microbial metabolic pathways. Recently, a GRE, trans-4-hydroxy-L-proline (Hyp) dehydratase (HypD), was discovered that catalyzes the dehydration of Hyp to (S)-Δ1-pyrroline-5-carboxylic acid (P5C). This enzyme is abundant in the human gut microbiome and also present in prominent bacterial pathogens. However, we lack an understanding of how HypD performs its unusual chemistry. Here, we have solved the crystal structure of HypD from the pathogen Clostridioides difficile with Hyp bound in the active site. Biochemical studies have led to the identification of key catalytic residues and have provided insight into the radical mechanism of Hyp dehydration.

Authors:
ORCiD logo [1]; ORCiD logo [2]; ORCiD logo [1]; ORCiD logo [1]; ORCiD logo [1]; ORCiD logo [2]; ORCiD logo [1]
  1. Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States)
  2. Harvard Univ., Cambridge, MA (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Science Foundation (NSF); National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22). Scientific User Facilities Division
OSTI Identifier:
1608056
Grant/Contract Number:  
AC02-06CH11357
Resource Type:
Accepted Manuscript
Journal Name:
eLife
Additional Journal Information:
Journal Volume: 9; Journal Issue: 03, 2020; Journal ID: ISSN 2050-084X
Publisher:
eLife Sciences Publications, Ltd.
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY

Citation Formats

Backman, Lindsey R. F., Huang, Yolanda Y., Andorfer, Mary C., Gold, Brian, Raines, Ronald T., Balskus, Emily P., and Drennan, Catherine L. Molecular basis for catabolism of the abundant metabolite trans-4-hydroxy-L-proline by a microbial glycyl radical enzyme. United States: N. p., 2020. Web. doi:10.7554/eLife.51420.
Backman, Lindsey R. F., Huang, Yolanda Y., Andorfer, Mary C., Gold, Brian, Raines, Ronald T., Balskus, Emily P., & Drennan, Catherine L. Molecular basis for catabolism of the abundant metabolite trans-4-hydroxy-L-proline by a microbial glycyl radical enzyme. United States. doi:https://doi.org/10.7554/eLife.51420
Backman, Lindsey R. F., Huang, Yolanda Y., Andorfer, Mary C., Gold, Brian, Raines, Ronald T., Balskus, Emily P., and Drennan, Catherine L. Tue . "Molecular basis for catabolism of the abundant metabolite trans-4-hydroxy-L-proline by a microbial glycyl radical enzyme". United States. doi:https://doi.org/10.7554/eLife.51420. https://www.osti.gov/servlets/purl/1608056.
@article{osti_1608056,
title = {Molecular basis for catabolism of the abundant metabolite trans-4-hydroxy-L-proline by a microbial glycyl radical enzyme},
author = {Backman, Lindsey R. F. and Huang, Yolanda Y. and Andorfer, Mary C. and Gold, Brian and Raines, Ronald T. and Balskus, Emily P. and Drennan, Catherine L.},
abstractNote = {The glycyl radical enzyme (GRE) superfamily utilizes a glycyl radical cofactor to catalyze difficult chemical reactions in a variety of anaerobic microbial metabolic pathways. Recently, a GRE, trans-4-hydroxy-L-proline (Hyp) dehydratase (HypD), was discovered that catalyzes the dehydration of Hyp to (S)-Δ1-pyrroline-5-carboxylic acid (P5C). This enzyme is abundant in the human gut microbiome and also present in prominent bacterial pathogens. However, we lack an understanding of how HypD performs its unusual chemistry. Here, we have solved the crystal structure of HypD from the pathogen Clostridioides difficile with Hyp bound in the active site. Biochemical studies have led to the identification of key catalytic residues and have provided insight into the radical mechanism of Hyp dehydration.},
doi = {10.7554/eLife.51420},
journal = {eLife},
number = 03, 2020,
volume = 9,
place = {United States},
year = {2020},
month = {3}
}

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