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Title: Who's on base? Revealing the catalytic mechanism of inverting family 6 glycoside hydrolases

Abstract

In several important classes of inverting carbohydrate-active enzymes, the identity of the catalytic base remains elusive, including in family 6 Glycoside Hydrolase (GH6) enzymes, which are key components of cellulase cocktails for cellulose depolymerization. Despite many structural and kinetic studies with both wild-type and mutant enzymes, especially on the Trichoderma reesei (Hypocrea jecorina) GH6 cellulase (TrCel6A), the catalytic base in the single displacement inverting mechanism has not been definitively identified in the GH6 family. Here, we employ transition path sampling to gain insight into the catalytic mechanism, which provides unbiased atomic-level understanding of key order parameters involved in cleaving the strong glycosidic bond. Our hybrid quantum mechanics and molecular mechanics (QM/MM) simulations reveal a network of hydrogen bonding that aligns two active site water molecules that play key roles in hydrolysis: one water molecule drives the reaction by nucleophilic attack on the substrate and a second shuttles a proton to the putative base (D175) via a short water wire. We also investigated the case where the putative base is mutated to an alanine, an enzyme that is experimentally still partially active. The simulations predict that proton hopping along a water wire via a Grotthuss mechanism provides a mechanism of catalyticmore » rescue. Further simulations reveal that substrate processive motion is 'driven' by strong electrostatic interactions with the protein at the product sites and that the -1 sugar adopts a 2SO ring configuration as it reaches its binding site. Lastly, this work thus elucidates previously elusive steps in the processive catalytic mechanism of this important class of enzymes.« less

Authors:
 [1];  [2];  [2];  [3];  [4];  [2]
+ Show Author Affiliations
  1. Northwestern Univ., Evanston, IL (United States); National Renewable Energy Lab. (NREL), Golden, CO (United States)
  2. National Renewable Energy Lab. (NREL), Golden, CO (United States)
  3. Northwestern Univ., Evanston, IL (United States)
  4. Swedish Univ. of Agricultural Sciences, Uppsala (Sweden)
Publication Date:
Research Org.:
National Renewable Energy Lab. (NREL), Golden, CO (United States)
Sponsoring Org.:
USDOE Office of Energy Efficiency and Renewable Energy (EERE), Sustainable Transportation Office. Bioenergy Technologies Office
OSTI Identifier:
1325070
Report Number(s):
NREL/JA-5100-67104
Journal ID: ISSN 2041-6520; CSHCBM
Grant/Contract Number:  
AC36-08GO28308
Resource Type:
Accepted Manuscript
Journal Name:
Chemical Science
Additional Journal Information:
Journal Volume: 7; Journal Issue: 9; Journal ID: ISSN 2041-6520
Publisher:
Royal Society of Chemistry
Country of Publication:
United States
Language:
English
Subject:
09 BIOMASS FUELS; catalytic mechanisms; hydrolases

Citation Formats

Mayes, Heather B., Knott, Brandon C., Crowley, Michael F., Broadbelt, Linda J., Ståhlberg, Jerry, and Beckham, Gregg T. Who's on base? Revealing the catalytic mechanism of inverting family 6 glycoside hydrolases. United States: N. p., 2016. Web. doi:10.1039/C6SC00571C.
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Mayes, Heather B., Knott, Brandon C., Crowley, Michael F., Broadbelt, Linda J., Ståhlberg, Jerry, & Beckham, Gregg T. Who's on base? Revealing the catalytic mechanism of inverting family 6 glycoside hydrolases. United States. https://doi.org/10.1039/C6SC00571C
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Mayes, Heather B., Knott, Brandon C., Crowley, Michael F., Broadbelt, Linda J., Ståhlberg, Jerry, and Beckham, Gregg T. Wed . "Who's on base? Revealing the catalytic mechanism of inverting family 6 glycoside hydrolases". United States. https://doi.org/10.1039/C6SC00571C. https://www.osti.gov/servlets/purl/1325070.
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@article{osti_1325070,
title = {Who's on base? Revealing the catalytic mechanism of inverting family 6 glycoside hydrolases},
author = {Mayes, Heather B. and Knott, Brandon C. and Crowley, Michael F. and Broadbelt, Linda J. and Ståhlberg, Jerry and Beckham, Gregg T.},
abstractNote = {In several important classes of inverting carbohydrate-active enzymes, the identity of the catalytic base remains elusive, including in family 6 Glycoside Hydrolase (GH6) enzymes, which are key components of cellulase cocktails for cellulose depolymerization. Despite many structural and kinetic studies with both wild-type and mutant enzymes, especially on the Trichoderma reesei (Hypocrea jecorina) GH6 cellulase (TrCel6A), the catalytic base in the single displacement inverting mechanism has not been definitively identified in the GH6 family. Here, we employ transition path sampling to gain insight into the catalytic mechanism, which provides unbiased atomic-level understanding of key order parameters involved in cleaving the strong glycosidic bond. Our hybrid quantum mechanics and molecular mechanics (QM/MM) simulations reveal a network of hydrogen bonding that aligns two active site water molecules that play key roles in hydrolysis: one water molecule drives the reaction by nucleophilic attack on the substrate and a second shuttles a proton to the putative base (D175) via a short water wire. We also investigated the case where the putative base is mutated to an alanine, an enzyme that is experimentally still partially active. The simulations predict that proton hopping along a water wire via a Grotthuss mechanism provides a mechanism of catalytic rescue. Further simulations reveal that substrate processive motion is 'driven' by strong electrostatic interactions with the protein at the product sites and that the -1 sugar adopts a 2SO ring configuration as it reaches its binding site. Lastly, this work thus elucidates previously elusive steps in the processive catalytic mechanism of this important class of enzymes.},
doi = {10.1039/C6SC00571C},
journal = {Chemical Science},
number = 9,
volume = 7,
place = {United States},
year = {Wed Jun 01 00:00:00 EDT 2016},
month = {Wed Jun 01 00:00:00 EDT 2016}
}
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https://doi.org/10.1039/C6SC00571C
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  • Laio, A.; Parrinello, M.
  • Proceedings of the National Academy of Sciences, Vol. 99, Issue 20
  • DOI: 10.1073/pnas.202427399

Traffic Jams Reduce Hydrolytic Efficiency of Cellulase on Cellulose Surface
journal, September 2011

Beyond directed evolution—semi-rational protein engineering and design
journal, December 2010

Computational tools for designing and engineering enzymes
journal, April 2014

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    Lignocellulosic biomass: Hurdles and challenges in its valorization
    journal, November 2019

    • Singhvi, Mamata S.; Gokhale, Digambar V.
    • Applied Microbiology and Biotechnology, Vol. 103, Issue 23-24
    • DOI: 10.1007/s00253-019-10212-7

    A biochemical comparison of fungal GH6 cellobiohydrolases
    journal, August 2019

    • Christensen, Stefan Jarl; Krogh, Kristian Bertel Rømer Mørkeberg; Spodsberg, Nikolaj
    • Biochemical Journal, Vol. 476, Issue 15
    • DOI: 10.1042/bcj20190185

    Insight into the process of product expulsion in cellobiohydrolase Cel6A from Trichoderma reesei by computational modeling
    journal, March 2018

    Discovery and characterization of a thermostable two-domain GH6 endoglucanase from a compost metagenome
    journal, May 2018

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