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

Mayes, Heather B.; Knott, Brandon C.; Crowley, Michael F.; Broadbelt, Linda J.; Ståhlberg, Jerry; Beckham, Gregg T.

doi:10.1039/C6SC00571C

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

Journal Article · Wed Jun 01 00:00:00 EDT 2016 · Chemical Science

DOI:https://doi.org/10.1039/C6SC00571C· OSTI ID:1325070

Mayes, Heather B. ^[1]; Knott, Brandon C. ^[2]; Crowley, Michael F. ^[2]; Broadbelt, Linda J. ^[3]; Ståhlberg, Jerry ^[4]; Beckham, Gregg T. ^[2]

Northwestern Univ., Evanston, IL (United States); National Renewable Energy Lab. (NREL), Golden, CO (United States)
National Renewable Energy Lab. (NREL), Golden, CO (United States)
Northwestern Univ., Evanston, IL (United States)
Swedish Univ. of Agricultural Sciences, Uppsala (Sweden)

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 ²S_O 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.

View Accepted Manuscript (DOE)

Research Organization:: NREL (National Renewable Energy Laboratory (NREL), Golden, CO (United States))

Sponsoring Organization:: USDOE Office of Energy Efficiency and Renewable Energy (EERE), Bioenergy Technologies Office (EE-3B)

Grant/Contract Number:: AC36-08GO28308

OSTI ID:: 1325070

Report Number(s):: NREL/JA--5100-67104

Journal Information:: Chemical Science, Journal Name: Chemical Science Journal Issue: 9 Vol. 7; ISSN 2041-6520; ISSN CSHCBM

Publisher:: Royal Society of ChemistryCopyright Statement

Country of Publication:: United States

Language:: English

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Lignocellulosic biomass: Hurdles and challenges in its valorization Singhvi, Mamata S.; Gokhale, Digambar V. Applied Microbiology and Biotechnology, Vol. 103, Issue 23-24 https://doi.org/10.1007/s00253-019-10212-7	journal	November 2019
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Insight into the process of product expulsion in cellobiohydrolase Cel6A from Trichoderma reesei by computational modeling Huang, Houhou; Han, Fei; Guan, Shanshan Journal of Biomolecular Structure and Dynamics, Vol. 37, Issue 5 https://doi.org/10.1080/07391102.2018.1450164	journal	March 2018
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