Assessing the impact of substrate-level enzyme regulations limiting ethanol titer in Clostridium thermocellum using a core kinetic model

Foster, Charles; Boorla, Veda Sheersh; Dash, Satyakam; Gopalakrishnan, Saratram; Jacobson, Tyler B.; Olson, Daniel G.; Amador-Noguez, Daniel; Lynd, Lee R.; Maranas, Costas D.

doi:10.1016/j.ymben.2021.12.012

Title: Assessing the impact of substrate-level enzyme regulations limiting ethanol titer in Clostridium thermocellum using a core kinetic model

Journal Article · 31 December 2021 · Metabolic Engineering

DOI: https://doi.org/10.1016/j.ymben.2021.12.012 · OSTI ID:1981799

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Pennsylvania State Univ., University Park, PA (United States); Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States). Center for Bioenergy Innovation (CBI)
Univ. of Wisconsin, Madison, WI (United States); Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States). Center for Bioenergy Innovation (CBI)
Dartmouth College, Hanover, NH (United States); Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States). Center for Bioenergy Innovation (CBI)

Clostridium thermocellum is a promising candidate for consolidated bioprocessing because it can directly ferment cellulose to ethanol. Despite significant efforts, achieved yields and titers fall below industrially relevant targets. This implies that there still exist unknown enzymatic, regulatory, and/or possibly thermodynamic bottlenecks that can throttle back metabolic flow. By (i) elucidating internal metabolic fluxes in wild-type C. thermocellum grown on cellobiose via ¹³C-metabolic flux analysis (¹³C-MFA), (ii) parameterizing a core kinetic model, and (iii) subsequently deploying an ensemble-docking workflow for discovering substrate-level regulations, this paper aims to reveal some of these factors and expand our knowledgebase governing C. thermocellum metabolism. Generated ¹³C labeling data were used with ¹³C-MFA to generate a wild-type flux distribution for the metabolic network. Notably, flux elucidation through MFA alluded to serine generation via the mercaptopyruvate pathway. Using the elucidated flux distributions in conjunction with batch fermentation process yield data for various mutant strains, we constructed a kinetic model of C. thermocellum core metabolism (i.e. k-ctherm138). Subsequently, we used the parameterized kinetic model to explore the effect of removing substrate-level regulations on ethanol yield and titer. Upon exploring all possible simultaneous (up to four) regulation removals we identified combinations that lead to many-fold model predicted improvement in ethanol titer. In addition, by coupling a systematic method for identifying putative competitive inhibitory mechanisms using K-FIT kinetic parameterization with the ensemble-docking workflow, we flagged 67 putative substrate-level inhibition mechanisms across central carbon metabolism supported by both kinetic formalism and docking analysis.

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Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States). Center for Bioenergy Innovation (CBI)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER); National Science Foundation (NSF)

Grant/Contract Number:: AC05-00OR22725

OSTI ID:: 1981799

Journal Information:: Metabolic Engineering, Journal Name: Metabolic Engineering Journal Issue: C Vol. 69; ISSN 1096-7176

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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Kinetic modeling
Ruminiclostridium thermocellum

Title: Assessing the impact of substrate-level enzyme regulations limiting ethanol titer in Clostridium thermocellum using a core kinetic model

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