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Metabolic flux and resource balance in the oleaginous yeast Rhodotorula toruloides

Mooney, Eric J. [Pennsylvania State Univ., University Park, PA (United States)]·Suthers, Patrick F. [Pennsylvania State Univ., University Park, PA (United States)]·Schroeder, Wheaton L. [Pennsylvania State Univ., University Park, PA (United States); Washington State Univ., Pullman, WA (United States)]·Dinh, Hoang V. [Pennsylvania State Univ., University Park, PA (United States)]·Li, Xi [Princeton Univ., NJ (United States)]·Shen, Yihui [Princeton Univ., NJ (United States); Univ. of Pennsylvania, Philadelphia, PA (United States)]·Xiao, Tianxia [Princeton Univ., NJ (United States); Peking University, Beijing (China)]·Call, Catherine M. [Princeton Univ., NJ (United States); Brown Univ., Providence, RI (United States)]·Baron, Heide [Princeton Univ., NJ (United States)]·Subramanian, Arjuna M. [Princeton Univ., NJ (United States)]·Weilandt, Daniel R. [Princeton Univ., NJ (United States); Ludwig Inst. for Cancer Research, Princeton, NJ (United States)]·Keber, Felix C. [Princeton Univ., NJ (United States)]·Wühr, Martin [Princeton Univ., NJ (United States)]·Rabinowitz, Joshua D. [Princeton Univ., NJ (United States); Ludwig Inst. for Cancer Research, Princeton, NJ (United States)]·Maranas, Costas D. [Pennsylvania State Univ., University Park, PA (United States)] (ORCID:0000000215081398)
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Abstract

The yeast Rhodotorula toruloides is a promising bioproduction organism due to its high lipid yields and ability to grow on cheap and abundant substrates. Quantitative, systems-level assessment of its metabolic activity is accordingly merited. Resource-balance analysis (RBA) models capture not only reaction stoichiometry but also enzyme requirements for catalysis, providing valuable tools for understanding metabolic trade-offs and optimizing metabolic engineering strategies. Here, in this work, we present systems-level measurements of R. toruloides metabolic flux based on isotope tracing and metabolic flux analysis. In combination with new proteomic measurements, these flux data are used to parameterize a genome-scale resource balance model rtRBA. We find that S. cerevisiae and R. toruloides grow at nearly indistinguishable rates using similar biosynthetic but dramatically different central metabolic programs. R. toruloides consumes one-fifth as much glucose, which it metabolizes primarily via the pentose phosphate pathway and TCA cycle unlike primarily glycolysis in S. cerevisiae . Overall, across these two divergent yeasts, protein abundances aligned more closely than metabolic flux. Resource balance modeling of these metabolic programs predicts superior theoretical yields but lower productivities in R. toruloides than S. cerevisiae for industrial chemicals, highlighting the value of rapid glucose uptake for productivity but respiratory metabolism for yields.

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60 APPLIED LIFE SCIENCES

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BibTeXRIS

Mooney, Eric J. [Pennsylvania State Univ., University Park, PA (United States)], Suthers, Patrick F. [Pennsylvania State Univ., University Park, PA (United States)], Schroeder, Wheaton L. [Pennsylvania State Univ., University Park, PA (United States); Washington State Univ., Pullman, WA (United States)], Dinh, Hoang V. [Pennsylvania State Univ., University Park, PA (United States)], Li, Xi [Princeton Univ., NJ (United States)], Shen, Yihui [Princeton Univ., NJ (United States); Univ. of Pennsylvania, Philadelphia, PA (United States)], Xiao, Tianxia [Princeton Univ., NJ (United States); Peking University, Beijing (China)], Call, Catherine M. [Princeton Univ., NJ (United States); Brown Univ., Providence, RI (United States)], Baron, Heide [Princeton Univ., NJ (United States)], Subramanian, Arjuna M. [Princeton Univ., NJ (United States)], Weilandt, Daniel R. [Princeton Univ., NJ (United States); Ludwig Inst. for Cancer Research, Princeton, NJ (United States)], Keber, Felix C. [Princeton Univ., NJ (United States)], Wühr, Martin [Princeton Univ., NJ (United States)], Rabinowitz, Joshua D. [Princeton Univ., NJ (United States); Ludwig Inst. for Cancer Research, Princeton, NJ (United States)], Maranas, Costas D. [Pennsylvania State Univ., University Park, PA (United States)] (ORCID:0000000215081398). 2026-12-01. Metabolic flux and resource balance in the oleaginous yeast Rhodotorula toruloides. https://doi.org/10.1016/j.ymben.2025.11.012

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