Design and application of a kinetic model of lipid metabolism in Saccharomyces cerevisiae

Mishra, Shekhar; Wang, Ziyu; Volk, Michael J.; Zhao, Huimin

doi:10.1016/j.ymben.2022.11.003

Design and application of a kinetic model of lipid metabolism in Saccharomyces cerevisiae

Journal Article · Wed Nov 09 00:00:00 EST 2022 · Metabolic Engineering

DOI:https://doi.org/10.1016/j.ymben.2022.11.003· OSTI ID:2420745

Mishra, Shekhar ^[1]; Wang, Ziyu ^[2]; Volk, Michael J. ^[2]; ^[2]

Univ. of Illinois at Urbana-Champaign, IL (United States); OSTI
Univ. of Illinois at Urbana-Champaign, IL (United States)

Lipid biosynthesis plays a vital role in living cells and has been increasingly engineered to overproduce various lipid-based chemicals. However, owing to the tightly constrained and interconnected nature of lipid biosynthesis, both understanding and engineering of lipid metabolism remain challenging, even with the help of mathematical models. Here we report the development of a kinetic metabolic model of lipid metabolism in Saccharomyces cerevisiae that integrates fatty acid biosynthesis, glycerophospholipid metabolism, sphingolipid metabolism, storage lipids, lumped sterol synthesis, and the synthesis and transport of relevant target-chemicals, such as fatty acids and fatty alcohols. The model was trained on lipidomic data of a reference S. cerevisiae strain, single knockout mutants, and lipid overproduction strains reported in literature. The model was used to design mutants for fatty alcohol overproduction and the lipidomic analysis of the resultant mutant strains coupled with model-guided hypothesis led to discovery of a futile cycle in the triacylglycerol biosynthesis pathway. In addition, the model was used to explain successful and unsuccessful mutant designs in metabolic engineering literature. Thus, this kinetic model of lipid metabolism can not only enable the discovery of new phenomenon in lipid metabolism but also the engineering of mutant strains for overproduction of lipids.

View Accepted Manuscript (DOE)

Research Organization:: Univ. of Illinois at Urbana-Champaign, IL (United States)

Sponsoring Organization:: USDOE; USDOE Office of Science (SC)

Grant/Contract Number:: SC0018260

OSTI ID:: 2420745

Alternate ID(s):: OSTI ID: 1897953

Journal Information:: Metabolic Engineering, Journal Name: Metabolic Engineering Journal Issue: C Vol. 75; ISSN 1096-7176

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

References (30)

Engineering Cellular Metabolism Nielsen, Jens; Keasling, Jay D. Cell, Vol. 164, Issue 6 https://doi.org/10.1016/j.cell.2016.02.004	journal	March 2016
An ER Protein Functionally Couples Neutral Lipid Metabolism on Lipid Droplets to Membrane Lipid Synthesis in the ER Markgraf, Daniel F.; Klemm, Robin W.; Junker, Mirco Cell Reports, Vol. 6, Issue 1 https://doi.org/10.1016/j.celrep.2013.11.046	journal	January 2014
The response to inositol: Regulation of glycerolipid metabolism and stress response signaling in yeast Henry, Susan A.; Gaspar, Maria L.; Jesch, Stephen A. Chemistry and Physics of Lipids, Vol. 180 https://doi.org/10.1016/j.chemphyslip.2013.12.013	journal	May 2014
A roadmap for interpreting 13 C metabolite labeling patterns from cells Buescher, Joerg M.; Antoniewicz, Maciek R.; Boros, Laszlo G. Current Opinion in Biotechnology, Vol. 34 https://doi.org/10.1016/j.copbio.2015.02.003	journal	August 2015
Microbial production of indolylglucosinolate through engineering of a multi-gene pathway in a versatile yeast expression platform Mikkelsen, Michael Dalgaard; Buron, Line Due; Salomonsen, Bo Metabolic Engineering, Vol. 14, Issue 2 https://doi.org/10.1016/j.ymben.2012.01.006	journal	March 2012
Metabolic engineering of Saccharomyces cerevisiae for production of fatty acid-derived biofuels and chemicals Runguphan, Weerawat; Keasling, Jay D. Metabolic Engineering, Vol. 21 https://doi.org/10.1016/j.ymben.2013.07.003	journal	January 2014
Metabolic engineering of Saccharomyces cerevisiae to improve 1-hexadecanol production Feng, Xueyang; Lian, Jiazhang; Zhao, Huimin Metabolic Engineering, Vol. 27 https://doi.org/10.1016/j.ymben.2014.10.001	journal	January 2015
A method for analysis and design of metabolism using metabolomics data and kinetic models: Application on lipidomics using a novel kinetic model of sphingolipid metabolism Savoglidis, Georgios; da Silveira dos Santos, Aline Xavier; Riezman, Isabelle Metabolic Engineering, Vol. 37 https://doi.org/10.1016/j.ymben.2016.04.002	journal	September 2016
Engineering high-level production of fatty alcohols by Saccharomyces cerevisiae from lignocellulosic feedstocks d’Espaux, Leo; Ghosh, Amit; Runguphan, Weerawat Metabolic Engineering, Vol. 42 https://doi.org/10.1016/j.ymben.2017.06.004	journal	July 2017
Homology-Integrated CRISPR–Cas (HI-CRISPR) System for One-Step Multigene Disruption in Saccharomyces cerevisiae Bao, Zehua; Xiao, Han; Liang, Jing ACS Synthetic Biology, Vol. 4, Issue 5 https://doi.org/10.1021/sb500255k	journal	September 2014
Simulation and validation of modelled sphingolipid metabolism in Saccharomyces cerevisiae Alvarez-Vasquez, Fernando; Sims, Kellie J.; Cowart, L. Ashley Nature, Vol. 433, Issue 7024 https://doi.org/10.1038/nature03232	journal	January 2005
A cross-platform toolkit for mass spectrometry and proteomics Chambers, Matthew C.; Maclean, Brendan; Burke, Robert Nature Biotechnology, Vol. 30, Issue 10 https://doi.org/10.1038/nbt.2377	journal	October 2012
DNA targeting specificity of RNA-guided Cas9 nucleases Hsu, Patrick D.; Scott, David A.; Weinstein, Joshua A. Nature Biotechnology, Vol. 31, Issue 9, p. 827-832 https://doi.org/10.1038/nbt.2647	journal	July 2013
Optimized sgRNA design to maximize activity and minimize off-target effects of CRISPR-Cas9 Doench, John G.; Fusi, Nicolo; Sullender, Meagan Nature Biotechnology, Vol. 34, Issue 2 https://doi.org/10.1038/nbt.3437	journal	January 2016
A futile metabolic cycle activated in adipocytes by antidiabetic agents Guan, Hong-Ping; Li, Yong; Jensen, Mette Valentin Nature Medicine, Vol. 8, Issue 10 https://doi.org/10.1038/nm780	journal	September 2002
High-efficiency yeast transformation using the LiAc/SS carrier DNA/PEG method Gietz, R. Daniel; Schiestl, Robert H. Nature Protocols, Vol. 2, Issue 1 https://doi.org/10.1038/nprot.2007.13	journal	January 2007
Genome scale models of yeast: towards standardized evaluation and consistent omic integration Sánchez, Benjamín J.; Nielsen, Jens Integrative Biology, Vol. 7, Issue 8 https://doi.org/10.1039/C5IB00083A	journal	January 2015
Global analysis of the yeast lipidome by quantitative shotgun mass spectrometry Ejsing, C. S.; Sampaio, J. L.; Surendranath, V. Proceedings of the National Academy of Sciences, Vol. 106, Issue 7 https://doi.org/10.1073/pnas.0811700106	journal	January 2009
Redirection of lipid flux toward phospholipids in yeast increases fatty acid turnover and secretion Ferreira, Raphael; Teixeira, Paulo Gonçalves; Siewers, Verena Proceedings of the National Academy of Sciences, Vol. 115, Issue 6 https://doi.org/10.1073/pnas.1715282115	journal	January 2018
AMICI: high-performance sensitivity analysis for large ordinary differential equation models Fröhlich, Fabian; Weindl, Daniel; Schälte, Yannik Bioinformatics, Vol. 37, Issue 20 https://doi.org/10.1093/bioinformatics/btab227	journal	April 2021
LibSBML: an API Library for SBML Bornstein, B. J.; Keating, S. M.; Jouraku, A. Bioinformatics, Vol. 24, Issue 6 https://doi.org/10.1093/bioinformatics/btn051	journal	February 2008
pymzML--Python module for high-throughput bioinformatics on mass spectrometry data Bald, T.; Barth, J.; Niehues, A. Bioinformatics, Vol. 28, Issue 7 https://doi.org/10.1093/bioinformatics/bts066	journal	February 2012
redLips: a comprehensive mechanistic model of the lipid metabolic network of yeast Tsouka, S.; Hatzimanikatis, V. FEMS Yeast Research, Vol. 20, Issue 2 https://doi.org/10.1093/femsyr/foaa006	journal	February 2020
Yeast lipid metabolism at a glance Klug, Lisa; Daum, Günther FEMS Yeast Research, Vol. 14, Issue 3 https://doi.org/10.1111/1567-1364.12141	journal	March 2014
Detecting and investigating substrate cycles in a genome-scale human metabolic network Gebauer, Juliane; Schuster, Stefan; de Figueiredo, Luís F. FEBS Journal, Vol. 279, Issue 17 https://doi.org/10.1111/j.1742-4658.2012.08700.x	journal	August 2012
Bringing metabolic networks to life: convenience rate law and thermodynamic constraints Liebermeister, Wolfram; Klipp, Edda Theoretical Biology and Medical Modelling, Vol. 3, Issue 1 https://doi.org/10.1186/1742-4682-3-41	journal	December 2006
Correction: Lessons Learned from Quantitative Dynamical Modeling in Systems Biology Raue, Andreas; Schilling, Marcel; Bachmann, Julie PLoS ONE, Vol. 8, Issue 12 https://doi.org/10.1371/annotation/ea0193d8-1f7f-492a-b0b7-d877629fdcee	journal	December 2013
PEtab—Interoperable specification of parameter estimation problems in systems biology Schmiester, Leonard; Schälte, Yannik; Bergmann, Frank T. PLOS Computational Biology, Vol. 17, Issue 1 https://doi.org/10.1371/journal.pcbi.1008646	journal	January 2021
Mathematical Modeling and Validation of the Ergosterol Pathway in Saccharomyces cerevisiae Alvarez-Vasquez, Fernando; Riezman, Howard; Hannun, Yusuf A. PLoS ONE, Vol. 6, Issue 12 https://doi.org/10.1371/journal.pone.0028344	journal	December 2011
Metabolism and Regulation of Glycerolipids in the Yeast Saccharomyces cerevisiae Henry, Susan A.; Kohlwein, Sepp D.; Carman, George M. Genetics, Vol. 190, Issue 2, p. 317-349 https://doi.org/10.1534/genetics.111.130286	journal	February 2012

Similar Records

Metabolic engineering of Saccharomyces cerevisiae for overproduction of triacylglycerols

Journal Article · Fri Jun 01 00:00:00 EDT 2018 · Metabolic Engineering Communications · OSTI ID:1629896

Investigating the role of the transcriptional regulator Ure2 on the metabolism of Saccharomyces cerevisiae: a multi-omics approach

Journal Article · Sun Jun 20 20:00:00 EDT 2021 · Applied Microbiology and Biotechnology · OSTI ID:1834389

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
Biotechnology & Applied Microbiology
Fatty alcohol
Free fatty acid
Kinetic model
Lipid metabolism

Design and application of a kinetic model of lipid metabolism in Saccharomyces cerevisiae

Citation Formats

References (30)

Similar Records

Related Subjects