OptRAM: In-silico strain design via integrative regulatory-metabolic network modeling

Shen, Fangzhou; Sun, Renliang; Yao, Jie; Li, Jian; Liu, Qian; Price, Nathan D.; Liu, Chenguang; Wang, Zhuo; Ouzounis, Christos A.

doi:10.1371/journal.pcbi.1006835

Title: OptRAM: In-silico strain design via integrative regulatory-metabolic network modeling

Journal Article · Fri Mar 08 00:00:00 EST 2019 · PLoS Computational Biology (Online)

DOI:https://doi.org/10.1371/journal.pcbi.1006835· OSTI ID:1503681

Shen, Fangzhou ^[1]; Sun, Renliang ^[2]; Yao, Jie ^[2]; Li, Jian ^[2]; Liu, Qian ^[2]; Price, Nathan D. ^[3];

^[2];

^[2]; Ouzounis, Christos A. ^[4]

Shanghai Jiao Tong Univ., Shanghai (China); Univ. of Michigan, Ann Arbor, MI (United States)
Shanghai Jiao Tong Univ., Shanghai (China)
Institute for Systems Biology, Seattle, WA (United States)
CPERI (Greece)

The ultimate goal of metabolic engineering is to produce desired compounds on an industrial scale in a cost effective manner. To address challenges in metabolic engineering, computational strain optimization algorithms based on genome-scale metabolic models have increasingly been used to aid in overproducing products of interest. However, most of these strain optimization algorithms utilize a metabolic network alone, with few approaches providing strategies that also include transcriptional regulation. Moreover previous integrated approaches generally require a pre-existing regulatory network. In this study, we developed a novel strain design algorithm, named OptRAM (Optimization of Regulatory And Metabolic Networks), which can identify combinatorial optimization strategies including overexpression, knockdown or knockout of both metabolic genes and transcription factors. OptRAM is based on our previous IDREAM integrated network framework, which makes it able to deduce a regulatory network from data. OptRAM uses simulated annealing with a novel objective function, which can ensure a favorable coupling between desired chemical and cell growth. The other advance we propose is a systematic evaluation metric of multiple solutions, by considering the essential genes, flux variation, and engineering manipulation cost. We applied OptRAM to generate strain designs for succinate, 2,3-butanediol, and ethanol overproduction in yeast, which predicted high minimum predicted target production rate compared with other methods and previous literature values. Moreover, most of the genes and TFs proposed to be altered by OptRAM in these scenarios have been validated by modification of the exact genes or the target genes regulated by the TFs, for overproduction of these desired compounds by in vivo experiments cataloged in the LASER database. Particularly, we successfully validated the predicted strain optimization strategy for ethanol production by fermentation experiment. As a result, OptRAM can provide a useful approach that leverages an integrated transcriptional regulatory network and metabolic network to guide metabolic engineering applications.

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Research Organization:: Center for Advanced Bioenergy and Bioproducts Innovation (CABBI), Urbana, IL (United States)

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

Grant/Contract Number:: SC0018420

OSTI ID:: 1503681

Journal Information:: PLoS Computational Biology (Online), Vol. 15, Issue 3; ISSN 1553-7358

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 27 works

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Title: OptRAM: In-silico strain design via integrative regulatory-metabolic network modeling

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