Metabolic impact assessment for heterologous protein production in Streptomyces lividans based on genome-scale metabolic network modeling |
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Authors: | Ivan Lule,Pieter-Jan D&rsquo Huys,Lieve Van Mellaert,Jozef Anné ,Kristel Bernaerts,Jan Van Impe |
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Affiliation: | 1. Chemical and Biochemical Process Technology and Control Section (BioTeC), Department of Chemical Engineering, Katholieke Universiteit Leuven, Willem de Croylaan 46, 3001 Leuven, Belgium;2. Laboratory of Molecular Bacteriology, Department of Microbiology and Immunology, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium |
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Abstract: | The metabolic impact exerted on a microorganism due to heterologous protein production is still poorly understood in Streptomyces lividans. In this present paper, based on exometabolomic data, a proposed genome-scale metabolic network model is used to assess this metabolic impact in S. lividans. Constraint-based modeling results obtained in this work revealed that the metabolic impact due to heterologous protein production is widely distributed in the genome of S. lividans, causing both slow substrate assimilation and a shift in active pathways. Exchange fluxes that are critical for model performance have been identified for metabolites of mouse tumor necrosis factor, histidine, valine and lysine, as well as biomass. Our results unravel the interaction of heterologous protein production with intracellular metabolism of S. lividans, thus, a possible basis for further studies in relieving the metabolic burden via metabolic or bioprocess engineering. |
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Keywords: | CBM, constraint-based modeling FBA, flux balance analysis FCP, fragmented cell pellets FVA, flux variability analysis gFBA, geometric flux balance analysis GP1, first growth phase GP2, second growth phase GSMN, genome-scale metabolic network AMN, active metabolic network NMMP, minimal liquid medium REC, recombinant (S. lividans) UCP, unfragmented cell pellets WT, wild-type (S. lividans) |
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