Publisher DOI: 10.1016/j.ymben.2018.05.001
Title: Discovery of feed-forward regulation in L-tryptophan biosynthesis and its use in metabolic engineering of E. coli for efficient tryptophan bioproduction
Language: English
Authors: Chen, Lin 
Chen, Minliang 
Ma, Cheng-Wei 
Zeng, An-Ping  
Keywords: Anthranilate;Dynamics;Feed-forward regulation;Indole glycerol phosphate synthase;L-tryptophan biosynthesis;Aldose-Ketose Isomerases;Aspergillus niger;Indole-3-Glycerol-Phosphate Synthase;Multienzyme Complexes;Saccharomyces cerevisiae;Saccharomyces cerevisiae Proteins;Escherichia coli;Metabolic Engineering;Microorganisms, Genetically-Modified;Tryptophan
Issue Date: May-2018
Source: Metabolic engineering (47): 434-444 (2018)
Journal or Series Name: Metabolic engineering 
Abstract (english): The L-tryptophan (Trp) biosynthesis pathway is highly regulated at multiple levels. The three types of regulations identified so far, namely repression, attenuation, and feedback inhibition have greatly impacted our understanding and engineering of cellular metabolism. In this study, feed-forward regulation is discovered as a novel regulation of this pathway and explored for engineering Escherichia coli for more efficient Trp biosynthesis. Specifically, indole glycerol phosphate synthase (IGPS) of the multifunctional enzyme TrpC from E. coli is found to be feed-forward inhibited by anthranilate noncompetitively. Surprisingly, IGPS of TrpC from both Saccharomyces cerevisiae and Aspergillus niger was found to be feed-forward activated, for which the glutamine aminotransferase domain is essential. The anthranilate binding site of IGPS from E. coli is identified and mutated, resulting in more tolerant variants for improved Trp biosynthesis. Furthermore, expressing the anthranilate-activated TrpC from A. niger in a previously engineered Trp producing E. coli strain S028 made the strain more robust in growth and more efficient in Trp production in bioreactor. It not only increased the Trp concentration from 19 to 29 g/L within 42 h, but also improved the maximum Trp yield from 0.15 to 0.18 g/g in simple fed-batch fermentations, setting a new level to rationally designed Trp producing strains. The findings are of fundamental interest for understanding and re-designing dynamics and control of metabolic pathways in general and provide a novel target and solution to engineering of E. coli for efficient Trp production particularly.
ISSN: 1096-7176
Institute: Bioprozess- und Biosystemtechnik V-1 
Type: (wissenschaftlicher) Artikel
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