Design and application of genetically-encoded malonyl-CoA biosensors for metabolic engineering of microbial cell factories

Abayomi Oluwanbe Johnson, Miriam Gonzalez-Villanueva, Lynn Wong, Alexander Steinbüchel, Kang Lan Tee*, Peng Xu, Tuck Seng Wong

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

47 Scopus citations

Abstract

Malonyl-CoA is the basic building block for synthesizing a range of important compounds including fatty acids, phenylpropanoids, flavonoids and non-ribosomal polyketides. Centering around malonyl-CoA, we summarized here the various metabolic engineering strategies employed recently to regulate and control malonyl-CoA metabolism and improve cellular productivity. Effective metabolic engineering of microorganisms requires the introduction of heterologous pathways and dynamically rerouting metabolic flux towards products of interest. Transcriptional factor-based biosensors translate an internal cellular signal to a transcriptional output and drive the expression of the designed genetic/biomolecular circuits to compensate the activity loss of the engineered biosystem. Recent development of genetically-encoded malonyl-CoA sensor has stood out as a classical example to dynamically reprogram cell metabolism for various biotechnological applications. Here, we reviewed the design principles of constructing a transcriptional factor-based malonyl-CoA sensor with superior detection limit, high sensitivity and broad dynamic range. We discussed various synthetic biology strategies to remove pathway bottleneck and how genetically-encoded metabolite sensor could be deployed to improve pathway efficiency. Particularly, we emphasized that integration of malonyl-CoA sensing capability with biocatalytic function would be critical to engineer efficient microbial cell factory. Biosensors have also advanced beyond its classical function of a sensor actuator for in situ monitoring of intracellular metabolite concentration. Applications of malonyl-CoA biosensors as a sensor-invertor for negative feedback regulation of metabolic flux, a metabolic switch for oscillatory balancing of malonyl-CoA sink pathway and source pathway and a screening tool for engineering more efficient biocatalyst are also presented in this review. We envision the genetically-encoded malonyl-CoA sensor will be an indispensable tool to optimize cell metabolism and cost-competitively manufacture malonyl-CoA-derived compounds.

Original languageEnglish
Pages (from-to)253-264
Number of pages12
JournalMetabolic Engineering
Volume44
DOIs
StatePublished - Nov 2017
Externally publishedYes

Keywords

  • Biosensors
  • Dynamic regulation
  • FapR
  • Fatty acid biosynthesis
  • Genetic circuits
  • Malonyl-CoA
  • Synthetic biology

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