Current Status and Future Strategies to Increase Secondary Metabolite Production from Cyanobacteria

Abstract

Cyanobacteria, given their ability to produce various secondary metabolites utilizing solar energy and carbon dioxide, are a potential platform for sustainable production of biochemicals. Until now, conventional metabolic engineering approaches have been applied to various cyanobacterial species for enhanced production of industrially valued compounds, including secondary metabolites and non-natural biochemicals. However, the shortage of understanding of cyanobacterial metabolic and regulatory networks for atmospheric carbon fixation to biochemical production and the lack of available engineering tools limit the potential of cyanobacteria for industrial applications. Recently, to overcome the limitations, synthetic biology tools and systems biology approaches such as genome-scale modeling based on diverse omics data have been applied to cyanobacteria. This review covers the synthetic and systems biology approaches for advanced metabolic engineering of cyanobacteria.

Keywords: cyanobacteria; genome-scale model; metabolic engineering; photosynthesis; secondary metabolites; synthetic biology; systems biology.

Figure 1

Cyanobacterial secondary metabolites. (A) Heatmap of the predicted cyanobacterial secondary metabolite biosynthstic gene clusters (BGCs). The left-most phylogenetic tree is constructed by up-to-date bacterial core gene (UBCG) phylogenetic analysis of the 196 cyanobacterial complete genome sequences. The evolutionary distances were provided by UBCG and plotted by RAxML [80,81]. The tree is not to scale. Red: Nostoc, purple: Calothrix, green: Synechocystis, pink: Synechoccus, blue: Microcystis, and yellow: Prochlorococcus. (B–F) Molecular structures of cyanobacterial secondary metabolites. (B) Terpenes, (C) alkaloids, (D) polyketides (PKs), non-ribosomal peptides (NRPs), (E) RiPPs, and (F) fatty acid amide. Abbreviations; NRPS, non-ribosomal peptide synthetase; HglE, heterocyst glycolipid synthase; LAP, linear azol(in)e-containing peptide; TfuA, ribosomally synthesized peptide antibiotic trifolitoxin; CDPS, cyclodipeptide synthase-based tRNA dependent peptide; PKS, polyketide synthase; Amglyccycl, aminoglycosides/aminocyclitols; TransAT, trans-acyltransferase type I PKS.

Figure 2

Genetic engineering tools. (A) Homologous recombination method using the recombination system in cyanobacteria. (B) RSF1010-derived vectors are self-replicating vectors used in episomal expression vector system. (C) CRISPR/Cas system utilizes Cas endonuclease to generate double-strand break to the gRNA-escorted loci inducing homologous recombination. Abbreviation; CRISPR, clustered regularly interspaced short palindromic repeat; gRNA, guide RNA; DSB, double-strand break.

Figure 3

Schematic representation of design–build–test–learn cycle in cyanobacteria.