Harnessing the potential: Advances in cyanobacterial natural product research and biotechnology

Baunach, Martin; Guljamow, Arthur; Miguel-Gordo, María; Dittmann, Elke

doi:10.1039/d3np00045a

Cited by 66Microbial Natural Products and BiosynthesisMicrobial Metabolic Engineering and BioproductionBiocrusts and Microbial Ecology

Harnessing the potential: Advances in cyanobacterial natural product research and biotechnology

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Baunach, Martin, Guljamow, Arthur, Miguel-Gordo, María, Dittmann, Elke·2024·Natural Product Reports

DOI 10.1039/d3np00045a

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Abstract

Covering: 2000 to 2023Cyanobacteria produce a variety of bioactive natural products that can pose a threat to humans and animals as environmental toxins, but also have potential for or inspire pharmaceutical use. As oxygenic phototrophs, cyanobacteria furthermore hold great promise for sustainable biotechnology. Yet, the necessary tools for exploiting their biotechnological potential have so far been established only for a few model strains of cyanobacteria, while large untapped biosynthetic resources are hidden in slow-growing cyanobacterial genera that are difficult to access by genetic techniques. In recent years, several approaches have been developed to circumvent the bottlenecks in cyanobacterial natural product research. Here, we summarize current progress that has been made in unlocking or characterizing cryptic metabolic pathways using integrated omics techniques, orphan gene cluster activation, use of genetic approaches in original producers, heterologous expression and chemo-enzymatic techniques. We are mainly highlighting genomic mining concepts and strategies towards high-titer production of cyanobacterial natural products from the last 10 years and discuss the need for further research developments in this field.

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Introduction of complex heterologous metabolic pathways can elevate cellular metabolic demands, potentially exacerbating growth restrictions and further reducing overall productivity.
“Additionally, the introduction of complex heterologous metabolic pathways can elevate cellular metabolic demands, potentially exacerbating growth restrictions and further reducing overall productivity [198].”
From Cyanobacteria as a Photosynthetic Chassis for Metabolic Pathway Engineering with Heterologous Gene Expression (2026) · cites this paper as [198]
Section 8 (page unavailable) says heterologous biosynthetic pathways can require additional substrates, cofactors, and host engineering, supporting the claim that they place demands on a host cell. Section 3 discusses growth bottlenecks, but does not link them to introducing heterologous pathways or say that such pathways further reduce growth and overall productivity. (LLM, conf=0.78)
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An Engineered Lantibiotic Synthetase That Does Not Require a Leader Peptide on Its Substrate
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Direct Pathway Cloning Combined with Sequence- and Ligation-Independent Cloning for Fast Biosynthetic Gene Cluster Refactoring and Heterologous Expression
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Photosynthetic Production of Sunscreen Shinorine Using an Engineered Cyanobacterium
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From Tryptophan to Toxin: Nature’s Convergent Biosynthetic Strategy to Aetokthonotoxin
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Promoter Activation in Δhfq Mutants as an Efficient Tool for Specialized Metabolite Production Enabling Direct Bioactivity Testing
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Assessment of Anabaena sp. Strain PCC 7120 as a Heterologous Expression Host for Cyanobacterial Natural Products: Production of Lyngbyatoxin A
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Progress and challenges in engineering cyanobacteria as chassis for light‐driven biotechnology
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Heterologous Production of 4-O-Demethylbarbamide, a Marine Cyanobacterial Natural Product
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Leader Peptide‐Free In Vitro Reconstitution of Microviridin Biosynthesis Enables Design of Synthetic Protease‐Targeted Libraries
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Phylogenomic Analysis of Secondary Metabolism in the Toxic Cyanobacterial Genera Anabaena, Dolichospermum and Aphanizomenon
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Nostopeptolide plays a governing role during cellular differentiation of the symbiotic cyanobacterium Nostoc punctiforme
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Leader Peptide and a Membrane Protein Scaffold Guide the Biosynthesis of the Tricyclic Peptide Microviridin
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Unique marine derived cyanobacterial biosynthetic genes for chemical diversity
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Phylogenomic Analysis of the Microviridin Biosynthetic Pathway Coupled with Targeted Chemo-Enzymatic Synthesis Yields Potent Protease Inhibitors
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A Genetic and Chemical Perspective on Symbiotic Recruitment of Cyanobacteria of the Genus Nostoc into the Host Plant Blasia pusilla L.
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Correlative metabologenomics of 110 fungi reveals metabolite–gene cluster pairs
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Modification of RSF1010-Based Broad-Host-Range Plasmids for Improved Conjugation and Cyanobacterial Bioprospecting
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Recent advances in hapalindole-type cyanobacterial alkaloids: biosynthesis, synthesis, and biological activity
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High-Density Cultivation of Terrestrial Nostoc Strains Leads to Reprogramming of Secondary Metabolome
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New Prenylated Aeruginosin, Microphycin, Anabaenopeptin and Micropeptin Analogues from a Microcystis Bloom Material Collected in Kibbutz Kfar Blum, Israel
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Metabolic Engineering of Saccharomyces cerevisiae for Production of Shinorine, a Sunscreen Material, from Xylose
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Expanding the Chemical Space of Synthetic Cyclic Peptides Using a Promiscuous Macrocyclase from Prenylagaramide Biosynthesis
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Biosynthesis of Guanitoxin Enables Global Environmental Detection in Freshwater Cyanobacteria
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Functional assessment of mycosporine-like amino acids in Microcystis aeruginosa strain PCC 7806.
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Cyanobacterial systematics and nomenclature as featured in the International Bulletin of Bacteriological Nomenclature and Taxonomy / International Journal of Systematic Bacteriology / International Journal of Systematic and Evolutionary Microbiology
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Cytotoxicity and secondary metabolites production in terrestrial Nostoc strains, originating from different climatic/geographic regions and habitats: Is their cytotoxicity environmentally dependent?
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Role of bacteria in the production and degradation of Microcystis cyanopeptides
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Unlocking the Spatial Control of Secondary Metabolism Uncovers Hidden Natural Product Diversity in Nostoc punctiforme
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Characterization of the locus of genes encoding enzymes producing heptadepsipeptide micropeptin in the unicellular cyanobacterium Microcystis
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Directing the Heterologous Production of Specific Cyanobacterial Toxin Variants
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SEVA-Cpf1, a CRISPR-Cas12a vector for genome editing in cyanobacteria
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Two-tier vessel for photoautotrophic high-density cultures
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Discovery of Cyanobacterial Natural Products Containing Fatty Acid Residues**
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Site-specific bioorthogonal protein labelling by tetrazine ligation using endogenous β-amino acid dienophiles
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Tribenzylbutyrolactones and Dibenzyldiphenyl-4,5,6,7-tetrahydrobenzofuranones from Kyrtuthrix maculans
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Study of the growth and biochemical composition of 20 species of cyanobacteria cultured in cylindrical photobioreactors
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Heterologous Expression of Cryptomaldamide in a Cyanobacterial Host
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A Multi-Omics Characterization of the Natural Product Potential of Tropical Filamentous Marine Cyanobacteria
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Non‐canonical localization of RubisCO under high‐light conditions in the toxic cyanobacterium Microcystis aeruginosa PCC7806
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Evaluation of Streptomyces coelicolor A3(2) as a heterologous expression host for the cyanobacterial protein kinase C activator lyngbyatoxin A
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15N Stable Isotope Labeling and Comparative Metabolomics Facilitates Genome Mining in Cultured Cyanobacteria
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Unique Biosynthetic Pathway in Bloom-Forming Cyanobacterial Genus Microcystis Jointly Assembles Cytotoxic Aeruginoguanidines and Microguanidines
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Heterologous production of cyanobacterial compounds
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Evaluating methods for purifying cyanobacterial cultures by qPCR and high-throughput Illumina sequencing
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Cyanochelins, an Overlooked Class of Widely Distributed Cyanobacterial Siderophores, Discovered by Silent Gene Cluster Awakening
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Discovery and Heterologous Expression of Microginins from Microcystis aeruginosa LEGE 91341
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A polyketide interferes with cellular differentiation in the symbiotic cyanobacterium Nostoc punctiforme
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Influence of local and global environmental parameters on the composition of cyanobacterial mats in a tropical lagoon
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Expanding the Natural Products Heterologous Expression Repertoire in the Model Cyanobacterium Anabaena sp. Strain PCC 7120: Production of Pendolmycin and Teleocidin B-4
Videau, P., Wells, K. N., Singh, A. J., Eiting, J., Proteau, P. J., & Philmus, B. (2020) · ACS Synthetic Biology · doi:10.1021/acssynbio.9b00334 · Cited by 27 · see citing works
Biosynthesis of cyanobacterin, a paradigm for furanolide core structure assembly
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Highlights of biosynthetic enzymes and natural products from symbiotic cyanobacteria
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Comprehensive Large-Scale Integrative Analysis of Omics Data To Accelerate Specialized Metabolite Discovery
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In Vivo Production of Diverse β‐Amino Acid‐Containing Proteins
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The Continuing Development of E. coli as a Heterologous Host for Complex Natural Product Biosynthesis
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Cyanobacterial Sfp-type phosphopantetheinyl transferases functionalize carrier proteins of diverse biosynthetic pathways
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More than just an eagle killer: The freshwater cyanobacterium Aetokthonos hydrillicola produces highly toxic dolastatin derivatives
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Deciphering Chemical Mediators Regulating Specialized Metabolism in a Symbiotic Cyanobacterium
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Mutagenesis of the Microcystin Tailoring and Transport Proteins in a Heterologous Cyanotoxin Expression System
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Heterologous Expression in Anabaena of the Columbamide Pathway from the Cyanobacterium Moorena bouillonii and Production of New Analogs
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Mycosporine-like amino acids (MAAs)-producing Microcystis in Lake Erie: Development of a qPCR assay and insight into its ecology.
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Structural basis for an unprecedented enzymatic alkylation in cylindrocyclophane biosynthesis
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Exploring cyanobacterial diversity for sustainable biotechnology
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Chemoenzymatic Late‐Stage Modifications Enable Downstream Click‐Mediated Fluorescent Tagging of Peptides
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Discovery, function, and engineering of graspetides
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Identification, Heterologous Expression, and Characterization of the Tolypodiol Biosynthetic Gene Cluster through an Integrated Approach
Back, D., O’Donnell, T. J., Axt, K. K., Gurr, J. R., Vanegas, J. M., Williams, P. G., & Philmus, B. J. (2023) · ACS Chemical Biology · doi:10.1021/acschembio.3c00225 · Cited by 15 · see citing works
Evaluation of inducible promoter–riboswitch constructs for heterologous protein expression in the cyanobacterial species Anabaena sp. PCC 7120
Svoboda, J., Cisneros, B., & Philmus, B. (2021) · Synthetic Biology · doi:10.1093/synbio/ysab019 · Cited by 11 · see citing works
One‐Pot Chemoenzymatic Synthesis of Microviridin Analogs Containing Functional Tags
Scholz, S., Kerestetzopoulou, S., Wiebach, V., Schnegotzki, R., Schmid, B., Reyna‐González, E., Ding, L., Süßmuth, R. D., Dittmann, E., & Baunach, M. (2022) · ChemBioChem · doi:10.1002/cbic.202200345 · Cited by 9 · see citing works
Self-citation
The influence of sigma factors and ribosomal recognition elements on heterologous expression of cyanobacterial gene clusters in Escherichia coli
Wells, K. N., Videau, P., Nelson, D., Eiting, J., & Philmus, B. J. (2018) · FEMS Microbiology Letters · doi:10.1093/femsle/fny164 · Cited by 8 · see citing works

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Authors: Baunach, M., Guljamow, A., Miguel-Gordo, M., & Dittmann, E.
Affiliations: University of Bonn (DE)
University of Potsdam (DE)
Corresponding author: Dittmann, Elke
ORCID: Baunach, Martin
Guljamow, Arthur
Miguel-Gordo, María
Dittmann, Elke
Venue: Natural Product Reports
Publisher: Royal Society of Chemistry (RSC)
Published: 2024
Volume: 41
Issue: 3
Pages: 347-369
ISSN: 0265-0568 (ISSN-L)
1460-4752
DOI: 10.1039/d3np00045a
OpenAlex: W4389696994
Cited by: 66
References: 158
Citations by year: 2026: 23 · 2025: 27 · 2024: 16
FWCI: 2.40
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc
creativecommons.org/licenses/by-nc/3.0/ (vor)
Locations: Natural Product Reports (publishedVersion, cc-by-nc)
PubMed (publishedVersion)
Funders: Deutsche Forschungsgemeinschaft (Project-ID 239748522, RTG 2473)
Topics: Health Sciences › Medicine › Pharmacology › Microbial Natural Products and Biosynthesis
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Microbial Metabolic Engineering and Bioproduction
Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Biocrusts and Microbial Ecology
Keywords: cyanobacterial natural products, cyanobacterial biotechnology, environmental toxins, bioactive compounds, genome mining, heterologous expression, chemoenzymatic synthesis, multi-omics integration, cyanobacterial genomics
MeSH terms: Cyanobacteria, Animals, Biological Products, Biotechnology, Humans, Genomics

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