Biosynthesis and Biological Activity of Cytochalasans

Cytochalasans are a diverse family of fungal secondary metabolites typified by a macrocyclic backbone derived from the coupled action of polyketide synthases and nonribosomal peptide synthetases. Biosynthetically, the assembly begins with polyketide chain elongation and cyclisation, followed by peptide extension using amino acid substrates. A suite of tailoring enzymes—including oxidases, epoxidases and transferases—introduce ring closures, epoxide moieties and methyl or glycosyl substituents, yielding structures that range from mono- to polycyclic and even polymerised derivatives. The recent elucidation of key gene clusters has revealed pathway‐switching mechanisms whereby oxidoreductases guide the flux between linear and complex architectures. Biologically, cytochalasans exert potent activities against actin polymerisation, leading to profound cytoskeletal disruption in tumour cells and pathogens. They also display antifungal, phytotoxic, anti-inflammatory and antibacterial effects, with efficacy determined by subtle variations in ring topology and substituent patterns. The global significance of these compounds spans potential chemotherapeutic adjuvants, antifouling agents and agrochemicals. Advances in heterologous expression and strain engineering now promise scalable production, while deeper mechanistic insights offer routes to bespoke analogue design with improved selectivity and reduced toxicity.

Research from Nature Portfolio

Recent studies have uncovered a novel berberine bridge enzyme-like oxidase that functions as a molecular switch in cytochalasan biosynthesis. This oxidase mediates a protonation-driven double bond isomerisation that directs intermediates either toward native mono-cytochalasan products or, via nonenzymatic pathways, to polycyclic and polymerised derivatives. Heterologous reconstitution of the entire pathway in a surrogate host confirmed the enzyme’s pivotal role and demonstrated feasibility of producing complex cytochalasans in a controlled setting. In parallel, structural investigations have expanded the known chemical space by reporting multiple new tetracyclic, pentacyclic and tricyclic cytochalasan frameworks isolated from filamentous fungi. Detailed spectroscopic and crystallographic analyses established unprecedented ring connectivities and stereochemical configurations, while bioassays revealed moderate cytotoxicity and apoptosis induction in selected human cancer cell lines, underscoring the value of systematic structural diversification.

Biosynthesis and Biological Activity of Cytochalasans publication trend

The graph below shows the total number of articles in biosynthesis and biological activity of cytochalasans across all publications each year (not limited to Nature Index journals).

Technical terms

Cytochalasan: fungal macrocyclic secondary metabolite characterised by a polyketide-nonribosomal peptide hybrid backbone that binds to actin filaments.

Polyketide-Nonribosomal Peptide (PK-NRP) Hybrid: natural product class formed by the concerted action of polyketide synthases and nonribosomal peptide synthetases.

Berberine Bridge Enzyme-like Oxidase (BBE-like Oxidase): enzyme family that catalyses oxidative transformations, including protonation-driven double bond isomerisation in cytochalasan biosynthesis.

Heterologous Expression: insertion and functional expression of biosynthetic genes in a non-native microbial host to reconstitute metabolite pathways.

Minimal Inhibitory Concentration (MIC): lowest concentration of a compound that prevents visible growth of a microorganism under defined conditions.

References

1. Construction of an Efficient Engineered Strain for Chaetoglobosin A Bioresource Production from Potato Starch Industrial Waste. Foods (2025).
2. Bioactive cytochalasans from the desert soil-derived fungus Chaetomium madrasense 375 obtained via a chemical engineering strategy. Frontiers in Microbiology (2024).
3. Bioactivities and Future Perspectives of Chaetoglobosins. Evidence-based Complementary and Alternative Medicine (2020).
4. Berberine bridge enzyme-like oxidase-catalysed double bond isomerization acts as the pathway switch in cytochalasin synthesis. Nature Communications (2022).