Phenazine Biosynthesis and Biological Activity

Phenazines are nitrogen-rich heterocyclic compounds synthesised by diverse bacteria through multi-enzymatic pathways that convert chorismic acid into the tricyclic phenazine core. The initial conversion of chorismic acid and glutamine to 2-amino-2-deoxyisochorismate is catalysed by an aminotransferase amidase, followed by a sequence of isomerisation, cyclisation and redox transformations mediated by enzymes such as PhzF and PhzD. Further tailoring steps, including hydroxylation, methylation, prenylation and oxidation, generate a broad spectrum of natural and semisynthetic derivatives. Phenazines exhibit versatile biological activities, acting as antibiotics, antitumour agents, antiparasitic and anti-inflammatory molecules and ecological signalling pigments. Their redox-active properties enable electron-shuttling processes that impact microbial competition and multicellular community formation, with practical applications in agriculture for biocontrol and in medicine as leads for novel therapeutics. Recent advances have elucidated key enzymatic mechanisms, structural bases for specificity and potential for pathway engineering, underscoring the global significance of phenazine research in addressing antimicrobial resistance and environmental sustainability.

Research from Nature Portfolio

Recent studies have elucidated the detailed mechanism and substrate specificity of the isomerase that forms the phenazine scaffold. By combining enzyme kinetics and quantum mechanics/molecular mechanics calculations, researchers demonstrated that the conserved glutamate residue mediates proton transfer more efficiently than a pericyclic rearrangement. The work also revealed how an active-site water molecule facilitates tautomerization, defining limits on substrate scope and suggesting opportunities to design inhibitors that block phenazine biosynthesis in pathogenic bacteria.

Phenazine Biosynthesis and Biological Activity publication trend

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

Technical terms

Phenazine: Tricyclic heterocycle containing two nitrogen atoms, produced by bacteria as secondary metabolites.

Biosynthetic gene cluster (BGC): A contiguous set of genes encoding enzymes responsible for the stepwise assembly and modification of a natural product.

Prenyltransferase: Enzyme that catalyses the transfer of prenyl groups (isoprenoid moieties) to aromatic substrates, diversifying phenazine structures.

Tautomerization: Chemical rearrangement in which a proton and a double bond shift positions, producing an isomeric form of a compound.

References

1. OSMAC-Based Discovery and Biosynthetic Gene Clusters Analysis of Secondary Metabolites from Marine-Derived Streptomyces globisporus SCSIO LCY30. Marine Drugs (2023).
2. Functionalized regioisomers of the natural product phenazines myxin and iodinin as potent inhibitors of Mycobacterium tuberculosis and human acute myeloid leukemia cells. European Journal of Medicinal Chemistry (2025).
3. Recent Advances in Phenazine Natural Products: Chemical Structures and Biological Activities. Molecules (2024).
4. Ligand Binding Induces an Ammonia Channel in 2-Amino-2-desoxyisochorismate (ADIC) Synthase PhzE*. Journal of Biological Chemistry (2011).
5. Mechanisms and Specificity of Phenazine Biosynthesis Protein PhzF. Scientific Reports (2017).