NRPS and PKS pathways in actinomycetes: A review of biosynthetic diversity and bioactive potential

Actinomycetes are Gram-positive bacteria renowned for their capacity to produce chemically diverse secondary metabolites with significant pharmaceutical relevance. Widely distributed across marine and terrestrial environments, they exhibit remarkable metabolic adaptability that supports the synthesis of novel compounds under environmental stress. This review examines the biosynthetic diversity of actinomycetes, with a focus on non-ribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs), the principal enzymatic systems responsible for complex metabolite assembly. A clear distinction is made between synthetases (ATP-dependent enzymes such as NRPSs) and synthases (ATP-independent enzymes such as PKSs), addressing a key conceptual ambiguity. The modular architecture of NRPSs, including adenylation, thiolation, and condensation domains, is discussed in relation to peptide biosynthesis, while PKS systems are outlined based on their classification (Types I-III), domain organization, and chain elongation mechanisms. Hybrid PKS-NRPS pathways and inter-domain interactions are further highlighted for their role in expanding chemical diversity. Collectively, these biosynthetic systems highlight the potential of actinomycetes as a rich source of therapeutically relevant compounds, particularly in antimicrobial and anticancer drug discovery.