Editorial: Metabolic engineering for the production of bioactive compounds

the authors highlight key challenges in developing compe22ve bioproduc2on plaSorms. These challenges include redirec2ng metabolic flux toward leucine-derived intermediates and reducing byproducts such as isobutanol and ethanol. The review outlines core strategies to address these issues, including engineering feedbackresistant variants of α-isopropylmalate synthase, rebalancing the NAD(P)H cofactors, and op2mizing gene expression levels. Furthermore, the review covers process innova2ons, alongside high-throughput technologies, that have accelerated the development of scalable and economically viable microbial plaSorms for 3MB produc2on.Zhihui Meng and colleagues iden2fy redox homeostasis as a crucial bo[leneck in polyke2de biosynthesis, demonstra2ng that targeted enhancement of NAD(P) metabolism substan2ally boosts natamycin produc2on in Streptomyces gilvosporeus.The authors increased natamycin yield by varying the organic nitrogen sources, thereby s2mula2ng ac2vity of the NAD(P) metabolic pathway. Integrated transcriptomic and metabolomic analyses confirmed upregula2on of genes involved in NAD and NADP biosynthesis, resul2ng in elevated intracellular redox cofactor levels and increased natamycin produc2on. The authors reinforce NAD(P) metabolism as a strategic target for ra2onal approaches for polyke2de biosynthesis. profiling. Their studies on Trichoderma longibrachiatum MD33 reveal that subtoxic levels of cinnabar enhance dendrobine production via coordinated upregulation of terpenoid pathways, whereas slightly higher HgS levels trigger oxidative damage and metabolic repression. Collectively, the work highlights that stress-induced secondary metabolism is highly non-linear, with a narrow window between activation and collapse, reflecting fundamental constraints on how far secondary metabolism can be pushed without compromising cell redox buffering, antioxidant capacity, and stressresponse networks.Microbacterium that effectively produces unsaturated disaccharides from various sulfated and non-sulfated substrates. Through thorough biochemical studies and docking analyses, they identified potential enzyme applications for producing glycosaminoglycan disaccharides and specific residues that may explain the enzyme's broad substrate range and unique mechanism of action. Their research can support future efforts to discover enzyme resources, rational enzyme design, and the improvement of enzymes relevant to the production of glycosaminoglycan disaccharides important for glycobiology and therapy development.Finally, Bowen Du and colleagues introduce a novel rare-codon replacement strategy, combined with mutagenesis and metabolic engineering, to efficiently identify and develop high-yield L-valine-producing strains. The authors engineered an artificial selection marker, LESG, by replacing common L-valine codons with the rare GTC codon in target genes. Since translation of rare codons depends on intracellular amino acid availability, fluorescence intensity directly correlates with L-valine production levels. This integrated approach led to the isolation of strain Escherichia coli DK2, which achieved 84.1 g/L of L-valine in 24 hours of bioreactor fermentation.Collectively, the contributions in this Research Topic demonstrate how metabolic engineering have evolved from focusing on individual pathways to becoming an integrated, systems-level discipline. The manuscripts showcase a wide range of advanced biotechnological tools, including multi-omics platforms, rare codon-based screening systems, high-throughput selection methods, computational modeling, and genome editing technologies. These approaches have greatly accelerated strain development and improved the translation of laboratory innovations into sustainable, environmentally friendly industrial processes.FMS drahed the Editorial while FJFP, JJA and YPC contributed to edi2ng. All authors conceived and designed the work and provided final approval of the version to be published.