Co-Production of Nattokinase and Menaquinone-7 by Bacillus subtilis Natto: Metabolic Trade-Offs, Regulatory Mechanisms, and Dynamic Fermentation Strategies

Bacillus subtilis natto can co-produce nattokinase (NK) and menaquinone-7 (MK-7), but their distinct biosynthetic demands, cellular localization, and production kinetics may be associated with condition-dependent trade-offs. This review critically evaluates the biosynthetic mechanisms and multi-omics regulatory characteristics of NK and MK-7 and examines how oxygen-related conditions, substrate composition, and redox state are associated with co-production performance. Dynamic two-stage fermentation has been proposed as a promising, system-dependent framework for coordinating the different production phases of NK and MK-7. However, current evidence remains limited to specific strains, substrates, and reactor configurations. Future studies should integrate 13C metabolic flux analysis, real-time sensing, standardized detection, and non-GM strain improvement to drive NK-MK-7 co-production from empirical optimization toward mechanism-driven predictive design, providing a theoretical and technical basis for dual-functional foods and multi-product fermentation.