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Background AdpA is a global regulator of morphological differentiation and secondary metabolism in  Streptomyces,  but the regulatory roles of the  Streptomyces  AdpA family on the biosynthesis of the natural product ε-poly- l -lysine (ε-PL) remain unidentified, and few studies have focused on increasing the production of ε-PL by manipulating transcription factors in  Streptomyces . Results In this study, we revealed the regulatory roles of different AdpA homologs in ε-PL biosynthesis and morphological differentiation and effectively promoted ε-PL production and sporulation in  Streptomyces  albulus  NK660 by heterologously expressing  adpA  from  S.  neyagawaensis  NRRLB-3092 ( adpA   Sn  ). First, we identified a novel AdpA homolog named AdpA  Sa   in  S.  albulus  NK660 and characterized its function as an activator of ε-PL biosynthesis and morphological differentiation. Subsequently, four heterologous AdpA homologs were selected to investigate their phylogenetic relationships and regulatory roles in  S.  albulus , and AdpA  Sn   was demonstrated to have the strongest ability to promote both ε-PL production and sporulation among these five AdpA proteins. The ε-PL yield of  S.  albulus  heterologously expressing  adpA   Sn   was approximately 3.6-fold higher than that of the control strain. Finally, we clarified the mechanism of AdpA  Sn   in enhancing ε-PL biosynthesis and its effect on ε-PL polymerization degree using real-time quantitative PCR, microscale thermophoresis and MALDI-TOF–MS. AdpA  Sn   was purified, and its seven direct targets,  zwf ,  tal ,  pyk2 ,  pta ,  ack ,  pepc  and a transketolase gene (DC74_2409), were identified, suggesting that AdpA  Sn   may cause the redistribution of metabolic flux in central metabolism pathways, which subsequently provides more carbon skeletons and ATP for ε-PL biosynthesis in  S.  albulus . Conclusions Here, we characterized the positive regulatory roles of  Streptomyces  AdpA homologs in ε-PL biosynthesis and their effects on morphological differentiation and reported for the first time that AdpA  Sn   promotes ε-PL biosynthesis by affecting the transcription of its target genes in central metabolism pathways. These findings supply valuable insights into the regulatory roles of the  Streptomyces  AdpA family on ε-PL biosynthesis and morphological differentiation and suggest that AdpA  Sn   may be an effective global regulator for enhanced production of ε-PL and other valuable secondary metabolites in  Streptomyces .

AdpA, a developmental regulator, promotes ε-poly-l-lysine biosynthesis in Streptomyces albulus