Secondary metabolism in Streptomyces is subjected to complex regulation. Compared to regulations on the transcriptional level, our knowledge of those on the post-translational level remains limited. Here, we identify a Gcn5-related N-acetyltransferase, SyPmatA, in the marine-derived Streptomyces youssoufiensis OUC6819, which negatively affects the production of nigericin, a polyether ionophore antibiotic with antifungal and antiparasitic activities. Inactivation of syPmatA enhanced the nigericin yield by 5.2-fold. Using in vitro and in vivo assays, we demonstrate that SyPmatA specifically catalyzes malonylation of P450 NigDSy at K224, negatively modulating its function. Overexpression of nigDSyK224R (mimicking demalonylation) in the ΔsyPmatA mutant further increased nigericin production. Fermentation optimization and scale-up in a 5L-bioreactor using the engineered strain ΔsyPmatA/nigDsyK224R achieved a final titer of 444.5 mg/L, representing a 61.9-fold improvement over the wild-type strain. Our findings reveal a novel lysine malonylation-mediated regulatory mechanism in nigericin biosynthesis and highlight the potential of targeting post-translational modification enzymes for metabolic engineering.
Yan et al. (Sat,) studied this question.