AUTHOR=Li Xiaobo , Chu Ju , Jensen Peter R. 

TITLE=The Expression of NOX From Synthetic Promoters Reveals an Important Role of the Redox Status in Regulating Secondary Metabolism of Saccharopolyspora erythraea

JOURNAL=Frontiers in Bioengineering and Biotechnology

VOLUME=Volume 8 - 2020

YEAR=2020

URL=https://www.frontiersin.org/journals/bioengineering-and-biotechnology/articles/10.3389/fbioe.2020.00818

DOI=10.3389/fbioe.2020.00818

ISSN=2296-4185

ABSTRACT=Redox cofactors play a pivotal role in cellular metabolism, whereas the clear link between redox status and secondary metabolism is still vague. In this study we investigated effects of redox perturbation on the production of erythromycin in Saccharopolyspora erythraea by expressing the water-forming NADH oxidase (NOX) from Streptococcus pneumonia at different levels with synthetic promoters. The expression of NOX reduced the intracellular [NADH]/[NAD+] ratio significantly in S. erythraea which resulted in an increased production of erythromycin by 19~29% and this increment rose to 60% as more oxygen was supplied. In contrast, the lower redox ratio resulted in a decreased production of another secondary metabolite, the reddish pigment (7-O-rahmnosyl flaviolin). The metabolic shifts of secondary metabolism could result in a higher NADH availability to compensate for its oxidization via NOX. The expression of erythromycin biosynthesis gene cluster in the NOX-expression strains was upregulated as the activity of diguanylate cyclase was inhibited moderately by NADH. This study also suggested that lower intracellular [NADH]/[NAD+] ratio benefits the biosynthesis of erythromycin by potentially affecting the biosynthesis of the secondary messenger, bis-(3'-5')-cyclic dimeric guanosine monophosphate (c-di-GMP), which may stimulate the positive regulation of erythromycin biosynthesis gene cluster by BldD. The present work provides a basis for future cofactor manipulation in S. erythraea to improve the industrial production of erythromycin.