Abstract
Monensin, produced by Streptomyces cinnamonensis, is a polyether ionophore antibiotic widely used as a coccidiostat and a growth-promoting agent in agricultural industry. In this study, cyclic AMP receptor protein (Crp), the global transcription factor for regulation of monensin biosynthesis, was deciphered. The overexpression and antisense RNA silencing of crp revealed that Crp plays a positive role in monensin biosynthesis. RNA sequencing analysis indicated that Crp exhibited extensive regulatory effects on genes involved in both primary metabolic pathways and the monensin biosynthetic gene cluster (mon). The primary metabolic genes, including acs, pckA, accB, acdH, atoB, mutB, epi and ccr, which are pivotal in the biosynthesis of monensin precursors malonyl-CoA, methylmalonyl-CoA and ethylmalonyl-CoA, are transcriptionally upregulated by Crp. Furthermore, Crp upregulates the expression of most mon genes, including all PKS genes (monAI to monAVIII), tailoring genes (monBI-monBII-monCI, monD and monAX) and a pathway-specific regulatory gene (monRI). Enhanced precursor supply and the upregulated expression of mon cluser by Crp would allow the higher production of monensin in S. cinnamonensis. This study gives a more comprehensive understanding of the global regulator Crp and extends the knowledge of Crp regulatory mechanism in Streptomyces.
Highlights
Streptomyces bacteria are a abundant source of natural products, providing more than half of medically valuable antimicrobial and anticancer drugs [1]
The mycelium growth was early stimulated by overexpressing the crp gene and retarded by silencing the crp gene (Figure 1b), implying that cyclic AMP receptor protein (Crp) has a positive effect on the vegetative development of S. cinnamonensis
The results indicated that Crp positively regulates monensin biosynthesis, which was not due to the mycelium growth
Summary
Streptomyces bacteria are a abundant source of natural products, providing more than half of medically valuable antimicrobial and anticancer drugs [1]. The antibiotic biosynthesis in Streptomyces is subject to strict control at the transcriptional level by pathway-specific regulators and global regulators [2]. The pathway-specific factors regulate the expression of antibiotic biosynthetic gene cluster and the regulatory patterns on antibiotic biosynthesis are comprehensively established [3]. The global regulators exhibit broader effects on both primary and secondary metabolism [4], which might directly or indirectly contribute to the antibiotic biosynthesis in streptomycetes. In addition to the regulation involved in primary metabolism, previous studies showed that the overexpression of the crp gene improved the biosynthesis of actinorhodin, undecylprodigiosin and calcium-dependent antibiotic in S. coelicolor and erythromycin in Saccharopolyspora erythraea [12,13]. CRP plays important regulatory roles in antibiotic biosynthesis
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