Abstract
BackgroundLincomycin, produced by Streptomyces lincolnensis, is a lincosamide antibiotic and widely used for the treatment of the infective diseases caused by Gram-positive bacteria. The mechanisms of lincomycin biosynthesis have been deeply explored in recent years. However, the regulatory effects of LmbU that is a transcriptional regulator in lincomycin biosynthetic (lmb) gene cluster have not been fully addressed.ResultsLmbU was used to search for homologous LmbU (LmbU-like) proteins in the genomes of actinobacteria, and the results showed that LmbU-like proteins are highly distributed regulators in the biosynthetic gene clusters (BGCs) of secondary metabolites or/and out of the BGCs in actinomycetes. The overexpression, inactivation and complementation of the lmbU gene indicated that LmbU positively controls lincomycin biosynthesis in S. lincolnensis. Comparative transcriptomic analysis further revealed that LmbU activates the 28 lmb genes at whole lmb cluster manner. Furthermore, LmbU represses the transcription of the non-lmb gene hpdA in the biosynthesis of l-tyrosine, the precursor of lincomycin. LmbU up-regulates nineteen non-lmb genes, which would be involved in multi-drug flux to self-resistance, nitrate and sugar transmembrane transport and utilization, and redox metabolisms.ConclusionsLmbU is a significant pleiotropic transcriptional regulator in lincomycin biosynthesis by entirely activating the lmb cluster and regulating the non-lmb genes in Streptomyces lincolnensis. Our results first revealed the pleiotropic regulatory function of LmbU, and shed new light on the transcriptional effects of LmbU-like family proteins on antibiotic biosynthesis in actinomycetes.
Highlights
Lincomycin, produced by Streptomyces lincolnensis, is a lincosamide antibiotic and widely used for the treatment of the infective diseases caused by Gram-positive bacteria
93 LmbU-like proteins were selected based on their complete flanking sequences, which were used to locate lmbU-like genes either in the Biosynthetic gene cluster (BGC) or not
Sequence analysis of upstream and downstream regions around the lmbU-like genes revealed that nearly two-thirds of lmbU-like genes are located in the BGCs with single copy, similar to lmbU in the lmb cluster of S. lincolnensis
Summary
Lincomycin, produced by Streptomyces lincolnensis, is a lincosamide antibiotic and widely used for the treatment of the infective diseases caused by Gram-positive bacteria. The mechanisms of lincomycin biosynthesis have been deeply explored in recent years. Lincomycin, produced by Streptomyces lincolnensis, is a lincosamide antibiotic used for the treatment of the infective diseases caused by Gram-positive bacteria [3]. The lincomycin biosynthetic (lmb) gene cluster has been partially characterized in S. lincolnensis [4, 5]. The lmb cluster harbors three resistance genes (lmrA, lmbrB and lmrC) and twenty-six open reading frames (ORFs) with putative biosynthetic and regulatory functions. The moiety MTL originates from a GDP-activated C8 sugar lincosamide (LSM), which is synthesized from the condensation of C5 donor α-d-ribose-5-phosphate and C3 donor fructose6-phosphate (or d-sedoheptulose-7-phosphate) by LmbR and LmbN [8]. Lincomycin is synthesized after modifications of thiols exchange, N-methylation, C–S bond cleavage and S-methylation [15, 16]
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