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Pleiotropic regulatory genes bldA, adpA and absB are implicated in production of phosphoglycolipid antibiotic moenomycin.

Makitrynskyy R, Ostash B, Tsypik O, Rebets Y, Doud E, Meredith T, Luzhetskyy A, Bechthold A, Walker S, Fedorenko V - Open Biol (2013)

Bottom Line: Unlike the majority of actinomycete secondary metabolic pathways, the biosynthesis of peptidoglycan glycosyltransferase inhibitor moenomycin in Streptomyces ghanaensis does not involve any cluster-situated regulators (CSRs).Our work highlights an underappreciated strategy for secondary metabolism regulation, in which the interaction between structural genes and pleiotropic regulators is not mediated by CSRs.This strategy might be relevant for a growing number of CSR-free gene clusters unearthed during actinomycete genome mining.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics and Biotechnology, Ivan Franko National University of Lviv, Hrushevskoho st. 4, Lviv 79005, Ukraine.

ABSTRACT
Unlike the majority of actinomycete secondary metabolic pathways, the biosynthesis of peptidoglycan glycosyltransferase inhibitor moenomycin in Streptomyces ghanaensis does not involve any cluster-situated regulators (CSRs). This raises questions about the regulatory signals that initiate and sustain moenomycin production. We now show that three pleiotropic regulatory genes for Streptomyces morphogenesis and antibiotic production-bldA, adpA and absB-exert multi-layered control over moenomycin biosynthesis in native and heterologous producers. The bldA gene for tRNA(Leu)UAA is required for the translation of rare UUA codons within two key moenomycin biosynthetic genes (moe), moeO5 and moeE5. It also indirectly influences moenomycin production by controlling the translation of the UUA-containing adpA and, probably, other as-yet-unknown repressor gene(s). AdpA binds key moe promoters and activates them. Furthermore, AdpA interacts with the bldA promoter, thus impacting translation of bldA-dependent mRNAs-that of adpA and several moe genes. Both adpA expression and moenomycin production are increased in an absB-deficient background, most probably because AbsB normally limits adpA mRNA abundance through ribonucleolytic cleavage. Our work highlights an underappreciated strategy for secondary metabolism regulation, in which the interaction between structural genes and pleiotropic regulators is not mediated by CSRs. This strategy might be relevant for a growing number of CSR-free gene clusters unearthed during actinomycete genome mining.

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A model of the regulatory pathway that governs moenomycin biosynthesis in S. ghanaensis.
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RSOB130121F9: A model of the regulatory pathway that governs moenomycin biosynthesis in S. ghanaensis.

Mentions: It is important to understand whether the expression of different ‘CSR-free’ gene clusters has a common mechanism(s) or principle of regulation. In this study, we show that expression of one such gene cluster, that for moenomycin production, is directly governed by two pleiotropic regulators, one of which is likely to be also under the influence of a third regulator. The described regulatory network is summarized in figure 9. Here, two pleiotropic regulators AdpA and BldA are involved in direct and multi-layered control over moenomycin production, whereas another protein, AbsB, limits AdpA abundance via ribonucleolytic activity. We would like to underscore the reciprocity of functional interactions enabling strict control over moenomycin production. The pleiotropic transcriptional regulator AdpA directly binds to the promoter regions of antibiotic biosynthetic genes as well as its own promoter. BldA contributes to the availability of developmentally regulated tRNALeuUAA, the absence of which limits the translation of both adpA and moe structural genes. Finally, absB-encoded RNaseIII influences antibiotic production by modulating AdpA abundance in addition to other, poorly understood way(s) evident from our heterologous expression experiments. This kind of regulatory network was initially elucidated in model streptomycetes, S. coelicolor and S. griseus [39], where it also governs antibiotic production. However, unlike these model cases, the influence of the studied regulators on moenomycin production does not appear to be mediated by CSRs.Figure 9.


Pleiotropic regulatory genes bldA, adpA and absB are implicated in production of phosphoglycolipid antibiotic moenomycin.

Makitrynskyy R, Ostash B, Tsypik O, Rebets Y, Doud E, Meredith T, Luzhetskyy A, Bechthold A, Walker S, Fedorenko V - Open Biol (2013)

A model of the regulatory pathway that governs moenomycin biosynthesis in S. ghanaensis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3814723&req=5

RSOB130121F9: A model of the regulatory pathway that governs moenomycin biosynthesis in S. ghanaensis.
Mentions: It is important to understand whether the expression of different ‘CSR-free’ gene clusters has a common mechanism(s) or principle of regulation. In this study, we show that expression of one such gene cluster, that for moenomycin production, is directly governed by two pleiotropic regulators, one of which is likely to be also under the influence of a third regulator. The described regulatory network is summarized in figure 9. Here, two pleiotropic regulators AdpA and BldA are involved in direct and multi-layered control over moenomycin production, whereas another protein, AbsB, limits AdpA abundance via ribonucleolytic activity. We would like to underscore the reciprocity of functional interactions enabling strict control over moenomycin production. The pleiotropic transcriptional regulator AdpA directly binds to the promoter regions of antibiotic biosynthetic genes as well as its own promoter. BldA contributes to the availability of developmentally regulated tRNALeuUAA, the absence of which limits the translation of both adpA and moe structural genes. Finally, absB-encoded RNaseIII influences antibiotic production by modulating AdpA abundance in addition to other, poorly understood way(s) evident from our heterologous expression experiments. This kind of regulatory network was initially elucidated in model streptomycetes, S. coelicolor and S. griseus [39], where it also governs antibiotic production. However, unlike these model cases, the influence of the studied regulators on moenomycin production does not appear to be mediated by CSRs.Figure 9.

Bottom Line: Unlike the majority of actinomycete secondary metabolic pathways, the biosynthesis of peptidoglycan glycosyltransferase inhibitor moenomycin in Streptomyces ghanaensis does not involve any cluster-situated regulators (CSRs).Our work highlights an underappreciated strategy for secondary metabolism regulation, in which the interaction between structural genes and pleiotropic regulators is not mediated by CSRs.This strategy might be relevant for a growing number of CSR-free gene clusters unearthed during actinomycete genome mining.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics and Biotechnology, Ivan Franko National University of Lviv, Hrushevskoho st. 4, Lviv 79005, Ukraine.

ABSTRACT
Unlike the majority of actinomycete secondary metabolic pathways, the biosynthesis of peptidoglycan glycosyltransferase inhibitor moenomycin in Streptomyces ghanaensis does not involve any cluster-situated regulators (CSRs). This raises questions about the regulatory signals that initiate and sustain moenomycin production. We now show that three pleiotropic regulatory genes for Streptomyces morphogenesis and antibiotic production-bldA, adpA and absB-exert multi-layered control over moenomycin biosynthesis in native and heterologous producers. The bldA gene for tRNA(Leu)UAA is required for the translation of rare UUA codons within two key moenomycin biosynthetic genes (moe), moeO5 and moeE5. It also indirectly influences moenomycin production by controlling the translation of the UUA-containing adpA and, probably, other as-yet-unknown repressor gene(s). AdpA binds key moe promoters and activates them. Furthermore, AdpA interacts with the bldA promoter, thus impacting translation of bldA-dependent mRNAs-that of adpA and several moe genes. Both adpA expression and moenomycin production are increased in an absB-deficient background, most probably because AbsB normally limits adpA mRNA abundance through ribonucleolytic cleavage. Our work highlights an underappreciated strategy for secondary metabolism regulation, in which the interaction between structural genes and pleiotropic regulators is not mediated by CSRs. This strategy might be relevant for a growing number of CSR-free gene clusters unearthed during actinomycete genome mining.

Show MeSH
Related in: MedlinePlus