Production of pikromycin using branched chain amino acid catabolism in <i>Streptomyces venezuelae</i> ATCC 15439

Yi, Jeong Sang; Kim, Minsuk; Kim, Eun-Jung; Kim, Byung‐Gee

doi:10.1007/s10295-018-2024-6

Cited by 20 publications

(13 citation statements)

References 43 publications

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“…A large number of CoA products, such as acetyl-CoA and propanyl-CoA can be produced in the process of amino acid metabolism. These substances act as precursors to secondary metabolites, especially compounds synthesized by the polyketonase pathway [38]. In this study, we demonstrated that the supplementation of L-Val influenced the biosynthesis of natamycin and fermentation process of S. natalensis HW-2.…”

Section: Discussionmentioning

confidence: 59%

“…The elicitor could either directly influence the transcription of the secondary metabolite gene clusters or induce a transcriptional activator of the target gene cluster [33]. There were some researches about activating silent gene clusters in fungi and myxobacteria, but the report about the activation of gene clusters in actinomycetes by elicitation method was little known [22,38]. Our previous studies found the addition of fungal elicitors from P.chrysogenum influenced the morphology of the colony and mycelium of S. and 316 down-regulated DEGs.…”

Section: Discussionmentioning

confidence: 99%

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Transcriptome analysis of the regulation of natamycin biosynthesis in Streptomyces natalensis HW-2 by fungal elicitor

Wang

Shen

Yuan

et al. 2019

Preprint

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Background Natamycin is a polyene macrolide polyketide antibiotics and used in 150 countries as a natural food preservative. Streptomyces natalensis is an important producer. Elicitation had been approved to be an effective method to improve the biosynthesis of secondary metabolites. Fungal elicitor from Penicillium chrysogenum AS 3.5163 showed inductive effect on the biosynthesis of natamycin in S. natalensis HW-2 fermentation. However, regarding the global gene expression of natamycin in response to fungal elicitor is not still reported. Results RNA-Seq analysis showed that there were 1265 differential expression genes (DEGs) at 40 h and 2196 DEGs at 80 h. The fungal elicitor had stronger effects on the transcription level of S. natalensis HW-2 at 80 h than that at 40 h. Gene Ontology (GO) enrichment analysis of DEGs showed significant enrichment in biological processes. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the fungal elicitor mainly affected the expression levels of some genes about cellular process, metabolism and genetic information, especially in pentose phosphate pathway (PPP), glycolytic pathway (EMP) and tricarboxylic acid cycle (TCA). KEGG pathway showed that fungal elicitor had a greater influence on the metabolism of branched-chain amino acids (BCAAs). Among them, 23 DEGs associated with BCAAs metabolism were up-regulated or down-regulated. The supplementation experiment with BCAAs confirmed that 0.2 g/L of L-Ile and 0.5 g/L of L-Val increased natamycin yield by 17.6% and 37.8%, respectively. Fungal elicitor also up-regulated the transcriptional levels of most of the enzymes associated with the biosynthesis of natamycin and two important transcription regulators ( pimR and pimM ). To confirm the accuracy of RNA-Seq, the results of qPCR showed that these gene expression levels were in agreement with the transcription changes by RNA-Seq. Conclusion In this study, the change of transcriptional levels in S. natalensis HW-2 under treated with the fungal elicitor was firstly reported. The major finding of our comparative transcriptome analysis is that the fungal elicitor improves the supply of precursor, and alters the expression of natamycin related genes and regulator of secondary metabolism. From our results, we conclude that regulatory alterations are important factors for the enhancement of natamycin.

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Section: Discussionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Transcriptome analysis of the regulation of natamycin biosynthesis in Streptomyces natalensis HW-2 by fungal elicitor

Wang

Shen

Yuan

et al. 2019

Preprint

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“…The list of genes whose expression was up-regulated in maltose but not in glucose-supplemented cultures before the onset of tacrolimus biosynthesis suggested a metabolic rewiring resulting into the accumulation of tacrolimus biosynthetic precursors. Besides both catalase encoding genes ( STSU_10876 and STSU_11535 ), this list includes genes encoding enzymes involved in branched chain amino acid (BCAA) catabolism ( STSU_03489 , STSU_09964 , STSU_23681 , STSU_23686 , STSU_23691 , STSU_23866 ) whose up-regulation would increase the availability of methylmalonyl-CoA [ 35 ]. For instance, the overexpression of STSU_23866 in S. tsukubaensis led to an 29% increase in tacrolimus production [ 36 ].…”

Section: Resultsmentioning

confidence: 99%

The Onset of Tacrolimus Biosynthesis in Streptomyces tsukubaensis Is Dependent on the Intracellular Redox Status

et al. 2020

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The oxidative stress response is a key mechanism that microorganisms have to adapt to changeling environmental conditions. Adaptation is achieved by a fine-tuned molecular response that extends its influence to primary and secondary metabolism. In the past, the role of the intracellular redox status in the biosynthesis of tacrolimus in Streptomyces tsukubaensis has been briefly acknowledged. Here, we investigate the impact of the oxidative stress response on tacrolimus biosynthesis in S. tsukubaensis. Physiological characterization of S. tsukubaensis showed that the onset of tacrolimus biosynthesis coincided with the induction of catalase activity. In addition, tacrolimus displays antioxidant properties and thus a controlled redox environment would be beneficial for its biosynthesis. In addition, S. tsukubaensis ∆ahpC strain, a strain defective in the H2O2-scavenging enzyme AhpC, showed increased production of tacrolimus. Proteomic and transcriptomic studies revealed that the tacrolimus over-production phenotype was correlated with a metabolic rewiring leading to increased availability of tacrolimus biosynthetic precursors. Altogether, our results suggest that the carbon source, mainly used for cell growth, can trigger the production of tacrolimus by modulating the oxidative metabolism to favour a low oxidizing intracellular environment and redirecting the metabolic flux towards the increase availability of biosynthetic precursors.

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“…Similarly, such approaches for enriching the acyl-CoA precursors have been used for an elevated level of diverse macrolides (Table 1). Recently, various engineering strategies for directing the catabolism of branched-chain amino acids (BCAA) into various acyl-CoA compounds has extended the opportunities for metabolic engineering of acyl-CoA pathways and yield improvement of macrolides [83].…”

Section: Metabolic Engineering Approaches In Actinomycetes For Macrolmentioning

confidence: 99%

Engineering actinomycetes for biosynthesis of macrolactone polyketides

2019

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Actinobacteria are characterized as the most prominent producer of natural products (NPs) with pharmaceutical importance. The production of NPs from these actinobacteria is associated with particular biosynthetic gene clusters (BGCs) in these microorganisms. The majority of these BGCs include polyketide synthase (PKS) or non-ribosomal peptide synthase (NRPS) or a combination of both PKS and NRPS. Macrolides compounds contain a core macro-lactone ring (aglycone) decorated with diverse functional groups in their chemical structures. The aglycon is generated by megaenzyme polyketide synthases (PKSs) from diverse acyl-CoA as precursor substrates. Further, post-PKS enzymes are responsible for allocating the structural diversity and functional characteristics for their biological activities. Macrolides are biologically important for their uses in therapeutics as antibiotics, anti-tumor agents, immunosuppressants, anti-parasites and many more. Thus, precise genetic/metabolic engineering of actinobacteria along with the application of various chemical/biological approaches have made it plausible for production of macrolides in industrial scale or generation of their novel derivatives with more effective biological properties. In this review, we have discussed versatile approaches for generating a wide range of macrolide structures by engineering the PKS and post-PKS cascades at either enzyme or cellular level in actinobacteria species, either the native or heterologous producer strains.

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Production of pikromycin using branched chain amino acid catabolism in Streptomyces venezuelae ATCC 15439

Cited by 20 publications

References 43 publications

Transcriptome analysis of the regulation of natamycin biosynthesis in Streptomyces natalensis HW-2 by fungal elicitor

Transcriptome analysis of the regulation of natamycin biosynthesis in Streptomyces natalensis HW-2 by fungal elicitor

The Onset of Tacrolimus Biosynthesis in Streptomyces tsukubaensis Is Dependent on the Intracellular Redox Status

Engineering actinomycetes for biosynthesis of macrolactone polyketides

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