Systems perspectives on erythromycin biosynthesis by comparative genomic and transcriptomic analyses of S. erythraea E3 and NRRL23338 strains

Li, Yuanyuan; Chang, Xiao; Yu, Wen-Bang; Li, Hao; Ye, Zhiqiang; Yu, Hui; Liu, Baohong; Zhang, Yan; Zhang, Siliang; Ye, Bang‐Ce; Li, Yixue

doi:10.1186/1471-2164-14-523

Cited by 39 publications

(66 citation statements)

References 61 publications

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“…Saccharopolyspora erythraea is a significant industrial producer of broad-spectrum macrolide antibiotic erythromycin. In recent years, many efforts have been made to explore the mechanism of high-yield erythromycin producer (Carata et al 2009;Marcellin et al 2013;Li et al 2013). One of these mechanisms may include the two-component system (TCS), which is one of the most important signal transduction systems in Streptomyces.…”

Section: Discussionmentioning

confidence: 99%

A two-component system gene SACE_0101 regulates copper homeostasis in Saccharopolyspora erythraea

Qiao

et al. 2020

Bioresour. Bioprocess.

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Background: Saccharopolyspora erythraea (S. erythraea) is a Gram-positive bacterium widely used for the production of erythromycin, a potent macrolide antibiotic. However, the mechanism behind erythromycin production is poorly understood. In the high erythromycin-producer strain S. erythraea HL3168 E3, the level of copper ions positively correlates with erythromycin production. To explain this correlation, we performed a genome-based comparison between the wild-type strain NRRL23338 and the mutant strain HL3168 E3, and further characterized the identified gene(s) by targeted genome editing, mRNA transcript analysis, and functional analysis. Results:The response regulator of the two-component system (TCS) encoded by the gene SACE_0101 in S. erythraea showed high similarity with CopR of TCS CopRS in Streptomyces coelicolor, which is involved in the regulation of copper metabolism. The deletion of SACE_0101 was beneficial for erythromycin synthesis most likely by causing changes in the intracellular copper homeostasis, leading to enhanced erythromycin production. In addition, Cu 2+ supplementation and gene expression analysis suggested that SACE_0101 may be involved in the regulation of copper homeostasis and erythromycin production. Conclusions:The mutation of SACE_0101 gene increased the yield of erythromycin, especially upon the addition of copper ions. Therefore, the two-component system gene SACE_0101 plays a crucial role in regulating copper homeostasis and erythromycin synthesis in S. erythraea.

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Section: Discussionmentioning

confidence: 99%

A two-component system gene SACE_0101 regulates copper homeostasis in Saccharopolyspora erythraea

Qiao

et al. 2020

Bioresour. Bioprocess.

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“…In the past decade, many studies have been performed to investigate the relationships among cell growth, erythromycin formation, medium compositions, morphogenesis,and process conditions (Chen et al, 2008(Chen et al, , 2013Li et al, 2013;Wang et al, 2007;Wu et al, 2011;Yin et al, 2013) and to explore the functional genes and transcriptional regulations in S. erythraea (Chen et al, 2008;Li et al, 2013;Wu et al, 2011). However, knowledge on the metabolism of S. erythraea is still limited.…”

Section: Introductionmentioning

confidence: 99%

Impacts of proline on the central metabolism of an industrial erythromycin-producing strain Saccharopolyspora erythraea via 13 C labeling experiments

Hong

Huang

Chu

et al. 2016

Journal of Biotechnology

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“…As the starter unit of erythromycin production, the metabolic fluxes of propionyl-CoA and (S)-methyl-malonyl-CoA are very important for the production of erythromycin. In S. erythraea, the propionyl-CoA carboxylase (PCC) pathway and the methylmalonyl-CoA mutase (MCM) pathway are found to play an important role in the precursor supply (11,38,39). Engineering the methylmalonyl-CoA flow has already been proved to be helpful for increasing erythromycin production (38,40,41).…”

Section: Figmentioning

confidence: 99%

“…Branched-chain amino acids have long been known as an important source of a range of different polyketide precursors, such as propionyl-CoA and methylmalonyl-CoA (1)(2)(3)(4)(5)(6)(7)(8). Some genes involved in the branched-chain amino acid synthesis and degradation pathway, such as ilvB (SACE_4565), acd (SACE_4125 and SACE_5025), and mmsA (SACE_4672), are significantly upregulated in industrial high-erythromycinproducing strains (11,12). Thus, upregulating the metabolic pathways of BCAAs can improve the yield of erythromycin (12,13).…”

Section: Figmentioning

confidence: 99%

PccD Regulates Branched-Chain Amino Acid Degradation and Exerts a Negative Effect on Erythromycin Production in Saccharopolyspora erythraea

Liu

2018

Appl Environ Microbiol

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Branched-chain amino acid (BCAA) degradation is a major source of propionyl coenzyme A (propionyl-CoA), a key precursor of erythromycin biosynthesis in In this study, we found that the operon, responsible for BCAA degradation, was regulated directly by PccD, a transcriptional regulator of propionyl-CoA carboxylase genes. The transcriptional level of the operon was upregulated 5-fold in a gene deletion strain (Δ strain) and decreased 3-fold in a overexpression strain (WT/pIB-), demonstrating that PccD was a negative transcriptional regulator of the operon. The deletion of significantly improved the Δ strain's growth rate, whereas overexpression repressed WT/pIB- growth rate, in basic Evans medium with 30 mM valine as the sole carbon and nitrogen source. The deletion of and the BcdhE1 gene (genes in the operon) resulted in lower growth rates of Δ and ΔBcdhE1 strains, respectively, on 30 mM valine, further suggesting that the operon is involved in BCAA degradation. Both overexpression (WT/pIB-) and inactivation (Δ strain) improve erythromycin production (38% and 64%, respectively), whereas the erythromycin production of strain WT/pIB- was decreased by 48%. Lastly, we explored the applications of engineering and in an industrial high-erythromycin-producing strain. deletion in industrial strain E3 (E3) improved erythromycin production by 20%, and the overexpression of in E3Δ (E3Δ/pIB-) increased erythromycin production by 39% compared with E3 in an industrial fermentation medium. Addition of 30 mM valine to industrial fermentation medium further improved the erythromycin production by 23%, a 72% increase from the initial strain E3. We describe a operon involved in BCAA degradation in The genes of the operon are repressed by a TetR regulator, PccD. The results demonstrated that PccD controlled the supply of precursors for biosynthesis of erythromycin via regulating the BCAA degradation and propionyl-CoA assimilation and exerted a negative effect on erythromycin production. The findings reveal a regulatory mechanism in feeder pathways and provide new strategies for designing metabolic engineering to increase erythromycin yield.

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Systems perspectives on erythromycin biosynthesis by comparative genomic and transcriptomic analyses of S. erythraea E3 and NRRL23338 strains

Cited by 39 publications

References 61 publications

A two-component system gene SACE_0101 regulates copper homeostasis in Saccharopolyspora erythraea

A two-component system gene SACE_0101 regulates copper homeostasis in Saccharopolyspora erythraea

Impacts of proline on the central metabolism of an industrial erythromycin-producing strain Saccharopolyspora erythraea via 13 C labeling experiments

PccD Regulates Branched-Chain Amino Acid Degradation and Exerts a Negative Effect on Erythromycin Production in Saccharopolyspora erythraea

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