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Multi-omics analysis of mutagenized S. rimosus reveals synergistic changes that drive oxytetracycline production towards industrial efficiency and opens a new route to heterologous polyketides

ABSTRACT: The present work provides a multi-omics systems-wide view on S. rimosus. Using genomics, transcriptomics, proteomics, and metabolomics, we compared the wild type with an OTC-overproducing derivative, previously obtained by classical mutagenesis. The integration of the data provided a deep insight into the underlying metabolic and regulatory networks that mediate high-level OTC formation. Strikingly, the overproducer revealed a synergistically activated supply of acetyl-CoA and malonyl CoA and increased abundance of various CoA thioesters.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Streptomyces Rimosus Subsp. Rimosus

SUBMITTER: Christian Rückert-Reed

LAB HEAD: Jörn Kalinowski

PROVIDER: PXD042182 | Pride | 2024-01-26

REPOSITORIES: Pride

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			Action	DRS
	2021-04-14_CR_P1.raw	Raw
	2021-04-14_CR_P2.raw	Raw
	2021-04-14_CR_P3.raw	Raw
	2021-04-14_CR_P4.raw	Raw
	2021-04-14_CR_P5.raw	Raw

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Publications

Systems biology of industrial oxytetracycline production in Streptomyces rimosus: the secrets of a mutagenized hyperproducer.

Beganovic Selma S Rückert-Reed Christian C Sucipto Hilda H Shu Wei W Gläser Lars L Patschkowski Thomas T Struck Ben B Kalinowski Jörn J Luzhetskyy Andriy A Wittmann Christoph C

Microbial cell factories 20231028 1

<h4>Background</h4>Oxytetracycline which is derived from Streptomyces rimosus, inhibits a wide range of bacteria and is industrially important. The underlying biosynthetic processes are complex and hinder rational engineering, so industrial manufacturing currently relies on classical mutants for production. While the biochemistry underlying oxytetracycline synthesis is known to involve polyketide synthase, hyperproducing strains of S. rimosus have not been extensively studied, limiting our knowl ...[more]

PMID: 37898787

Similar Datasets

Multi-omics analysis of mutagenized S. rimosus reveals synergistic changes that drive oxytetracycline production towards industrial efficiency and opens a new route to heterologous polyketides

Project description:The present work provides a multi-omics systems-wide view on S. rimosus. Using genomics, transcriptomics, proteomics, and metabolomics, we compared the wild type with an OTC-overproducing derivative, previously obtained by classical mutagenesis. The integration of the data provided a deep insight into the underlying metabolic and regulatory networks that mediate high-level OTC formation. Strikingly, the overproducer revealed a synergistically activated supply of acetyl-CoA and malonyl CoA and increased abundance of various CoA thioesters.

2023-05-16 | GSE232318 | GEO

Amino Acids Downregulate SIRT4 to Detoxify Ammonia through the Urea Cycle

Project description:Ammonia production via glutamate dehydrogenase is inhibited by SIRT4, a sirtuin that displays both amidase and non-amidase activities. The processes underlying the regulation of ammonia removal by amino acids remain unclear. Here, we report that SIRT4 acts as a decarbamylase that responds to amino acid sufficiency and regulates ammonia removal. Amino acids promote lysine 307 carbamylation (OTCCP-K307) of ornithine transcarbamylase (OTC), which activates OTC and the urea cycle. Proteomic and interactome screening identified OTC as a substrate of SIRT4. SIRT4 decarbamylates OTCCP-K307 and inactivates OTC in a NAD+-dependent manner. SIRT4 expression was transcriptionally upregulated by the amino acid insufficiency-activated GCN2–eIF2a–ATF4 axis. SIRT4 knockout in cultured cells caused higher OTCCP-K307 levels, activated OTC, elevated urea cycle intermediates, and urea production via amino acid catabolism. Sirt4 ablation decreased mouse blood ammonia levels and ameliorated CCl4-induced hepatic encephalopathy phenotypes. We reveal that SIRT4 safeguards cellular ammonia toxicity during amino acid catabolism.

2023-03-29 | PXD037101 | Pride

Determination of the transcription start sites of heterologous promoters in Actinoplanes sp. SE50/110 by 5'-end specific transcriptome sequencing

Project description:The promoter structure influences binding and clearance of RNA polymerase and therefore substantially influences expression of a gene. A promoter usually consists of a -10 and a -35-region, an extended -10-motif and A+T-rich upstream promoter elements. Most of these elements are optional, whereas the -10-region is essential (Albersmeier et al. 2017). Knowledge about the transcription start sites (TSS) of genes allows genome-wide localization and determination of the promoter regions. In our group, a special protocol for the amplification of primary transcripts was developed, including the capture of primary transcripts, rewriting them into cDNA (complementary DNA) and amplification in the further course of the protocol (Pfeifer-Sancar et al. 2013). Here, TSS were manually determined with special regard to the heterologous promoters. For each construct, at least one and up to three different TSS were found, leading to the identification of one or several -10-core-hexamers. These were located mostly 6 to 7 nucleotides upstream of each TSS, which corresponds to the average distance of 6.4 nt described for Actinoplanes sp. SE50/110 by Schwientek et al. (2014).

2019-10-26 | E-MTAB-8433 | biostudies-arrayexpress

Colobanthus quitensis differential proteomics

Project description:Global warming is strongly affecting the Maritime Antarctica climate and the consequent melting of perennial snow and ice covers resulted in increased colonization by plants. Colobanthus quitensis is a vascular plant highly adapted to the harsh environmental conditions of Antarctic Peninsula and understanding how the plant is responding to global warming is a new challenging target for modern cell physiology. To this aim, we performed differential proteomic analysis on C. quitensis plants grown in natural conditions compared to plants grown for one year inside Open Top Chambers (OTCs) which determine an increase of about 4 °C at midday, mimicking the effect of global warming. A thorough analysis of the up- and down-regulated proteins highlighted an extensive metabolism reprogramming leading to the hypothesis that (i) photorespiration could play an important role in reducing ROS-mediated photodamage improving OTC plants protection against photoinhibition; (ii) OTC plants activate stronger antioxidant defenses as confirmed by enzymatic activity and TBARS content measurement; (iii) the deposition of cell wall components is impaired in OTC plants due to the down-regulation of many enzymes involved in their biosyn-thesis; (iv) OTC plants could suffer of a reduced freezing tolerance due to lower concentration of soluble sugars acting as osmoprotectants.

2021-07-26 | PXD027038 | Pride

Genome wide H3K9ac and SAGA occupancy at OX growth phase and RC quiescent phase of yeast metabolic cycle

Project description:We found acetyl-CoA levels increase when cells are committed to growth. We also found 3 components of the SAGA complex, Spt7p, Sgf73p and Ada3p as well as histones are dynamically acetylated in tune with the acetyl-CoA levels. ChIP-seq study reveals SAGA and H3K9ac predominantly occupy growth genes at the OX growth phase of the yeast metabolic cycle indicating acetyl-CoA levels may drive growth gene transcription program through acetylation of these proteins. Examination of H3K9ac and SAGA binding over two timepoints using H3 and Input as controls

2011-05-19 | E-GEOD-28734 | biostudies-arrayexpress

Project description:OTC SDZ

| PRJNA879125 | ENA

Project description:OTC-AFM

| PRJNA988244 | ENA

Disease-linked lysine glutarylation impairs function and interactions of mitochondrial proteins and contribute to mitochondrial heterogeneity

Project description:Inherited deficiencies of the lysine and tryptophan catabolic pathways, due to mutations in the glutaryl-CoA-dehydrogenase (GCDH) gene, cause glutaric aciduria type 1 (GA1). In mammals two metabolic routes for L-lysine oxidation exist, the mitochondrial saccharopine pathway, which is predominant in extracerebral tissue and the peroxysomal/cytosolic pipecolate pathway, the main pathway in adult brain. A unique feature of all pathways is the formation of glutaryl-CoA that is converted into crotonyl-CoA via GCDH. In this study we identified increased lysine glutarylation, a novel reversible post-translational modification, in various tissues and cultured cells of Gcdh KO mice as a result of glutaryl-CoA accumulation. Our analysis revealed that glutarylation is widespread in mitochondria. By using a proteomic approach, we identified 37 and 154 glutarylated mitochondrial proteins in brain and liver tissue from Gcdh KO mice, respectively. We further showed that glutarylation supresses glutamate dehydrogenase (GDH) and carbonic anhydrase 5B activity, plus the direct interaction between GCDH and GDH.

2018-07-11 | PXD007881 | Pride

Elucidation of the biosynthesis pathway and heterologous construction of a sustainable route for producing umbelliferone.

Project description:BackgroundCoumarins play roles in many biological processes. Angelica decursiva is one of the major sources of coumarins in China. Due to increasing demand for coumarins in the marketplace, traditional extraction from plants is now considered economically insufficient and unsustainable. Microbial synthesis is a promising strategy for scalable production of coumarins. However, the biosynthetic pathway of coumarin remains poorly understood, and even more, the genes associated with this process have not been characterized in A. decursiva.ResultsRNA-seq was employed to elucidate the umbelliferone biosynthetic pathway. The results indicated that three enzymes, phenylalanine ammonia-lyase (PAL), 4-Coumarate: Coenzyme A Ligase (4CL), and p-coumaroyl CoA 2'-hydroxylase (C2'H) were involved in umbelliferone biosynthesis. Using the cloned genes, we generated a synthetic biology based microbial cell factory that produces coumarins from tyrosine utilizing Rhodotorula glutinis tyrosine ammonia lyase (RgTAL) to bypass cinnamic acid 4-hydroxylase (C4H). With metabolic engineering strategies, we deleted prephenate dehydratase (pheA), anthranilate synthase (trpE) and transcriptional regulatory protein (tyrR) and overexpressed six related genes involved in tyrosine biosynthesis, to drive the carbon flux from tyrosine. To overcome the limitation of 4CL, a virtual screening and site-specific mutagenesis-based protein engineering approach was applied. In addition, induction/culture conditions and different ions were employed to further improve the yield of umbelliferone. Finally, a yield of 356.59 mg/L umbelliferone was obtained.ConclusionsThe current study elucidated the umbelliferone biosynthesis pathway in A. decursiva. The results also demonstrated the feasibility of integrating gene mining with synthetic biology techniques to produce natural compounds.

| S-EPMC6530170 | biostudies-literature

Transcription profiling of tomato - organ specificity of wax biosynthesis

Project description:Fruits and leaves of the tomato (Solanum lycopersicum L.) cultivar MicroTom were investigated. MicroTom wild type and lecer6 mutant with a deficiency in a fatty acid beta-ketoacyl-CoA synthase (LeCER6) were used. The samples were composed of mature green, whole fruits with seeds being removed (fruit developmental category II). The locular tissue (gel) that surrounded the seeds and fills the locular cavity were detached. Otherwise, the samples contained fully developed leaves. After sampling point the plant material was immediately frozen in liquid nitrogen and stored at -80 C until use.

2009-06-09 | E-MEXP-2162 | biostudies-arrayexpress

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