An integrative-omics analysis of an industrial clavulanic acid-overproducing Streptomyces clavuligerus

Date

2022-09-01

Author

KURT KIZILDOĞAN, ASLIHAN
Celik, Gozde
unsaldi, Eser
ÖZCAN, SERVET
AYAZ GÜNER, ŞERİFE
Özcengiz, Gülay

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Clavulanic acid (CA) is a clinically important secondary metabolite used to treat infectious diseases. We aimed to decipher complex regulatory mechanisms acting in CA biosynthesis by analyzing transcriptome- and proteome-wide alterations in an industrial CA overproducer Streptomyces clavuligerus strain, namely DEPA and its wild-type counterpart NRRL3585. A total of 924 differentially expressed genes (DEGs) and 271 differentially produced proteins (DPPs) were obtained by RNA-seq and nanoLC-MS/MS analyses, respectively. In particular, CA biosynthetic genes, namely, car (cad), cast, oat2, pah, bls, ceas2, orf12, and claR, a cluster situated regulatory (CSR) gene, were significantly upregulated as shown by RNA-seq. Enzymes of clavam biosynthesis were downregulated considerably in the DEPA strain, while the genes involved in the arginine biosynthesis, one of the precursors of CA pathway, were overexpressed. However, the biosynthesis of the other CA precursor, glyceraldehyde-3-phosphate (G3P), was not affected. CA overproduction in the DEPA strain was correlated with BldD, BldG, BldM, and BldN (AdsA) overrepresentation. In addition, TetR, WhiB, and Xre family transcriptional regulators were shown to be significantly overrepresented. Several uncharacterized/unknown proteins differentially expressed in the DEPA strain await further studies for functional characterization. Correlation analysis indicated an acceptable degree of consistency between the transcriptome and proteome data. The study represents the first integrative-omics analysis in a CA overproducer S. clavuligerus strain, providing insights into the critical control points and potential rational engineering targets for a purposeful increase of CA yields in strain improvement.

Subject Keywords

Streptomyces clavuligerus DEPA, Clavulanic acid overproduction, RNA-seq, nanoLC-MS/MS, CEPHAMYCIN-C, SECONDARY METABOLISM, MORPHOLOGICAL-DIFFERENTIATION, BIOSYNTHESIS, PROTEIN, CCAR, EXPRESSION, STRAIN, GENE, REGULATOR

URI

https://hdl.handle.net/11511/99938

Journal

APPLIED MICROBIOLOGY AND BIOTECHNOLOGY

DOI

https://doi.org/10.1007/s00253-022-12098-4

Collections

Department of Biology, Article

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Citation Formats

A. KURT KIZILDOĞAN, G. Celik, E. unsaldi, S. ÖZCAN, Ş. AYAZ GÜNER, and G. Özcengiz, “An integrative-omics analysis of an industrial clavulanic acid-overproducing Streptomyces clavuligerus,” APPLIED MICROBIOLOGY AND BIOTECHNOLOGY, vol. 106, no. 18, pp. 6139–6156, 2022, Accessed: 00, 2022. [Online]. Available: https://hdl.handle.net/11511/99938.