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


KURT KIZILDOĞAN A., Celik G., unsaldi E., ÖZCAN S., AYAZ GÜNER Ş., ÖZCENGİZ G.

APPLIED MICROBIOLOGY AND BIOTECHNOLOGY, vol.106, no.18, pp.6139-6156, 2022 (SCI-Expanded) identifier identifier

  • Publication Type: Article / Article
  • Volume: 106 Issue: 18
  • Publication Date: 2022
  • Doi Number: 10.1007/s00253-022-12098-4
  • Journal Name: APPLIED MICROBIOLOGY AND BIOTECHNOLOGY
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, ABI/INFORM, Applied Science & Technology Source, Aqualine, Aquatic Science & Fisheries Abstracts (ASFA), BIOSIS, Biotechnology Research Abstracts, CAB Abstracts, Chemical Abstracts Core, Compendex, Computer & Applied Sciences, EMBASE, Environment Index, Food Science & Technology Abstracts, Geobase, MEDLINE, Pollution Abstracts, Veterinary Science Database
  • Page Numbers: pp.6139-6156
  • 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
  • Abdullah Gül University Affiliated: Yes

Abstract

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.