Systems metabolic engineering of Streptomyces venezuelae for the enhanced production of pikromycin

Min Kyung Cho, Byung Tae Lee, Hyun Uk Kim, Min Kyu Oh

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)


Pikromycin is an important precursor of drugs, for example, erythromycin. Hence, systems metabolic engineering for the enhanced pikromycin production can contribute to the development of pikromycin-related drugs. In this study, metabolic genes in Streptomyces venezuelae were systematically engineered for enhanced pikromycin production. For this, a genome-scale metabolic model of S. venezuelae was reconstructed and simulated, which led to the selection of 11 metabolic gene targets. These metabolic genes, including four overexpression targets and seven knockdown targets, were individually engineered first. Next, two overexpression targets and two knockdown targets were selected based on the 11 strains' production performances to engineer two to four of these genes together for the potential synergistic effects on the pikromycin production. As a result, the NM1 strain with AQF52_RS24510 (methenyltetrahydrofolate cyclohydrolase/methylenetetrahydrofolate dehydrogenase) overexpression and AQF52_RS30320 (sulfite reductase) knockdown showed the best production performance among all the 22 strains constructed in this study. Fed-batch fermentation of the NM1 strain produced 295.25 mg/L of pikromycin, by far the best production titer using the native producer S. venezuelae, to the best of our knowledge. The systems metabolic engineering strategy demonstrated herein can also be applied to the overproduction of other secondary metabolites using S. venezuelae.

Original languageEnglish
Pages (from-to)2250-2260
Number of pages11
JournalBiotechnology and Bioengineering
Issue number8
Publication statusPublished - 2022 Aug

Bibliographical note

Funding Information:
This study was supported by the Bio & Medical Technology Development Program (NRF‐2018M3A9F3079662 and NRF‐2018M3A9F3079664) from the Ministry of Science and ICT (MSIT) through the National Research Foundation of Korea (NRF). This study was also carried out with the support of “Cooperative Research Program for Agriculture Science and Technology Development (Project No. PJ01577901)” from Rural Development Administration, Republic of Korea.

Publisher Copyright:
© 2022 Wiley Periodicals LLC.


  • Streptomyces venezuelae
  • gene manipulation targets
  • genome-scale metabolic model
  • pikromycin
  • systems metabolic engineering

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Applied Microbiology and Biotechnology


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