Journal
FRONTIERS IN MICROBIOLOGY
Volume 12, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fmicb.2021.626881
Keywords
ohmyungsamycin; non-ribosomal peptide synthetase; adenylation domain engineering; site-directed mutagenesis; culture condition optimization
Categories
Funding
- Collaborative Genome Program of the Korea Institute of Marine Science and Technology Promotion (KIMST) - Ministry of Oceans and Fisheries (MOF) [20180430]
- National Research Foundation of Korea (NRF) - Ministry of Science and ICT (MSIT) [2019R1A2B5B03069338, 2018R1A4A1021703]
- Bio and Medical Technology Development Program of the NRF - MSIT [2018M3A9F3079662]
- National Research Foundation of Korea [2018M3A9F3079662, 2019R1A2B5B03069338] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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OMS A displays greater potency against Mycobacterium tuberculosis and human cancer cells compared to OMS B, with substrate promiscuous adenylation domain in the second module of OMS synthetase playing a key role in the synthesis process.
Ohmyungsamycins (OMSs) A and B are cyclic depsipeptides produced by marine Streptomyces strains, which are synthesized by a non-ribosomal peptide synthetase. Notably, OMS A exhibits more potent activity against Mycobacterium tuberculosis and human cancer cells than OMS B. The substrate promiscuous adenylation (A) domain in the second module of OMS synthetase recruits either L-Val or L-Ile to synthesize OMSs A and B, respectively. Engineering of the substrate-coding residues of this A domain increased OMS A production by 1.2-fold, coupled with a drastic decrease in OMS B production. Furthermore, the culture conditions (sea salt concentration, inoculum size, and the supply of amino acids to serve as building blocks for OMS) were optimized for OMS production in the wild-type strain. Finally, cultivation of the A2-domain-engineered strain under the optimized culture conditions resulted in up to 3.8-fold increases in OMS A yields and an 8.4-fold decrease in OMS B production compared to the wild-type strain under the initial culture conditions.
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