Targeted and Logical Discovery of Piperazic Acid-Bearing Natural Products Based on Genomic and Spectroscopic Signatures
- 주제(기타) Chemistry, Multidisciplinary
- 설명문(일반) [Shin, Daniel; Byun, Woong Sub; Kang, Sangwook; Bae, Eun Seo; An, Joon Soo; Im, Ji Hyeon; Park, Jiyoon; Kim, Eunji; Ko, Keebeom; Hwang, Sunghoon; Yoon, Yeo Joon; Lee, Sang Kook; Oh, Dong-Chan] Seoul Natl Univ, Nat Prod Res Inst, Coll Pharm, Seoul 08826, South Korea; [Kang, Ilnam; Hong, Suckchang; Cho, Jang-Cheon] Inha Univ, Dept Biol Sci, Incheon 22212, South Korea; [Lee, Honghui; Hong, Suckchang] Seoul Natl Univ, Nat Prod Res Inst, Seoul 08826, South Korea; [Lee, Honghui; Hong, Suckchang] Seoul Natl Univ, Res Inst Pharmaceut Sci, Coll Pharm, Seoul 08826, South Korea; [Kwon, Yun] Kyungpook Natl Univ, Res Inst Pharmaceut Sci, Coll Pharm, Daegu 41566, South Korea; [Ko, Yoon-Joo] Seoul Natl Univ, Natl Ctr Interuniv Res Facil NCIRF, Lab Nucl Magnet Resonance, Seoul 08826, South Korea; [Nam, Sang-Jip] Ewha Womans Univ, Dept Chem & Nanosci, Seoul 03760, South Korea; [Kim, Seung Bum] Chungnam Natl Univ, Coll Biosci & Biotechnol, Dept Microbiol & Mol Biol, Daejeon 34134, South Korea; [Fenical, William] Univ Calif San Diego, Ctr Marine Biotechnol & Biomed, Scripps Inst Oceanog, La Jolla, CA 92093 USA; [Fenical, William] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USA; [Yoon, Yeo Joon] MolGenBio Co Ltd, Seoul 08826, South Korea
- 등재 SCIE, SCOPUS
- 발행기관 AMER CHEMICAL SOC
- 발행년도 2023
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000211601
- 본문언어 영어
- Published As https://doi.org/10.1021/jacs.3c04699
- PubMed 37642383
초록/요약
A targeted and logical discovery method was devised for natural products containing piperazic acid (Piz), which is biosynthesized from ornithine by L-ornithine N- hydroxylase (KtzI) and N-N bond formation enzyme (KtzT). Genomic signature-based screening of a bacterial DNA library (2020 strains) using polymerase chain reaction (PCR) primers targeting ktzT identified 62 strains (3.1%). The PCR amplicons of KtzT-encoding genes were phylogenetically analyzed to classify the 23 clades into two monophyletic groups, I and II. Cultivating hit strains in media supplemented with (NH4Cl)-N-15 and applying H-1-N-15 heteronuclear multiple bond correlation (HMBC) along with H-1-N-15 heteronuclear single quantum coherence (HSQC) and H-1-N-15 HSQC-total correlation spectroscopy (HSQCTOCSY) NMR experiments detected the spectroscopic signatures of Piz and modified Piz. Chemical investigation of the hit strains prioritized by genomic and spectroscopic signatures led to the identification of a new azinothricin congener, polyoxyperuin B seco acid (1), previously reported chloptosin (2) in group I, depsidomycin D (3) incorporating two dehydropiperazic acids (Dpz), and lenziamides A and B (4 and 5), structurally novel 31-membered cyclic decapeptides in group II. By consolidating the phylogenetic and chemical analyses, clade-structure relationships were elucidated for 19 of the 23 clades. Lenziamide A (4) inhibited STAT3 activation and induced G(2)/M cell cycle arrest, apoptotic cell death, and tumor growth suppression in human colorectal cancer cells. Moreover, lenziamide A (4) resensitized 5-fluorouracil (5-FU) activity in both in vitro cell cultures and the in vivo 5-FU-resistant tumor xenograft mouse model. This work demonstrates that the genomic and spectroscopic signature-based searches provide an efficient and general strategy for new bioactive natural products containing specific structural motifs.
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