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J. Am. Chem. Soc., Sep 27 2023 | https://doi.org/10.1021/jacs.3c07140
Exploring the Diverse Landscape of Biaryl-Containing Peptides Generated by Cytochrome P450 Macrocyclases.
Hyunsung Nama,#, Joon Soo Anb,#, Jaepil Leec, Yonghwan Yund, Hyunbin Leea, Hyungou Parka, Yousung Jungd, Ki-Bong Ohc, Dong-Chan Oh*,b, Seokhee Kim*,a,b
aDepartment of Chemistry, bNatural Products Research Institute, College of Pharmacy, cDepartment of Agricultural Biotechnology, College of Agriculture and Life Sciences, dSchool of Chemical and Biological Engineering, and Institute of Chemical Processes, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Republic of Korea
*Corresponding authors: Dong-Chan Oh, Seokhee Kim
#These authors contributed equally to this work.
Abstract
Cytochrome P450 enzymes (P450s) catalyze diverse oxidative cross-coupling reactions between aromatic substrates in the natural product biosynthesis. Specifically, P450s install distinct biaryl macrocyclic linkages in three families of ribosomally synthesized and post-translationally modified peptides (RiPPs). However, the chemical diversity of biaryl-containing macrocyclic RiPPs remains largely unexplored. Here, we demonstrate that P450s have the capability to generate diverse biaryl linkages on RiPPs, collectively named "cyptides". Homology-based genome mining for P450 macrocyclases revealed 19 novel groups of homologous biosynthetic gene clusters (BGCs) with distinct aromatic residue patterns in the precursor peptides. Using the P450-modified precursor peptides heterologously coexpressed with corresponding P450s in
Escherichia coli, we determined the NMR structures of three novel biaryl-containing peptides─the enzymatic products, roseovertin (
1), rubrin (
2), and lapparbin (
3)─and confirmed the formation of three unprecedented or rare biaryl linkages: Trp C-7'-to-His N-τ in
1, Trp C-7'-to-Tyr C-6 in
2, and Tyr C-6-to-Trp N-1' in
3. Biochemical characterization indicated that certain P450s in these pathways have a relaxed substrate specificity. Overall, our studies suggest that P450 macrocyclases have evolved to create diverse biaryl linkages in RiPPs, promoting the exploration of a broader chemical space for biaryl-containing peptides encoded in bacterial genomes.
논문정보
- Research article
- 2023년 09월 (BRIC 등록일 2023-10-10)
- 국내 연구진
- 생명과학 > 생화학
관련 보도자료
사이토크롬 P450 거대고리화 효소에 의한 다양화된 바이아릴 구조 함유 펩타이드 탐색
서울대는 화학부 김석희 교수 연구진(천연물과학연구소 겸무)과 천연과학연구소 오동찬 교수 연구진이 P450 펩타이드 거대고리화 효소의 다양성을 생물정보 분석으로 크게 확장하고 그 결과물인 거대고리 펩타이드 구조를 규명하였다고 보고하였다. 이 연구는 서울대 오기봉 교수 연구진, 정유성 교수 연구진과 공동으로 수행했으며, 화학 분야 저명 학술지인 미국화학회지 (Journal of the American Chemical Society, 피인용지수 15.0)에 ‘Exploring the Diverse Landscape of Biaryl-Containing Peptides Generated by Cytochrome P450 Macrocylcases’라는 제목으로 게재되었다. (https://doi.org/10.1021/jacs.3c07140, 공동 제1저자: 서울대학교 남현성 연구원, 안준수 박사, 교신저자: 서울대학교 김석희 교수, 오동찬 교수)
- Bio통신원
- 2023. 10. 12
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