TY - JOUR
T1 - Discovery and Biosynthesis of Cihunamides, Macrocyclic Antibacterial RiPPs with a Unique C−N Linkage Formed by CYP450 Catalysis
AU - An, Joon Soo
AU - Lee, Hyunbin
AU - Kim, Hyungyu
AU - Woo, Seungyeon
AU - Nam, Hyunsung
AU - Lee, Jayho
AU - Lee, Ji Yun
AU - Nam, Sang Jip
AU - Lee, Sang Kook
AU - Oh, Ki Bong
AU - Kim, Seokhee
AU - Oh, Dong Chan
N1 - Publisher Copyright:
© 2023 Wiley-VCH GmbH.
PY - 2023/6/26
Y1 - 2023/6/26
N2 - Cihunamides A–D (1–4), novel antibacterial RiPPs, were isolated from volcanic-island-derived Streptomyces sp. The structures of 1–4 were elucidated by 1H, 13C, and 15N NMR, MS, and chemical derivatization; they contain a tetrapeptide core composed of WNIW, cyclized by a unique C−N linkage between two Trp units. Genome mining of the producer strain revealed two biosynthetic genes encoding a cytochrome P450 enzyme and a precursor peptide. Heterologous co-expression of the core genes demonstrated the biosynthesis of cihunamides through P450-mediated oxidative Trp-Trp cross-linking. Further bioinformatic analysis uncovered 252 homologous gene clusters, including that of tryptorubins, which possess a distinct Trp-Trp linkage. Cihunamides do not display the non-canonical atropisomerism shown in tryptorubins, which are the founding members of the “atropitide” family. Therefore, we propose to use a new RiPP family name, “bitryptides”, for cihunamides, tryptorubins, and their congeners, wherein the Trp-Trp linkages define the structural class rather than non-canonical atropisomerism.
AB - Cihunamides A–D (1–4), novel antibacterial RiPPs, were isolated from volcanic-island-derived Streptomyces sp. The structures of 1–4 were elucidated by 1H, 13C, and 15N NMR, MS, and chemical derivatization; they contain a tetrapeptide core composed of WNIW, cyclized by a unique C−N linkage between two Trp units. Genome mining of the producer strain revealed two biosynthetic genes encoding a cytochrome P450 enzyme and a precursor peptide. Heterologous co-expression of the core genes demonstrated the biosynthesis of cihunamides through P450-mediated oxidative Trp-Trp cross-linking. Further bioinformatic analysis uncovered 252 homologous gene clusters, including that of tryptorubins, which possess a distinct Trp-Trp linkage. Cihunamides do not display the non-canonical atropisomerism shown in tryptorubins, which are the founding members of the “atropitide” family. Therefore, we propose to use a new RiPP family name, “bitryptides”, for cihunamides, tryptorubins, and their congeners, wherein the Trp-Trp linkages define the structural class rather than non-canonical atropisomerism.
KW - Antibacterial Natural Products
KW - Biosynthesis
KW - Cytochrome P450 Enzymes
KW - RIPPs
KW - Structural Elucidation
UR - http://www.scopus.com/inward/record.url?scp=85159067671&partnerID=8YFLogxK
U2 - 10.1002/anie.202300998
DO - 10.1002/anie.202300998
M3 - Article
C2 - 37114290
AN - SCOPUS:85159067671
SN - 1433-7851
VL - 62
JO - Angewandte Chemie - International Edition
JF - Angewandte Chemie - International Edition
IS - 26
M1 - e202300998
ER -