TY - JOUR
T1 - A ribosomally synthesised and post-translationally modified peptide containing a beta-enamino acid and a macrocyclic motif
AU - Wang, Shan
AU - Lin, Sixing
AU - Fang, Qing
AU - Gyampoh, Roland
AU - Lu, Zhou
AU - Gao, Yingli
AU - Clarke, David J.
AU - Wu, Kewen
AU - Trembleau, Laurent
AU - Yu, Yi
AU - Kyeremeh, Kwaku
AU - Milne, Bruce F.
AU - Tabudravu, Jioji
AU - Deng, Hai
N1 - Funding Information:
This work received financial support from Biotechnology and Biological Sciences Research Council UK (S.W. and H.D., BB/P00380X/1 and BB/R00479X/1, D.J.C., BB/R013993/1), Scottish Funding Council Covid-19 Grant extension and Bridging Fund (S.W. and H.D.); UKRI Covid-19 Extension Allocation Fund (S.W. and H.D.); The Elphinstone Scholarship of University of Aberdeen (QF), Leverhulme Trust-Royal Society Africa award (AA090088) and the jointly funded UK Medical Research Council UK Department for International Development (MRC/DFID) Concordat agreement African Research Leaders Award (MR/S00520X/1 to K.K. and H.D.), and National Natural Science Foundation of China (31570033, 31811530299, and 31870035 to Y.Y., 31929001 to H.D.), and the Royal Society-NSFC Newton Mobility Grant Award (IEC\NSFC\170617 to H.D. and Y.Y.). B.F.M. thanks the Portuguese Foundation for Science and Technology for financial support (POCI-01-0145-FEDER-032229 and CENTRO-01-0145-FEDER-000014, 2017-2020). H.D. and S.W. thank Professor Brady Moore in the Scripps Institute of Oceanography, University of San Diego, USA, for the gift of pCAP003 plasmid, Dr. Vladimir Larionov in National Cancer Institute, National Institute of Health, Bethesda, USA for the gift of Sacharomyces cerevisiae VL6-48N strain, Dr Juan-Pablo Gomez-Escribano and Professor Mervyn Bibb in John Innes Centre, UK for the gift of Streptomyces coelicolor M1152, and Samantha Law and Carol Philips in NCIMB Ltd (UK) for the kind gift of Streptomyces kurssanovii NCIMB12788.
Funding Information:
This work received financial support from Biotechnology and Biological Sciences Research Council UK (S.W. and H.D., BB/P00380X/1 and BB/R00479X/1, D.J.C., BB/R013993/1), Scottish Funding Council Covid-19 Grant extension and Bridging Fund (S.W. and H.D.); UKRI Covid-19 Extension Allocation Fund (S.W. and H.D.); The Elphinstone Scholarship of University of Aberdeen (QF), Leverhulme Trust-Royal Society Africa award (AA090088) and the jointly funded UK Medical Research Council UK Department for International Development (MRC/DFID) Concordat agreement African Research Leaders Award (MR/S00520X/1 to K.K. and H.D.), and National Natural Science Foundation of China (31570033, 31811530299, and 31870035 to Y.Y., 31929001 to H.D.), and the Royal Society-NSFC Newton Mobility Grant Award (IEC\NSFC\170617 to H.D. and Y.Y.). B.F.M. thanks the Portuguese Foundation for Science and Technology for financial support (POCI-01-0145-FEDER-032229 and CENTRO-01-0145-FEDER-000014, 2017-2020). H.D. and S.W. thank Professor Brady Moore in the Scripps Institute of Oceanography, University of San Diego, USA, for the gift of pCAP003 plasmid, Dr. Vladimir Larionov in National Cancer Institute, National Institute of Health, Bethesda, USA for the gift of Sacharomyces cerevisiae VL6-48N strain, Dr Juan-Pablo Gomez-Escribano and Professor Mervyn Bibb in John Innes Centre, UK for the gift of Streptomyces coelicolor M1152, and Samantha Law and Carol Philips in NCIMB Ltd (UK) for the kind gift of Streptomyces kurssanovii NCIMB12788.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/8/26
Y1 - 2022/8/26
N2 - Ribosomally synthesized and post-translationally modified peptides (RiPPs) are structurally complex natural products with diverse bioactivities. Here we report discovery of a RiPP, kintamdin, for which the structure is determined through spectroscopy, spectrometry and genomic analysis to feature a bis-thioether macrocyclic ring and a β-enamino acid residue. Biosynthetic investigation demonstrated that its pathway relies on four dedicated proteins: phosphotransferase KinD, Lyase KinC, kinase homolog KinH and flavoprotein KinI, which share low homologues to enzymes known in other RiPP biosynthesis. During the posttranslational modifications, KinCD is responsible for the formation of the characteristic dehydroamino acid residues including the β-enamino acid residue, followed by oxidative decarboxylation on the C-terminal Cys and subsequent cyclization to provide the bis-thioether ring moiety mediated by coordinated action of KinH and KinI. Finally, conserved genomic investigation allows further identification of two kintamdin-like peptides among the kin-like BGCs, suggesting the occurrence of RiPPs from actinobacteria.
AB - Ribosomally synthesized and post-translationally modified peptides (RiPPs) are structurally complex natural products with diverse bioactivities. Here we report discovery of a RiPP, kintamdin, for which the structure is determined through spectroscopy, spectrometry and genomic analysis to feature a bis-thioether macrocyclic ring and a β-enamino acid residue. Biosynthetic investigation demonstrated that its pathway relies on four dedicated proteins: phosphotransferase KinD, Lyase KinC, kinase homolog KinH and flavoprotein KinI, which share low homologues to enzymes known in other RiPP biosynthesis. During the posttranslational modifications, KinCD is responsible for the formation of the characteristic dehydroamino acid residues including the β-enamino acid residue, followed by oxidative decarboxylation on the C-terminal Cys and subsequent cyclization to provide the bis-thioether ring moiety mediated by coordinated action of KinH and KinI. Finally, conserved genomic investigation allows further identification of two kintamdin-like peptides among the kin-like BGCs, suggesting the occurrence of RiPPs from actinobacteria.
U2 - 10.1038/s41467-022-32774-3
DO - 10.1038/s41467-022-32774-3
M3 - Article
C2 - 36028509
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
ER -