Discovery of unusual dimeric piperazyl cyclopeptides encoded by a Lentzea flaviverrucosa DSM 44664 biosynthetic supercluster

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dc.citation.titleProceedings of the National Academy of Sciences
dc.citation.volume119(17)
dc.contributor.orcidhttps://orcid.org/0000-0002-3134-8224
dc.contributor.orcidhttps://orcid.org/0000-0002-0150-1777
dc.contributor.orcidhttps://orcid.org/0000-0002-8991-716X
dc.contributor.orcidhttps://orcid.org/0000-0002-8151-0306
dc.contributor.orcidhttps://orcid.org/0000-0001-6684-8221
dc.contributor.orcidhttps://orcid.org/0000-0002-7080-5870
dc.creatorLi, Chun-shun
dc.creatorHuc, Yifei
dc.creatorWua, Xiaohua
dc.creatorStumpf, Spencer D.
dc.creatorQic, Yunci
dc.creatorD’Alessandro, John M.
dc.creatorNepal, Keshav K.
dc.creatorSarotti, Ariel Marcelo
dc.creatorCao, Shugeng
dc.creatorBlodgett, Joshua A. V.
dc.date.accessioned2025-03-28T16:14:26Z
dc.date.available2025-03-28T16:14:26Z
dc.date.issued2022-04-19
dc.description.abstractRare actinomycetes represent an underexploited source of new bioactive compounds. Here, we report the use of a targeted metabologenomic approach to identify piperazyl compounds in the rare actinomycete Lentzea flaviverrucosa DSM 44664. These efforts to identify molecules that incorporate piperazate building blocks resulted in the discovery and structural elucidation of two dimeric biaryl-cyclohexapeptides, petrichorins A and B. Petrichorin B is a symmetric homodimer similar to the known compound chloptosin, but petrichorin A is unique among known piperazyl cyclopeptides because it is an asymmetric heterodimer. Due to the structural complexity of petrichorin A, solving its structure required a combination of several standard chemical methods plus in silico modeling, strain mutagenesis, and solving the structure of its biosynthetic intermediate petrichorin C for confident assignment. Furthermore, we found that the piperazyl cyclopeptides comprising each half of the petrichorin A heterodimer are made via two distinct nonribosomal peptide synthetase (NRPS) assembly lines, and the responsible NRPS enzymes are encoded within a contiguous biosynthetic supercluster on the L. flaviverrucosa chromosome. Requiring promiscuous cytochrome p450 crosslinking events for asymmetric and symmetric biaryl production, petrichorins A and B exhibited potent in vitro activity against A2780 human ovarian cancer, HT1080 fibrosarcoma, PC3 human prostate cancer, and Jurkat human T lymphocyte cell lines with IC50 values at low nM levels. Cyclic piperazyl peptides and their crosslinked derivatives are interesting drug leads, and our findings highlight the potential for heterodimeric bicyclic peptides such as petrichorin A for inclusion in future pharmaceutical design and discovery programs
dc.description.filFil: Li, Chun-shun. University of Hawaii at Hilo. Daniel K. Inouye College of Pharmacy. Department of Pharmaceutical Sciences; United States.
dc.description.filFil: Huc, Yifei. Washington University. Department of Biology; United States.
dc.description.filFil: Wua, Xiaohua. University of Hawaii at Hilo. Daniel K. Inouye College of Pharmacy. Department of Pharmaceutical Sciences; United States.
dc.description.filFil: Stumpf, Spencer D. Washington University. Department of Biology; United States.
dc.description.filFil: Qic, Yunci. Washington University. Department of Biology; United States.
dc.description.filFil: D’Alessandro, John M. Washington University. Department of Biology; United States.
dc.description.filFil: Nepal, Keshav K. Washington University. Department of Biology; United States.
dc.description.filFil: Sarotti, Ariel Marcelo. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario (IQUIR-CONICET); Argentina.
dc.description.filFil: Cao, Shugeng. University of Hawaii at Hilo. Daniel K. Inouye College of Pharmacy. Department of Pharmaceutical Sciences; United States.
dc.description.filFil: Blodgett, Joshua A. V. Washington University. Department of Biology; United States.
dc.description.sponsorshipHawaii Community Foundation: 15ADVC-74420, 17CON-86295, 20CON-102163
dc.description.sponsorshipHawaii IDeA Network for Biomedical Research Excellence III and IV: 5P20GM103466
dc.format.extent1-10
dc.identifier.citationLi, C., Hu, Y., Wu, X., Stumpf, S. D., Qi, Y., D’Alessandro, J. M., Nepal, K. K., Sarotti, A. M., Cao, S., & Blodgett, J. A. V. (2022). Discovery of unusual dimeric piperazyl cyclopeptides encoded by a Lentzea flaviverrucosa DSM 44664 biosynthetic supercluster. Proceedings of the National Academy of Sciences, 119(17). https://doi.org/10.1073/pnas.2117941119
dc.identifier.issn0027-8424
dc.identifier.urihttps://hdl.handle.net/2133/29142
dc.language.isoen
dc.publisherNational Academy of Sciences
dc.relation.publisherversionhttps://doi.org/10.1073/pnas.2117941119
dc.relation.publisherversionhttps://www.pnas.org/doi/epdf/10.1073/pnas.2117941119
dc.rightsopenAccess
dc.rights.holderLi, Chun-shun
dc.rights.holderHuc, Yifei
dc.rights.holderWua, Xiaohua
dc.rights.holderStumpf, Spencer D.
dc.rights.holderQic, Yunci
dc.rights.holderD’Alessandro, John M.
dc.rights.holderNepal, Keshav K.
dc.rights.holderSarotti, Ariel Marcelo
dc.rights.holderCao, Shugeng
dc.rights.holderBlodgett, Joshua A. V.
dc.rights.holderUniversidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas
dc.rights.textAttribution-NonCommercial-NoDerivatives 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectRare actinomycete
dc.subjectLentzea
dc.subjectCytochrome P450
dc.subjectCyclopeptide
dc.subjectBiosynthesis
dc.titleDiscovery of unusual dimeric piperazyl cyclopeptides encoded by a Lentzea flaviverrucosa DSM 44664 biosynthetic supercluster
dc.typearticulo
dc.type.collectionarticulo
dc.type.versionpublishedVersion

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