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dc.contributor.author
Li, Chunshun
dc.contributor.author
Hu, Yifei
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Wu, Xiaohua
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Stumpf, Spencer D.
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Qi, Yunci
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D'Alessandro, John M.
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Nepal, Keshav K.
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Sarotti, Ariel Marcelo
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Cao, Shugeng
dc.contributor.author
Blodgett, Joshua A.V.
dc.date.available
2023-07-17T17:19:36Z
dc.date.issued
2022-04-19
dc.identifier.citation
Li, Chunshun; Hu, Yifei; Wu, Xiaohua; Stumpf, Spencer D.; Qi, Yunci; et al.; Discovery of unusual dimeric piperazyl cyclopeptides encoded by a Lentzea flaviverrucosa DSM 44664 biosynthetic supercluster; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 19; 17; 19-4-2022; 1-10
dc.identifier.issn
0027-8424
dc.identifier.uri
http://hdl.handle.net/11336/204198
dc.description.abstract
Rare 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.format
application/pdf
dc.language.iso
eng
dc.publisher
National Academy of Sciences
dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.subject
BIOSYNTHESIS
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CYCLOPEPTIDE
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CYTOCHROME P450
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LENTZEA
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RARE ACTINOMYCETE
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Química Orgánica
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Ciencias Químicas
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CIENCIAS NATURALES Y EXACTAS
dc.title
Discovery of unusual dimeric piperazyl cyclopeptides encoded by a Lentzea flaviverrucosa DSM 44664 biosynthetic supercluster
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2023-07-10T10:41:22Z
dc.journal.volume
19
dc.journal.number
17
dc.journal.pagination
1-10
dc.journal.pais
Estados Unidos
dc.journal.ciudad
Washington D.C
dc.description.fil
Fil: Li, Chunshun. University Of Hawaii; Estados Unidos
dc.description.fil
Fil: Hu, Yifei. University Of Hawaii; Estados Unidos. Washington University in St. Louis; Estados Unidos
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Fil: Wu, Xiaohua. University Of Hawaii; Estados Unidos
dc.description.fil
Fil: Stumpf, Spencer D.. Washington University in St. Louis; Estados Unidos
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Fil: Qi, Yunci. Washington University in St. Louis; Estados Unidos
dc.description.fil
Fil: D'Alessandro, John M.. Washington University in St. Louis; Estados Unidos
dc.description.fil
Fil: Nepal, Keshav K.. Washington University in St. Louis; Estados Unidos
dc.description.fil
Fil: Sarotti, Ariel Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; Argentina
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Fil: Cao, Shugeng. University Of Hawaii; Estados Unidos
dc.description.fil
Fil: Blodgett, Joshua A.V.. Washington University in St. Louis; Estados Unidos
dc.journal.title
Proceedings of the National Academy of Sciences of The United States of America
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://www.pnas.org/doi/10.1073/pnas.2117941119
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/https://doi.org/10.1073/pnas.2117941119
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