Genome mining and metabolomics uncover a rare D-capreomycidine containing natural product and its biosynthetic gene cluster

Neil L. Kelleher; Regan J. Thomson; James H. Tryon; Jennifer C. Rote; Li Chen; Matthew T. Robey; Marvin M. Vega; Wan Cheng Phua; William W. Metcalf; Kou San Ju

doi:10.1021/acschembio.0c00663

Genome mining and metabolomics uncover a rare D-capreomycidine containing natural product and its biosynthetic gene cluster

Neil L. Kelleher, Regan J. Thomson, James H. Tryon, Jennifer C. Rote, Li Chen, Matthew T. Robey, Marvin M. Vega, Wan Cheng Phua, William W. Metcalf, Kou San Ju

Research output: Contribution to journal › Article › peer-review

Abstract

We report the metabolomics-driven genome mining of a new cyclic-guanidino incorporating non-ribosomal peptide synthetase (NRPS) gene cluster and full structure elucidation of its associated hexapeptide product, faulknamycin. Structural studies unveiled that this natural product contained the previously unknown (R,S)-stereoisomer of capreomycidine, D-capreomycidine. Furthermore, heterologous expression of the identified gene cluster successfully reproduces faulknamycin production without an observed homologue of VioD, the pyridoxal phosphate (PLP)dependent enzyme found in all previous L-capreomycidine biosynthesis. An alternative NRPS-dependent pathway for D-capreomycidine biosynthesis is proposed.

Original language	English (US)
Pages (from-to)	3013-3020
Number of pages	8
Journal	ACS chemical biology
Volume	15
Issue number	11
DOIs	https://doi.org/10.1021/acschembio.0c00663
State	Published - Nov 20 2020

ASJC Scopus subject areas

Biochemistry
Molecular Medicine

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10.1021/acschembio.0c00663

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title = "Genome mining and metabolomics uncover a rare D-capreomycidine containing natural product and its biosynthetic gene cluster",

abstract = "We report the metabolomics-driven genome mining of a new cyclic-guanidino incorporating non-ribosomal peptide synthetase (NRPS) gene cluster and full structure elucidation of its associated hexapeptide product, faulknamycin. Structural studies unveiled that this natural product contained the previously unknown (R,S)-stereoisomer of capreomycidine, D-capreomycidine. Furthermore, heterologous expression of the identified gene cluster successfully reproduces faulknamycin production without an observed homologue of VioD, the pyridoxal phosphate (PLP)dependent enzyme found in all previous L-capreomycidine biosynthesis. An alternative NRPS-dependent pathway for D-capreomycidine biosynthesis is proposed.",

author = "Kelleher, {Neil L.} and Thomson, {Regan J.} and Tryon, {James H.} and Rote, {Jennifer C.} and Li Chen and Robey, {Matthew T.} and Vega, {Marvin M.} and Phua, {Wan Cheng} and Metcalf, {William W.} and Ju, {Kou San}",

note = "Publisher Copyright: {\textcopyright} 2020 American Chemical Society",

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doi = "10.1021/acschembio.0c00663",

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T1 - Genome mining and metabolomics uncover a rare D-capreomycidine containing natural product and its biosynthetic gene cluster

AU - Kelleher, Neil L.

AU - Thomson, Regan J.

AU - Tryon, James H.

AU - Rote, Jennifer C.

AU - Chen, Li

AU - Robey, Matthew T.

AU - Vega, Marvin M.

AU - Phua, Wan Cheng

AU - Metcalf, William W.

AU - Ju, Kou San

PY - 2020/11/20

Y1 - 2020/11/20

N2 - We report the metabolomics-driven genome mining of a new cyclic-guanidino incorporating non-ribosomal peptide synthetase (NRPS) gene cluster and full structure elucidation of its associated hexapeptide product, faulknamycin. Structural studies unveiled that this natural product contained the previously unknown (R,S)-stereoisomer of capreomycidine, D-capreomycidine. Furthermore, heterologous expression of the identified gene cluster successfully reproduces faulknamycin production without an observed homologue of VioD, the pyridoxal phosphate (PLP)dependent enzyme found in all previous L-capreomycidine biosynthesis. An alternative NRPS-dependent pathway for D-capreomycidine biosynthesis is proposed.

AB - We report the metabolomics-driven genome mining of a new cyclic-guanidino incorporating non-ribosomal peptide synthetase (NRPS) gene cluster and full structure elucidation of its associated hexapeptide product, faulknamycin. Structural studies unveiled that this natural product contained the previously unknown (R,S)-stereoisomer of capreomycidine, D-capreomycidine. Furthermore, heterologous expression of the identified gene cluster successfully reproduces faulknamycin production without an observed homologue of VioD, the pyridoxal phosphate (PLP)dependent enzyme found in all previous L-capreomycidine biosynthesis. An alternative NRPS-dependent pathway for D-capreomycidine biosynthesis is proposed.

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Genome mining and metabolomics uncover a rare D-capreomycidine containing natural product and its biosynthetic gene cluster

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