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. 2020 Nov 20;15(11):3013-3020.
doi: 10.1021/acschembio.0c00663. Epub 2020 Nov 5.

Genome Mining and Metabolomics Uncover a Rare d-Capreomycidine Containing Natural Product and Its Biosynthetic Gene Cluster

James H Tryon  1 , Jennifer C Rote  1 , Li Chen  2 , Matthew T Robey  1 , Marvin M Vega  1 , Wan Cheng Phua  1 , William W Metcalf  3 , Kou-San Ju  2   4 , Neil L Kelleher  1 , Regan J Thomson  1
Affiliations

Genome Mining and Metabolomics Uncover a Rare d-Capreomycidine Containing Natural Product and Its Biosynthetic Gene Cluster

James H Tryon et al. ACS Chem Biol. .

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.

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Conflict of interest statement

The authors declare the following competing financial interest(s): W.W.M., N.L.K., and R.J.T, declare competing financial interests in MicroMGx, Inc.

Figures

Figure 1.
Figure 1.
(a) Previously identified stereoisomers of the arginine-derived cyclic-guanadino amino acid, l-capreomycidine (1) and l-epi-capreomycidine (2). (b) Representative previously observed capreomycidine-incorporating natural products. (c) Previously unidentified stereoisomers of capreomycidine, d-capreomycidine (7) and d-epi-capreomycidine (8), possessing enantiomeric structures to 1 and 2.
Figure 2.
Figure 2.
Established synthesis of l-capreomycidine (1) from studies of tuberactin biosynthesis.
Figure 3.
Figure 3.
Annotation of ORFs within the NRPS_GCF.259 biosynthetic gene cluster and their proposed functions.
Figure 4.
Figure 4.
Extracted ion chromatograms for the 750.415 m/z ion corresponding to faulknamycin production. Relative abundances normalized to 7 × 107 ion count.
Figure 5.
Figure 5.
Ornithine-d7 incorporation pattern suggested two enzymatic steps acting upon the arginine side chain during biosynthesis.
Figure 6.
Figure 6.
Proposed linear biosynthesis and peptidase-mediated offloading of faulknamycin (12).
Figure 7.
Figure 7.
Previously established PLP-dependent biosynthesis of l-capreomycidine (1) and the proposed NRPS-dependent biosynthesis of d-capreomycidine (7) observed in the structure of faulknamycin (12).
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