An isotopic labeling approach linking natural products with biosynthetic gene clusters
Open accessAbstract
Major advances in genome sequencing and large-scale biosynthetic gene cluster (BGC) analysis have prompted an age of natural product discovery driven by genome mining. Still, connecting molecules to their cognate BGCs is a substantial bottleneck for this approach. We have developed a mass-spectrometry-based parallel stable isotope labeling platform, termed IsoAnalyst, which assists in associating metabolite stable isotope labeling patterns with BGC structure prediction to connect natural products to their corresponding BGCs. Here we show that IsoAnalyst can quickly associate both known metabolites and unknown analytes with BGCs to elucidate the complex chemical phenotypes of these biosynthetic systems. We validate this approach for a range of compound classes, using both the type strain Saccharopolyspora erythraea and an environmentally isolated Micromonospora sp. We further demonstrate the utility of this tool with the discovery of lobosamide D, a new and structurally unique member of the family of lobosamide macrolactams.
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Stable isotope tracers are widely applied in the natural product field for discovery, structure elucidation, and investigation of biosynthetic origin.
“Besides the study of metabolic flux of primary metabolism, the use of stable isotope tracers has been widely applied in the natural product field. Both, for the discovery and structure elucidation of metabolites as well as the investigation of their biosynthetic origin, the use of stable isotope is a powerful tool.”
From Connecting metabolome and phenotype: recent advances in functional metabolomics tools for the identification of bioactive natural products (2024) · cites this paper as [66]
The Introduction (page unavailable) says isotope labeling has historically been used to determine compounds’ biosynthetic origins. The Discussion (page unavailable) describes using stable-isotope incorporation to discover novel natural-product variants. Our copy does not establish the claim that stable-isotope tracers are widely used for structure elucidation; it describes MS and NMR as the chemical-characterization methods in its example. (LLM, conf=0.84)
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References 49 · Cited by 39
- Authors
- McCaughey, C. S., van Santen, J. A., van der Hooft, J. J. J., Medema, M. H., & Linington, R. G.
- Affiliations
- Simon Fraser University (CA)
- Wageningen University & Research (NL)
- Corresponding author
- Linington, Roger G.
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2021-12-30
- Volume
- 18
- Issue
- 3
- Pages
- 295-304
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC8891042
- OpenAlex
- W4200056213
- Cited by
- 39
- References
- 49
- Citations by year
- 2026: 11 · 2025: 12 · 2024: 9 · 2023: 5 · 2022: 2
- FWCI
- 2.34
- Type
- journal article
- Language
- en
- Open access
- green
- research.wur.nl
- Licence
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- Socio-Environmental Systems Modeling (acceptedVersion, other-oa)
- PubMed Central (acceptedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- Netherlands eScience Center (ASDI.2017.030)
- U.S. Department of Health & Human Services | National Institutes of Health (AT008718)
- Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada (Discovery)
- Topics
- Health Sciences › Medicine › Pharmacology › Microbial Natural Products and Biosynthesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Physical Sciences › Chemistry › Spectroscopy › Mass Spectrometry Techniques and Applications
- Keywords
- biosynthetic gene clusters, natural products, stable isotope labeling, genome mining, Saccharopolyspora erythraea, Micromonospora, mass spectrometry
- MeSH terms
- Biological Products, Multigene Family, Isotope Labeling, Micromonospora, Biosynthetic Pathways
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