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A widespread metabolic gene cluster family in metazoans

Nature Chemical Biology volume 21, pages 1509–1518 (2025)Cite this article

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Abstract

Octocorals are metazoans that prolifically produce terpenoid natural products, rivaling the chemical diversity of plants and microbes. We recently established that these cnidarians uniformly express terpene cyclases and that their encoding genes often reside within putative biosynthetic gene clusters (BGCs). Here we report the discovery and characterization of a widespread gene cluster family for briarane diterpenoid biosynthesis. We sequence five genomes from evolutionarily distinct families of briarane-producing octocorals, revealing a conserved five-gene cluster. Expressing these genes in heterologous hosts, we reconstitute the biosynthesis of cembrene B γ-lactone, an established molecule that contains the lactone structural feature distinctive of briarane diterpenoids. The discovery of the genomic basis of briarane biosynthesis establishes that animals also use gene cluster families to produce specialized metabolites. Furthermore, the presence of BGCs in octocorals proves that the formation and maintenance of BGCs related to specialized metabolite biosynthesis is a more widespread phenomenon than previously realized.

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Fig. 1: Gene clustering trends across eukaryotes.
Fig. 2: Distribution of briarane diterpenoids in the phylum Octocorallia.
Fig. 3: Genome-guided discovery of a conserved octocoral BGC family.
Fig. 4: Biochemical validation of clustered biosynthesis genes across syntenic homologs.
Fig. 5: Proposed biosynthetic pathway for briarane production and estimated time points for the evolution of the briarane BGC.

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Data availability

The feature-based molecular network parameters used and raw data are available through MASSIVE (MSV000094792). NCBI BioSample accession numbers for the genomes generated in this paper are as follows: R. koellikeri (SAMN40621396), B. asbestinum (SAMN40621398), D. gemmacea (SAMN40621399), E. caribaeorum (SAMN41659149) and S. elongata (SAMN40621397). NMR and EI-MS spectra of characterized compounds are available in Supplementary Information. Sequence Read Archive accession numbers for raw sequencing reads generated in this study are available in Supplementary Table 4. Genbank accession numbers for annotated BGC-containing contigs are available in Supplementary Table 5. A list of all protein sequences used in the study is available in Supplementary Note 1. The sources of all CYPs used for phylogenetic analysis are available in Supplementary Table 6. X-ray diffraction data are available from the CCDC (2371467). The conserved domain database webtool used to explore genomic neighborhoods can be accessed online (https://www.ncbi.nlm.nih.gov/cdd/).

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Acknowledgements

We thank P. Zerofski (Scripps Institution of Oceanography) for collecting R. koellikeri and S. elongata, J. Sprung (Two Little Fishes) for the D. gemmacea tissue and J. Garrabou for the C. rubrum tissue. For her help in species identification, we would like to recognize C. S. McFadden (Harvey Mudd College). For coral images, we thank C. S. McFadden for D. gemmacea, F. Zuberer (CNRS) for C. rubrum, P. Webster (@underwaterpat) for S. elongata and J. Simpson (Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology) for B. asbestinum and E. caribaeorum. We thank T. Damiani (IOCB Prague) and A. M. C. Rodriguez (UC San Diego) for their assistance with feature-based molecular networking. Chemical isolation and elucidation of the R. koellikeri briarane diterpene was aided by A. Bogdanov (Scripps Institution of Oceanography). We thank N. M. Lacerna (University of Utah) for aid with gel electrophoresis. This work was supported by the NIH (R01-GM146224 to B.S.M., R35-GM148283 to E.W.S, and K99-GM148783 to P.D.S.), a Margaret A. Davidson Graduate Fellowship to N.E.G (NERRS NA22NOS4200050), a National Science Foundation Graduate Research Fellowship to M.L.M., Tang Genomics Fund to T.P.M. and Fundaço para a Ciência e a Tecnologia funds (UIDB/04423/2020, UIDP/04423/2020 and 2021.00855.CEECIND) to J.-B.L. X-ray diffraction research reported in this publication was performed by R. T. Vanderlinden (U. Utah) and supported by the Office of the Director, NIH under award S10OD030326. NMR data collection at UC San Diego (the Scripps Institution of Oceanography and Biomolecular NMR Facilities) was assisted by B. Duggan. Additional NMR data were obtained at the University of Utah Health Sciences NMR Core. GC–MS data were obtained at the University of Utah Health Sciences Proteomics Core by Q. Pearce.

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Author notes

  1. These authors contributed equally: Natalie E. Grayson, Paul D. Scesa.

Authors and Affiliations

  1. Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California, San Diego, La Jolla, CA, USA

    Natalie E. Grayson, Malia L. Moore, Todd P. Michael, Immo Burkhardt & Bradley S. Moore

  2. Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT, USA

    Paul D. Scesa & Eric W. Schmidt

  3. The Plant Molecular and Cellular Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA

    Malia L. Moore & Todd P. Michael

  4. CIIMAR/CIMAR LA, Centro Interdisciplinar de Investigação Marinha e Ambiental, Universidade do Porto, Porto, Portugal

    Jean-Baptiste Ledoux

  5. Centro Nacional de Análisis Genómico (CNAG), Barcelona, Spain

    Jessica Gomez-Garrido & Tyler Alioto

  6. Universitat de Barcelona (UB), Gran Via de les Corts Catalanes, Barcelona, Spain

    Jessica Gomez-Garrido & Tyler Alioto

  7. Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA

    Bradley S. Moore

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Conceptualization, P.D.S., I.B., E.W.S. and B.S.M. Data creation, N.E.G., P.D.S., M.L.M. and I.B. Formal analysis and validation, N.E.G., P.D.S., I.B., J.G.-G. and T.A. Funding acquisition, P.D.S., J.-B.L., T.P.M., E.W.S. and B.S.M. Investigation and methodology, N.E.G., P.D.S., M.L.M. and I.B. Project administration, P.D.S., I.B., E.W.S. and B.S.M. Resources, J.-B.L., T.P.M., E.W.S. and B.S.M. Writing—original draft, N.E.G., P.D.S., I.B. and B.S.M. Writing—review and editing, all authors.

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Correspondence to Immo Burkhardt, Eric W. Schmidt or Bradley S. Moore.

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Extended data

Extended Data Fig. 1 Stylatula elongata species identification.

To accurately differentiate between two visually similar southern California sea pen species, Stylatula elongata and Virgularia sp., we examined the presence or absence of sclerites at the base of the polyp leaves. Sclerites are microscopic carbonate structures that provide structural support and serve as important taxonomic markers in octocorals. We imaged these sclerites at 10x magnification to assess their morphology and distribution. The observed sclerites, measuring approximately 0.5–1.5 mm in length, confirmed the identification of the specimen as Stylatula elongata, as this species is known to possess these structures, whereas Virgularia lacks them. The figure illustrates the presence of the sclerites in our sample tissue, providing critical diagnostic evidence for species determination.

Extended Data Fig. 2 The briarane terpenoid-containing complete molecular network.

Feature-based molecular networking (FBMN) was used to visualize relationships among metabolites detected in liquid chromatography-tandem mass spectrometry (LC-MS/MS) data from crude extracts of the six focal coral species analyzed in this study. Each node in the network represents a molecular feature, while edges indicate spectral similarity, grouping structurally related metabolites into clusters. The boxed region specifically highlights the briarane diterpene network, as shown in Fig. 2c, distinguishing this family of metabolites within the broader chemical space.

Extended Data Fig. 3 Full to scale synteny of the briarane BGCs in Scleralcyonacea corals.

Full, to-scale micro synteny representation of the briarane biosynthetic gene clusters (BGCs) identified in briarane producing octocoral. Annotated arrows indicate genes within the BGCs, with intron sequences included. Gene lengths and intergenic gaps are shown to scale, providing an accurate depiction of cluster organization. The total length of the contig containing the BGC is displayed in black adjacent to each contig, while the specific BGC-containing region depicted in the figure is indicated in parentheses. This visualization highlights the conserved and variable elements of briarane BGCs across coral species, offering insights into their genetic architecture and potential biosynthetic capabilities.

Extended Data Fig. 4 %ID matrices for all syntenic briarane BGC genes.

Heat maps illustrating the percent identity (% ID) across five biosynthetic gene cluster (BGC) genes identified in the focal Scleralcyonacea corals. Each row represents a gene from a specific coral species analyzed in this study. Percent identity is color-coded, with red indicating the highest sequence similarity and blue representing the lowest. This visualization provides a comparative overview of sequence conservation and divergence among BGC genes, offering insights into the evolutionary relationships and potential functional variations in briarane biosynthesis across coral species.

Extended Data Fig. 5 LCMS for co-expression of cembrene A, B, and C synthases with cembrene 19-hydroxylase Ecar cbCYPb.

EIC trace monitored at m/z 271.2. Co-expressed TC genes are as follows: Top) Basb caTC; Middle) Stro ccTC; Bottom) Basb cbTC. Oxidized products are only produced in the presence of cembrene B.

Extended Data Table 1 Basic assembly statistics for octocoral genomes
Full size table
Extended Data Table 2 Long and short read sequencing statistics across all in house genomes
Full size table

Supplementary information

Supplementary Information

Supplementary Tables 1–10, Figs. 1–15 and Notes 1–10.

Reporting Summary

Supplementary Data 1

Crystallographic information file for diol (13).

Supplementary Data 2

Validation summary of the corresponding.cif for diol (13).

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Grayson, N.E., Scesa, P.D., Moore, M.L. et al. A widespread metabolic gene cluster family in metazoans. Nat Chem Biol 21, 1509–1518 (2025). https://doi.org/10.1038/s41589-025-01927-y

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