Constraint Geometry in Natural Product Biosynthesis

Simon Gibbons

doi:10.53941/npa.2026.100011

Abstract

Natural product biosynthesis is often framed through the lenses of enzymatic novelty, pathway diversity, and evolutionary contingency. Yet across systems, a deeper, more profound regularity emerges, biosynthetic space is shaped not only by genetic potential but by the geometric constraints imposed by ecological context, metabolic flux, and structural feasibility. This perspective outlines a minimal conceptual framework for understanding how constraint geometry governs the emergence, stability, and diversification of natural product families. Rather than proposing new theory, it synthesizes existing observations into a coherent lens that highlights why certain scaffolds recur, why others remain rare, and how ecological pressures delimit the accessible chemical landscape. The aim of this paper is to provide a compact, integrative reference point for researchers seeking to understand the deeper architecture underlying biosynthetic outcomes.

References

1.
Bogart, J.W.; Cabezas, M.D.; Vögeli, B.; et al. Cell-Free Exploration of the Natural Product Chemical Space. Chembiochem 2021, 22, 84–91.
2.
Angeles Flores, G.; Cusumano, G.; Venanzoni, R.; et al. Biodiversity-Driven Natural Products and Bioactive Metabolites. Plants 2025, 15, 104
3.
Pye, C.R.; Bertin, M.J.; Lokey, R.S.; et al. Retrospective analysis of natural products provides insights for future discovery trends. Proc. Natl. Acad. Sci. USA 2017, 114, 5601–5606.
4.
Zuk, M.; Pelc, K.; Szperlik, J.; et al. Metabolism of the Cyanogenic Glucosides in Developing Flax: Metabolic Analysis, and Expression Pattern of Genes. Metabolites 2020, 10, 288.
5.
Nelson, A.; Karageorgis, G. Natural product-informed exploration of chemical space to enable bioactive molecular discovery. RSC Med. Chem. 2021, 12, 353–362.
6.
Lipinski, C.; Hopkins, A. Navigating chemical space for biology and medicine. Nature 2004, 432, 855–861.
7.
Anderson, V.M.; Wendt, K.L.; Najar, F.Z.; et al. Building Natural Product Libraries Using Quantitative Clade-Based and Chemical Clustering Strategies. mSystems 2021, 6, e00644-21. https://doi.org/10.1128/msystems.00644-21.
8.
Koch, M.A.; Ansgar, S.; Michael, S.; et al. Charting Biologically Relevant Chemical Space: A Structural Classification of Natural Products (SCONP). Proc. Natl. Acad. Sci. USA. 2005, 102, 17272–17277.
9.
Dairi, T.; Kuzuyama, T.; Nishiyama, M.; et al. Convergent strategies in biosynthesis. Nat. Prod. Rep. 2011, 28, 1054–1086.
10.
Wei, X.; Wang, W.G.; Matsuda, Y. Branching and converging pathways in fungal natural product biosynthesis. Fungal Biol. Biotechnol. 2022, 9, 6.
11.
Alberts, A.W.; Chen, J.; Kuron, G.; et al. Mevinolin: A highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent. Proc. Natl. Acad. Sci. USA 1980, 77, 3957–3961.
12.
Gibbons, S.; Gray, A.I.; Waterman, P.G. Clerodane diterpenes from the bark of Casearia tremula. Phytochemistry 1996, 41, 565–570.
13.
Riddick, E.W. Potential of Quercetin to Reduce Herbivory without Disrupting Natural Enemies and Pollinators. Agriculture 2021, 11, 476.
14.
Köllner, T.G.; Held, M.; Lenk, C.; et al. A maize (E)-beta-caryophyllene synthase implicated in indirect defense responses against herbivores is not expressed in most American maize varieties. Plant Cell 2008, 20, 482–494.
15.
Vizcaino, M.I.; Guo, X.; Crawford, J.M. Merging chemical ecology with bacterial genome mining for secondary metabolite discovery. J. Ind. Microbiol. Biotechnol. 2014, 41, 285–299.
16.
Sana; Aftab, T.; Naeem, M.; et al. Production of secondary metabolites under challenging environments: Understanding functions and mechanisms of signalling molecules. Front. Plant Sci. 2025, 16, 1569014.
17.
Miyao, T.; Reker, D.; Schneider, P.; et al. Chemography of natural product space. Planta Med. 2015, 81, 429–435.
18.
Ali, J.G.; Casteel, C.L.; Mauck, K.E.; et al. Chemical Ecology of Multitrophic Microbial Interactions: Plants, Insects, Microbes and the Metabolites that Connect Them. J. Chem. Ecol. 2020, 46, 645–648.
19.
Jacoby, R.P.; Koprivova, A.; Kopriva, S. Pinpointing secondary metabolites that shape the composition and function of the plant microbiome. J. Exp. Bot. 2021, 72, 57–69.
20.
Duggar, B.M. Aureomycin: A Product of The Continuing Search for New Antibiotics. Ann. N. Y. Acad. Sci. 1948, 51, 177–181.
21.
Sikandar, A.; Popoff, A.; Jumde, R.P.; et al. Revision of the Absolute Configurations of Chelocardin and Amidochelocardin. Angew. Chem. Int. Ed. 2023, 62, e202306437.
22.
Walsh, C.T.; Tang, Y. Major Classes of Natural Product Scaffolds and Enzymatic Biosynthetic Machinery. In Natural Product Biosynthesis; The Royal Society of Chemistry: London, UK, 2022; p. 1–21.
23.
Tewksbury, J.J.; Nabhan, G.P. Seed dispersal. Directed deterrence by capsaicin in chilies. Nature 2001, 412, 403–404.
24.
Castañeda-Tamez, P.; Ramírez-Peris, J.; Pérez-Velázquez, J.; et al. Pyocyanin Restricts Social Cheating in Pseudomonas aeruginosa. Front. Microbiol. 2018, 9, 1348.
25.
Jensen, P.R. Natural Products and the Gene Cluster Revolution. Trends Microbiol. 2016, 24, 968–977.
26.
Atanasov, A.G.; Zotchev, S.B.; Dirsch, V.M.; et al. Natural products in drug discovery: Advances and opportunities. Nat. Rev. Drug Discov. 2021, 20, 200–216.
27.
Barry, S.M. Rethinking natural product discovery to unblock the antibiotic pipeline. Future Microbiol. 2025, 20, 179–182.
28.
Harris, L.A.; Mitchell, D.A. Reactivity-based screening for natural product discovery. Methods Enzymol. 2022, 665, 177–208.
29.
Mei, S. A Multi-Label Learning Framework for Predicting Chemical Classes and Biological Activities of Natural Products from Biosynthetic Gene Clusters. J. Chem. Ecol. 2023, 49, 681–695.
30.
Liu, G.; Li, Y.; Ong, G.; et al. Unified genomic and chemical representations enable bidirectional biosynthetic gene cluster and natural product retrieval. Sci. Rep. 2026, 16, 49955.
31.
Yongye, A.B.; Waddell, J.; Medina-Franco, J.L. Molecular scaffold analysis of natural products databases in the public domain. Chem. Biol. Drug Des. 2012, 80, 717–724.
32.
Ertl, P.; Schuhmann, T. Cheminformatics Analysis of Natural Product Scaffolds: Comparison of Scaffolds Produced by Animals, Plants, Fungi and Bacteria. Mol. Inform. 2020, 39, 2000017.
33.
Yan, L.-H.; Li, X.; Wang, B.-G. Natural products with 1,2-oxazine scaffold: Occurrence, chemical diversity, bioactivity, synthesis, and biosynthesis. Nat. Prod. Rep. 2023, 40, 1874–1900.
34.
Hou, C. Energetic cost of biosynthesis is a missing link between growth and longevity in mammals. Proc. Natl. Acad. Sci. USA 2024, 121, e2315921121.
35.
Wortel, M.T.; Noor, E.; Ferris, M.; et al. Metabolic enzyme cost explains variable trade-offs between microbial growth rate and yield. PLOS Comput. Biol. 2018, 14, e1006010.
36.
Reshi, Z.A.; Ahmad, W.; Lukatkin, A.S.; et al. From Nature to Lab: A Review of Secondary Metabolite Biosynthetic Pathways, Environmental Influences, and In Vitro Approaches. Metabolites 2023, 13, 895.
37.
Erb, M.; Kliebenstein, D.J. Plant Secondary Metabolites as Defenses, Regulators, and Primary Metabolites: The Blurred Functional Trichotomy. Plant Physiol. 2020, 184, 39–52.
38.
Medema, M.H.; Fischbach, M.A. Computational approaches to natural product discovery. Nat. Chem. Biol. 2015, 11, 639–648.
39.
Cheng, J.; Zhao, Z.; Teng, B.; et al. Rethinking Microbial Chemical Ecology: Secondary Metabolites as Concentration-Dependent Signaling Hubs with Implications for Anti-Virulence Intervention. Microorganisms 2026, 14, 1074.
40.
Kessler, A.; Kalske, A. Plant Secondary Metabolite Diversity and Species Interactions. Annu. Rev. Ecol. Evol. Syst. 2018, 49, 115–138.

Scilight Press

Author Information

Abstract

Keywords

References

About Scilight

Journals

Publishing Policies

Contact Us