The relationship between enzymes and natural products is profoundly synergistic, operating through three key dimensions:
I. Enzymes as Biosynthetic Architects of Natural Products
The structural diversity of natural products arises from dedicated enzyme systems—such as polyketide synthases and terpene cyclases—that assemble, diversify, and tailor their molecular scaffolds.
II. Natural Products as Modulators and Evolutionary Drivers
Beyond being end-products, many natural products regulate enzyme activity through feedback or allosteric mechanisms. Their ecological roles also drive the evolution of novel catalytic functions in producing and competing organisms.
III. The Discovery Cycle
This synergy fuels an innovation loop: novel natural products lead to the discovery of their biosynthetic enzymes, which in turn enable the engineering of new derivatives with enhanced bioactivity—a continuous “molecule–catalyst–new molecule” cycle that generates leads for pharmaceuticals and agrochemicals. Current research is accelerating this cycle, bridging mechanism, molecule, and application through novel enzymatic reactions, advanced enzyme engineering, and mechanistic target studies.
This collection of recent articles from Natural Products and Bioprospecting illustrates this dynamic interplay across the three dimensions outlined above.
I. Enzymes as Biosynthetic Architects of Natural Products
1. Biotransformation of selected secondary metabolites by Alternaria species and the pharmaceutical, food and agricultural application of biotransformation products
This review highlights the role of microbial biotransformation in natural product discovery. Focusing on Alternaria species as biocatalysts, it details how their enzymatic systems, particularly cytochrome P450s, promote reactions with high stereoselectivity and regioselectivity under mild conditions to generate novel derivatives. The applications of these biotransformation products across pharmaceutical, food, and agricultural sectors are also discussed.
https://link.springer.com/article/10.1007/s13659-024-00469-5
2. Purification and immobilization of β-glucosidase using surface modified mesoporous silica Santa Barbara Amorphous 15 for eco-friendly preparation of sagittatoside A
Presenting an efficient one-step strategy, this work describes the purification and immobilization of a β-glucosidase (BgpA) on functionalized mesoporous silica (R-SBA-15). The resulting immobilized enzyme, R-SBA-15@BgpA, exhibited robust properties including a higher optimal temperature, superior stability, and excellent reusability, demonstrating its high potential for the green synthesis of bioactive glycosides like sagittatoside A.
https://link.springer.com/article/10.1007/s13659-024-00471-x
3. Novel polycyclic meroterpenoids with protein tyrosine phosphatase 1B inhibitory activity isolated from desert-derived fungi Talaromyces sp. HMT-8
This study reports the discovery of seven new polycyclic meroterpenoids (talarines K-Q) from a desert-adapted fungus. Intriguingly, several feature rare chlorine substitutions, pointing to the action of specific halogenase enzymes during biosynthesis. Selected compounds were identified as potent inhibitors of protein tyrosine phosphatase 1B (PTP1B), offering valuable leads for therapeutic development.
https://link.springer.com/article/10.1007/s13659-025-00530-x
II. Natural Products as Modulators of Enzyme Function
4. Metabolism characterization and toxicity of N-hydap, a marine candidate drug for lung cancer therapy by LC-MS method
Providing a detailed metabolic profile, this research reveals that the marine-derived drug candidate N-hydap is metabolized by CYP450 and UGT enzymes (primarily UGT1A3). Significantly, it also acts as a modulator that can alter the activity of these very drug-metabolizing enzymes. This dual substrate-regulator relationship is crucial for understanding its pharmacokinetics and potential drug-drug interactions.
https://link.springer.com/article/10.1007/s13659-024-00455-x
5. Chemically engineered essential oils prepared through thiocyanation under solvent-free conditions: chemical and bioactivity alteration
This study describes a strategy to enhance enzyme inhibition by chemically engineering natural essential oils. Solvent-free thiocyanation transformed their chemical composition and tripled their acetylcholinesterase (AChE) inhibitory activity. Bio-guided isolation from the modified mixture yielded four new AChE inhibitors with potency matching or exceeding the standard control, validating the approach of directed chemical transformation to discover potent enzyme inhibitors.
https://link.springer.com/article/10.1007/s13659-024-00456-w
6. New semisynthetic α-glucosidase inhibitor from a doubly-chemically engineered extract
By applying a sequential two-step chemical modification to a natural propolis extract, researchers achieved a 22-fold increase in α-glucosidase inhibition. From this engineered mixture, a novel fluorinated pyrazole inhibitor was isolated, exhibiting approximately 20-fold greater potency than its natural precursor, chrysin. This study demonstrates that directed chemical engineering of natural products effectively enhances their function as enzyme inhibitors.
https://link.springer.com/article/10.1007/s13659-024-00488-2
III. The Discovery Cycle
7. Precision enzyme discovery through targeted mining of metagenomic data
This perspective examines computational strategies for mining novel enzymes from metagenomic data. To address the challenge of efficiently discovering enzymes with desired catalytic properties from vast sequence resources, the study highlights approaches grounded in the “sequence–structure–function” relationship of enzymes. By integrating intelligent prediction—using homology-based modeling and machine learning—with experimental validation, this combined computational and experimental framework offers an effective route to discover new biocatalysts from complex microbial communities, thereby advancing enzyme discovery for natural product applications.
https://link.springer.com/article/10.1007/s13659-023-00426-8
This study combines computational and experimental methods to mine enzyme inhibitors from traditional Chinese medicine. Virtual screening identified candidate molecules, leading to the experimental discovery that delphinidin inhibits SARS-CoV-2 through dual mechanisms (3CL protease and viral entry blockade), while deapio platycodin D also shows anti-coronavirus activity. The work establishes a complete "prediction-validation-confirmation" pipeline for rapidly discovering natural viral enzyme inhibitors.
https://link.springer.com/article/10.1007/s13659-025-00523-w