A Comprehensive Review on the Biosynthesis of Tropane Alkaloids

Amaryllidaceae Alkaloids and Isoquinoline Alkaloids: A Perspective on Historical Approaches to Pathway Elucidation

This review compares the historical and methodological trajectories that have shaped IA and AA pathway elucidation, from compound isolation, radiotracer experiments, and biochemical inference to transcriptomics, metabolomics, functional enzymology, isotope-guided active-tissue identification, regulatory studies, and heterologous pathway reconstruction.

Recent progress in the natural products research on the phenanthrene-fused indolizidine ring scaffold: Structural diversity, biological activity, and synthetic studies.

Phenanthroindolizidine alkaloids (PIA) are a class of natural nitrogen-containing secondary metabolites characterized by a unique fused five-ring skeleton. They possess multiple modification sites and exhibit a wide range of pharmacological activities. These compounds are widely distributed in various plants and some herbivorous insects, though they occur in very low content. To date, over a hundred individual compounds have been isolated from natural sources. In vitro and in vivo studies have demonstrated that PIA possesses a variety of pharmacological effects, including antitumor, anti-inflammatory, antiviral, antibacterial, and antiparasitic properties. It also exhibits agricultural bioactivities such as plant antibacterial and insecticidal effects; however, issues such as central nervous system toxicity and gastrointestinal toxicity severely limit its clinical translation. This paper systematically reviews research progress on PIA from 1935 to 2025, summarizing the natural distribution, biosynthetic pathways, and chemical synthesis routes of these compounds, and providing a comprehensive overview of their diverse biological activities, mechanisms of action, and structure-activity relationships. Additionally, in light of the toxicological characteristics of PIA, the paper explores strategies for reducing toxicity and enhancing efficacy, such as structural modifications and dosage form optimization. This review synthesizes the scattered research findings in this field and clarifies the structure-activity and structure-toxicity relationships, thereby providing a systematic theoretical framework for the molecular design, targeted synthesis, and innovative drug development of this class of alkaloids.

From botanical origins to modern laboratories: 50 year journey in protoberberine alkaloid total synthesis.

This review systematically categorizes recent advances in the total synthesis of these alkaloids based on core-ring-closure strategies, highlighting innovations in reaction design and underscores the importance of modular, catalytic, and bio-inspired methods for future alkaloid synthesis.

Biosynthesis and Biotransformation of Plant Triterpenoids: Current Advances and Future Perspectives.

The Biosynthesis of a Fungal Flavonoid, Chlorflavonin, Precisely Controlled by Two Types of Equilibrium States.

Flavonoids are polyphenolic natural products predominantly isolated from plants and exhibit a diverse array of biological activities. Because they serve as important pharmaceuticals and nutraceuticals, there is a strong demand for their sustainable supply. Chlorflavonin is a rare fungal flavonoid with potent antitubercular activity. While its biosynthetic enzymes are expected to be valuable tools for application in fungal production of flavonoids, the biosynthetic pathway remains unknown. Here, we elucidate the complete biosynthetic pathway for chlorflavonin through detailed functional analysis of each biosynthetic enzyme. Previously, stepwise and straightforward introduction of 3-, 7-, and 8-methoxy; 2'-hydroxy; and 3'-chloro functionalities have been proposed. In contrast to this proposal, we uncovered an intricate biosynthetic route involving a dynamic interconversion between the 6- and 8-methoxy forms of flavonoid skeletons mediated by the chalcone isomerase CfvF and the flavin-dependent oxygenase CfvI. CfvF interconverted the 6- and 8-methoxyflavanones, likely via a chalcone intermediate. CfvI oxidized the chemically inert 2,3-double bond of flavanone, giving the hemiacetal product. Although these enzymes generate products existing in equilibrium states, respective downstream enzymes catalyze selective conversion of one specific species, facilitating smooth progression to the final product. We also solved the crystal structure of CfvK, the dehydratase that selectively converts the 8-methoxy form of the CfvI product. Through analyzing the structure complexed with its substrate and product and site-directed mutagenesis, key residues determining the substrate selectivity were identified. Our comprehensive analysis established a rational framework for preparing 46 flavonoids, including unnatural ones, setting the stage for fungal production of structurally diverse flavonoids.

Recent Advances in the Production and Biosynthesis of Oleanane-Type Pentacyclic Triterpenoids

Oleanane-type pentacyclic triterpenoids are a class of naturally occurring specialized metabolites with diverse biological activities. Conventional plant extraction and chemical synthesis are constrained by low yields, high costs, and a reliance on natural resources. With the development of synthetic biology and metabolic engineering, the biosynthetic pathways of these compounds can now be systematically reconstructed and optimized, providing new opportunities for efficient production. This review summarizes the classification of oleanane-type pentacyclic triterpenoids and outlines their biosynthetic pathways and recent progress in production platforms such as plant in vitro culture and microbial cell factories. In addition, we discuss major engineering strategies used to improve triterpenoid production, including increasing precursor supply, reducing competing pathways, implementing enzyme engineering and engineering cofactors, improving protein performance, subcellular compartmentalization, enhancing transport, and optimizing fermentation conditions. In view of the current progress, this review also identifies persistent challenges in the biosynthesis of these compounds and outlines potential strategies to address them.