Diterpenoids in medicinal plants: structure, distribution, biological activities, biosynthesis, and bioengineering...

Diterpenoids are important natural secondary metabolites characterized by a 20-carbon backbone and classified into acyclic, monocyclic, bicyclic, tricyclic, tetracyclic, and macrocyclic types based on their ring structures. Abundant in medicinal plants, these compounds function in defense against pathogens and herbivores and exhibit diverse pharmacological activities, including anticancer, anti-inflammatory, cardiovascular-protective, antidiabetic, and antimicrobial effects. The biosynthetic precursor (E,E,E)-geranylgeranyl diphosphate (GGPP) is primarily generated through the methylerythritol 4-phosphate (MEP) pathway in plants. The carbon skeleton of diterpenoids is then constructed by diterpene synthases (diTPSs) and undergoes diverse modifications catalyzed by cytochrome P450 monooxygenases (CYP450s), alcohol dehydrogenases (ADHs), and UDP-dependent glycosyltransferases (UGTs), while transcription factors orchestrate pathway gene expression. Advances in synthetic biology and metabolic engineering have enabled heterologous production of diterpenoids in genetically tractable hosts, with yields enhanced through promoter optimization, targeted mutagenesis, and fermentation optimization. This review systematically summarizes the structure, distribution, biological activities, and biosynthetic pathways of diterpenoids, and discusses future directions including structural modification for enhanced bioactivity, pathway elucidation via omics analysis, modular biosynthesis for overproduction, and machine learning applications in pharmacology and enzyme engineering. These efforts provide a foundation for discovering novel bioactive diterpenoids, elucidating complete biosynthetic pathways, and enabling sustainable production through biotechnological breeding and synthetic biology.