The research team led by Professor Liu Jikai and Associate Professor Chen Heping from the School of Pharmacy focuses on the discovery of bioactive natural products and the mechanisms underlying their biosynthesis. Recently, the team made important advances in studies on crinipellin diterpenes. Using the higher fungus Marasmius fiardii PR‑910 as the research object, the team systematically clarified the cyclization mechanism and biosynthetic pathway of this class of compounds.
On August 21, the relevant research paper entitled Biosynthesis of Crinipellin Diterpenes in Mushroom Marasmius fiardii PR‑910 was published in the academic journal Journal of the American Chemical Society (JACS). This marks the first paper from the School of Pharmacy of our university published in this journal with the school as the primary affiliation. Doctoral candidate Guo Lili (Class of 2024), Master’s student Su Facheng (Class of 2023), and Doctoral candidate Wei Jinjuan (Class of 2025) are co‑first authors. Associate Professor Chen Heping and Professor Liu Jikai serve as co‑corresponding authors. South‑Central Minzu University is the sole institutional affiliation of the paper.
Paper link: https://doi.org/10.1021/jacs.6c10016.
Gene cluster, cyclization mechanism and oxidative‑modification sites for crinipellin biosynthesis. Photo by the School of Pharmacy
Since first reported in 1979, 14 crinipellin diterpenes have been isolated from fungi of the genus Crinipellis. Featuring a distinctive fused 5/5/5/5 tetracyclic scaffold and prominent biological activities including antibacterial, anticancer and anti‑inflammatory properties, these natural products have long attracted scientific attention. To date, six research teams have accomplished the total synthesis of crinipellin diterpenes. Despite repeated breakthroughs in their chemical synthesis, their biosynthetic pathway has remained unresolved for a long time. Such natural products were previously reported exclusively in higher fungi of the genus Crinipellis. The genus Marasmius and Crinipellis both belong to the higher‑fungus family Marasmiaceae; nevertheless, the capacity to biosynthesize crinipellin diterpenes had never been documented in Marasmius fungi prior to this work. In this study, the team for the first time identified the crinipellin diterpene biosynthetic gene cluster (mfd) from the mushroom Marasmius fiardii PR-910. Building upon this finding, the group combined site-directed mutagenesis, isotope tracing and density functional theory (DFT) calculations to fully decipher the cyclization process by which diterpene synthase MfdB assembles this unusual tetracyclic scaffold. It was also discovered that MfdB mutants can generate structurally diverse diterpenes via multiple divergent cyclization branches, including a rearranged 5/5/5/7 tetracyclic diterpene skeleton.
This study further uncovered an arginine‑centered diphosphate‑binding domain within MfdB, expanding known binding modes between terpene synthases and diphosphate substrates. Regarding post‑modification of crinipellin diterpenes, through chemical synthesis and heterologous‑expression assays, the team elucidated the oxidative network governed by three cytochrome P450 oxidases MfdC, MfdD and MfdE, and obtained 19 novel oxidized products. Among them, MfdE of the CYP5136 family catalyzes an oxidative demethylation reaction with C‑C bond cleavage, broadening the catalytic repertoire of P450 oxidases within this family. This work systematically delineates the complete biosynthetic route of crinipellin diterpenes, ranging from core-scaffold construction to post‑modification oxidation, and reveals the enormous catalytic‑diversity potential of fungal diterpene synthases and P450 oxidases. The discovery of the mfd gene cluster and its cognate enzymes lays a foundation for the future targeted generation of structurally novel diterpenoids via synthetic-biology approaches, and also provides valuable references for mining “cryptic” natural products from rare medicinal fungal resources.
Editor‑in‑charge: Liu Qiong Reviewed by: Lei Changsheng Uploaded by: Liu Hong Release Date: August 24, 2026
