新型干细胞分化诱导物SCI-001的生物合成途径研究

Some natural products have been ascertained to be able induce stem cell differentiations (SCD), but the structures of those inducers are known and it remains to be a challenge to discover SCD-inducing natural products with unprecedented architectures. The research group has characterized SCI-001 as a skeletally undescribed fungal polyketide capable of inducing the differentiation of marrow mesenchymal stem cells into neuronal cells. With such an impressive finding, this project is designed to reveal a novel small molecule inducer for stem cell differentiations, which deserves further investigations and/or possess clinical potentials. To achieve the goal, the proposed investigation mainly includes the clarification of the SCI-001 biosynthetic pathway, the biotechnological generation of the SCI-001 variants using the clarified bioassembly line, and the evaluation of the SCD-inducing activity of this family of fungal polyketides.

某些天然产物具有诱导干细胞分化的作用，但其化学结构大多已知；具有干细胞分化诱导作用的全新天然分子尚未见报道。项目组已发现骨架全新真菌聚酮SCI-001可将小鼠骨髓间充质干细胞诱导分化成神经元细胞，本项目拟研究揭示SCI-001独特骨架的产生过程，结合合成生物学方法与技术巧借真菌生物合成组装线构建SCI-001的骨架相关物，评价比较SCI-001及其骨架相关物的干细胞分化诱导效果与特点，旨在优化发现有望用于干细胞与再生医学研究和/临床治疗目的的全新分子，推动天然产物化学、化学生物学、干细胞与再生医学、合成生物学等相关学科的发展。

Polyketide–polyketide hybrids are unique natural products with promising bioactivity, but the hybridization processes remain poorly understood. Herein, we present that the biosynthetic pathways of two immunosuppressants, dalmanol A and acetodalmanol A, result from an unspecific monooxygenase triggered hybridization of two distinct polyketide (naphthalene and chromane) biosynthetic gene clusters. The orchestration of the functional dimorphism of the polyketide synthase (ChrA) ketoreductase (KR) domain (shortened as ChrA KR) with that of the KR partner (ChrB) in the bioassembly line increases the polyketide diversity and allows the fungal generation of plant chromanes (e.g., noreugenin) and phloroglucinols (e.g., 2,4,6-trihydroxyacetophenone). The simultaneous fungal biosynthesis of 1,3,6,8- and 2-acetyl-1,3,6,8-tetrahydroxynaphthalenes was addressed as well. Collectively, the work may symbolize a movement in understanding the multiple-gene-cluster involved natural product biosynthesis.