《生命科学》 2026, 38(5): 917-931
安丝菌素的生物合成途径及高产菌株研究现状
摘 要：
安丝菌素作为抗体-药物偶联物的关键细胞毒素，其高产机制与工艺研究具有重要意义。本文系统梳理了高产策略的核心进展：生物合成机制解析阐明了聚酮合酶基因簇功能及后修饰酶催化网络，揭示了安丝菌素对生产菌株的多靶点自身毒性效应；菌种选育与改造融合传统诱变与分子技术，通过定向削弱竞争途径、强化限速步骤及调控因子工程，显著提升合成通量；代谢调控创新实现了前体供应精准优化与辅因子动态平衡；发酵工艺突破在规模化体系中验证了碳源时序调控与氧传递强化策略的工业可行性。未来研究需整合动态调控与智能发酵技术，推动产业化进程。
通讯作者：曹广祥 , Email:caoguangxiang@sdfmu.edu.cn
Abstract:
Ansamitocin P-3 (AP-3), a potent cytotoxic payload for antibody-drug conjugates (ADCs), holds significant clinical value in targeted tumor therapy. However, its industrialization is hindered by low fermentation titers and high production costs, underscoring the critical need for research into its high-yield mechanisms and technologies. This review systematically summarizes recent advances in strategies to enhance AP-3 production, focusing on its biosynthetic pathway and the engineering of high-yield strains of Actinosynnema pretiosum. Elucidation of the AP-3 biosynthetic mechanism has clarified the modular organization of the polyketide synthase (PKS) gene cluster and the nonlinear post-modification enzymatic network. Furthermore, it has revealed the multi-target self-cytotoxicity of AP-3 against the producing strain and identified the regulatory roles of key factors, such as Asm8 and AdpA_1075. In strain development, the integration of traditional mutagenesis (e.g., UV, MNNG) and atmospheric and room temperature plasma (ARTP) with modern molecular tools like CRISPR-Cas9 has yielded remarkable results. Success has been achieved through targeted attenuation of competitive pathways, reinforcement of rate-limiting steps (e.g., supply of AHBA and methylmalonyl-CoA), engineering of regulatory factors, and alleviation of product feedback inhibition. Innovations in metabolic regulation have enabled precise optimization of precursor supply and the dynamic balancing of cofactors such as SAM and NADPH. In addition, breakthroughs in fermentation technology, including time-dependent carbon source control, enhanced oxygen transfer, and pulse-feeding strategies, have been validated for industrial feasibility in scaled-up bioreactors. The highest reported AP-3 titer of 757.7 mg/L stands as a key milestone. Finally, we summarize the primary bottlenecks hindering the industrialization of AP-3 production and propose future research directions. These focus on integrating dynamic metabolic regulation with intelligent fermentation technologies to further improve efficiency and reduce costs. This integrated approach is expected to accelerate the industrial translation of AP-3 and ensure a stable supply of this high-value cytotoxic payload for the development and clinical application of ADC drugs.
Communication Author：CAO Guang-Xiang , Email:caoguangxiang@sdfmu.edu.cn
SciCloud投稿系统