Al-Qiam Reema A, Khan Firoz S T, Raja Huzefa A, Graf Tyler N, Pearce Cedric J, Oberlies Nicholas H, Hematian Shabnam
Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina 27402, United States.
Mycosynthetix, Inc., Hillsborough, North Carolina 27278, United States.
ACS Chem Biol. 2025 Sep 19;20(9):2063-2068. doi: 10.1021/acschembio.5c00369. Epub 2025 Aug 12.
Perylenequinones (PQs) such as hypocrellins and hypomycins are fungal-derived redox-active metabolites with known roles as photosensitizers in the oxidative stress response and applications in photodynamic therapy (PDT). Here, we report that sp., a filamentous fungus, can survive and grow under strictly anaerobic (argon) conditions─an unexpected finding for a multicellular eukaryote. Modulating redox homeostasis through chemical reduction and oxygen limitation promotes the intramolecular cyclization of hypocrellins, enhancing hypomycin biosynthesis. Moisture content further influences these transformations, with high water levels favoring keto-enol tautomerization and dry, reducing environments promoting hydride substitution at the peripheral positions. These findings highlight redox modulation as a key driver of perylenequinone metabolism and suggest that PQs may contribute to maintaining redox balance under anaerobic stress, hinting at a broader role in oxygen-independent adaptation in filamentous fungi. This work offers new insights at the interface of redox biology, chemical signaling, and fungal metabolism, with potential implications for the stability and function of PQ-based PDT agents in hypoxic, reducing conditions such as tumor microenvironments.
诸如竹红菌素和腐霉素等苝醌类化合物（PQs）是真菌衍生的具有氧化还原活性的代谢产物，已知其在氧化应激反应中作为光敏剂发挥作用，并应用于光动力疗法（PDT）。在此，我们报告了一种丝状真菌在严格厌氧（氩气）条件下能够存活和生长，这对于多细胞真核生物来说是一个意外发现。通过化学还原和限制氧气来调节氧化还原稳态可促进竹红菌素的分子内环化，增强腐霉素的生物合成。水分含量进一步影响这些转化，高水分含量有利于酮 - 烯醇互变异构，而干燥、还原性环境则促进外围位置的氢化物取代。这些发现突出了氧化还原调节作为苝醌代谢的关键驱动因素，并表明PQs可能有助于在厌氧应激下维持氧化还原平衡，暗示其在丝状真菌的非氧依赖性适应中具有更广泛的作用。这项工作在氧化还原生物学、化学信号传导和真菌代谢的交叉领域提供了新的见解，对基于PQ的PDT药物在缺氧、还原性条件（如肿瘤微环境）下的稳定性和功能具有潜在影响。
