Enzyme-inhibitory secondary metabolites and their exudation in the marine-derived fungus <em>Epicoccum nigrum</em> link

Abstract

The kingdom of fungi harbors a huge diversity of life forms. The Ascomycota in particular are a prolific source of medicinal drugs and new lead structures with potent bioactivities. During this work, two marine-derived strains of <em>Epicoccum nigrum</em> – strains 749 and 800 – were assessed for their production of bioactive secondary metabolites, which could serve as lead structures for medicinal use. In this way, 12 compounds with different scaffolds were discovered and identified. Three of these structures are new chemical entities, 5´-6´-dihydroxyacetosellin, 1F4-1-6 and epicaronic acid. Pronounced inhibitory activities against human serine- and cysteine-proteases were revealed for epipyrones. Furthermore, epipyrones were shown to be the first inhibitors of human cerebroside sulfotransferase (hCST). <br /> Through the use of trace metals, the biosynthesis of the two main secondary metabolites – epipyrones and acetosellin – could be controlled. The optimized production of acetosellin enabled studies on its unusual biosynthetic origin. Thus, the assembly from two separate polyketide-derived chains was shown using ¹³C-labeled sodium acetate. Furthermore, the excretion of epipyrones and acetosellin into guttation droplets was studied in dependence of the trace metal content in the medium. Thereby, the eligibility of guttation droplets for the study of the secondary metabolism in fungi was to be studied. Surprisingly, the concentration of epipyrones was strongly elevated in the guttation fluid under optimal production conditions (in comparison to the culture extracts). In contrary, acetosellin was mainly found in the culture extracts. The underlying mechanisms of this observation could be elucidated in future studies.