ABSTRACT
Coprinoferrin (CPF), originally isolated from a genetically engineered strain (ΔlaeA) of the mushroom fungus Coprinopsis cinerea, is an acylated tripeptide hydroxamate consisting of tandem aligned N5-hexanoyl-N5-hydroxy-L-ornithine with modifications of N-acetyl and C-carboxamide. These unique chemical properties make CPF an iron(III) binder (siderophore), which helps in iron acquisition from the environment and promotes hyphal growth as well as fruiting body formation in C. cinerea. However, CPF's detailed mode of action remains enigmatic. In this study, we have accomplished the synthesis of CPF from N-Boc-L-glutamic acid 5-benzyl ester. The physicochemical characteristics, spectroscopic features, and biological activity observed in the synthetic CPF closely match those of natural CPF. This alignment provides unequivocal confirmation of the proposed chemical structure, facilitating a deeper understanding of its physiological role in nature, particularly in fruiting body formation.
Subject(s)
Ferric Compounds , Siderophores , Siderophores/chemistry , Iron , Hydroxamic Acids/pharmacologyABSTRACT
Chaetomium globosum is a filamentous fungus from which we have previously isolated a series of interesting natural products. Here, we isolated a previously unknown natural product from the culture of C. globosum. Through spectroscopic and crystallographic characterization, we determined the compound to be a new dimerized azaphilone-type product which we termed cochliodone J (1). Furthermore, our investigation into the biological activity of the natural product determined that 1 was cytotoxic to human cervix carcinoma HeLa cells with an IC50 of 17.3 µM. Lastly, a plausible biosynthetic mechanism for 1 is suggested based on our previous study on the biosynthesis of a closely related compound, cochliodone A (2).
Subject(s)
Antineoplastic Agents/pharmacology , Benzopyrans/pharmacology , Chaetomium/chemistry , Pigments, Biological/pharmacology , Uterine Cervical Neoplasms/drug therapy , Antineoplastic Agents/chemistry , Antineoplastic Agents/isolation & purification , Benzopyrans/chemistry , Benzopyrans/isolation & purification , Female , HeLa Cells , Humans , Inhibitory Concentration 50 , Pigments, Biological/chemistry , Pigments, Biological/isolation & purificationABSTRACT
LaeA is a positive global regulator of secondary metabolism in Ascomycetes, but its role in Basidiomycetes, including medicinal mushrooms, remains uncharacterized. Here, knockout of laeA in the model mushroom Coprinopsis cinerea unexpectedly upregulated the biosynthesis of a novel siderophore, coprinoferrin. Furthermore, knockout of the nonribosomal peptide synthetase-encoding cpf1 responsible for coprinoferrin biosynthesis resulted in growth defect and loss of fruiting body formation, indicating the complex role that this natural product plays in fungal cell development.
