Phomoxanthone A, a bioactive xanthone dimer isolated from the endophytic fungus Phomopsis sp., is a mitochondrial toxin weakening cellular respiration and electron transport chain activity by a fast breakup of the mitochondrial assembly. Here, a multi-disciplinary strategy has been developed and applied for identifying phomoxanthone A target(s) to fully address its mechanism of action, based on drug affinity response target stability and targeted limited proteolysis. Both approaches point to the identification of carbamoyl-phosphate synthase 1 as a major phomoxanthone A target in mitochondria cell lysates, giving also detailed insights into the ligand/target interaction sites by molecular docking and assessing an interesting phomoxanthone A stimulating activity on carbamoyl-phosphate synthase 1. Thus, phomoxanthone A can be regarded as an inspiring molecule for the development of new leads in counteracting hyperammonemia states.
Carbamoyl-phosphate synthase 1 as a novel target of phomoxanthone a, a bioactive fungal metabolite / Ceccacci, S.; Deitersen, J.; Mozzicafreddo, M.; Morretta, E.; Proksch, P.; Wesselborg, S.; Stork, B.; Monti, M. C.. - In: BIOMOLECULES. - ISSN 2218-273X. - 10:6(2020), p. 846. [10.3390/biom10060846]