Fatty Acid Synthase as Interacting Anticancer Target of the Terpenoid Myrianthic Acid Disclosed by MS-Based Proteomics Approaches

• Published in: International journal of molecular sciences Vol. 25; no. 11; p. 5918
• Main Authors: Capuano, Alessandra, D'Urso, Gilda, Gazzillo, Erica, Lauro, Gianluigi, Chini, Maria Giovanna, D'Auria, Maria Valeria, Ferraro, Maria Grazia, Iazzetti, Federica, Irace, Carlo, Bifulco, Giuseppe, Casapullo, Agostino
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01-06-2024; MDPI
• Subjects: Amino acids; Analysis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cancer; Care and treatment; Cell Line, Tumor; Cell Proliferation - drug effects; DARTS; drug discovery; Enzymes; Experiments; fatty acid synthase; Fatty Acid Synthases - antagonists & inhibitors; Fatty Acid Synthases - chemistry; Fatty Acid Synthases - metabolism; Fatty acids; functional proteomics; Humans; Ligands; Mass Spectrometry; molecular docking; Molecular Docking Simulation; Natural products; Peptides; Proteins; Proteolysis; Proteomics - methods; R&D; Research & development; Scientific imaging; Signal transduction; Software; Synthesis; t-LiP; Terpenes - chemistry; Terpenes - metabolism; Terpenes - pharmacology; Triterpenes - chemistry; Triterpenes - metabolism; Triterpenes - pharmacology; Tumors; t-LiP; molecular docking; drug discovery; fatty acid synthase; functional proteomics; preclinical investigations; DARTS
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25115918

This research focuses on the target deconvolution of the natural compound myrianthic acid, a triterpenoid characterized by an ursane skeleton isolated from the roots of
and from
Nutt. (Onagraceae), using MS-based chemical proteomic techniques. Application of drug affinity responsive target stability (DARTS) and targeted-limited proteolysis coupled to mass spectrometry (t-LiP-MS) led to the identification of the enzyme fatty acid synthase (FAS) as an interesting macromolecular counterpart of myrianthic acid. This result, confirmed by comparison with the natural ursolic acid, was thoroughly investigated and validated in silico by molecular docking, which gave a precise picture of the interactions in the MA/FAS complex. Moreover, biological assays showcased the inhibitory activity of myrianthic acid against the FAS enzyme, most likely related to its antiproliferative activity towards tumor cells. Given the significance of FAS in specific pathologies, especially cancer, the myrianthic acid structural moieties could serve as a promising reference point to start the potential development of innovative approaches in therapy.