Didemnin Binds to the Protein Palmitoyl Thioesterase Responsible for Infantile Neuronal Ceroid Lipofuscinosis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 93; no. 9; pp. 4316 - 4319
• Main Authors: Crews, Craig M., Lane, William S., Schreiber, Stuart L.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 30.04.1996; National Acad Sciences; National Academy of Sciences
• Subjects: Amino Acid Sequence; Amino acids; Animals; Base Sequence; Biochemistry; Brain; Brain - enzymology; Brain - metabolism; Carrier proteins; Cattle; Chromatography; Complementary DNA; Consensus Sequence; Depsipeptides; DNA Primers; GTP-Binding Proteins - metabolism; Humans; Infant; Medical disorders; Messenger RNA; Molecular Sequence Data; Molecular Weight; Neuronal Ceroid-Lipofuscinoses - enzymology; Peptides, Cyclic - biosynthesis; Peptides, Cyclic - isolation & purification; Peptides, Cyclic - metabolism; Polymerase Chain Reaction; Protein Binding; Protein synthesis; Proteins; Rats; Sequence Homology, Amino Acid; T lymphocytes; Thiolester Hydrolases - chemistry; Thiolester Hydrolases - metabolism; Ungulates
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.93.9.4316

The marine natural product didemnin B, currently in clinical trials as an antitumor agent, has several potent biological activities apparently mediated by distinct mechanisms. Our initial investigation of didemnin B resulted in the discovery of its GTP-dependent binding of the translation elongation factor EF1α . This finding is consistent with the protein synthesis inhibitory activity of didemnin B observed at intermediate concentrations. To begin to dissect the mechanisms involved in the cytostatic and immunosuppressive activities of didemnin B, observed at low concentrations, additional didemnin-binding proteins were sought. Here we report the purification of a 36-kDa glycosylated didemninbinding protein from bovine brain lysate. Cloning of the human cDNA encoding this protein revealed a strong sequence similarity with palmitoyl protein thioesterase (PPT), an enzyme that removes palmitate from H-Ras and the Gα s subunits of heterotrimeric GTP-binding proteins in vitro. Mutations in PPT have recently been shown to be responsible for infantile neuronal ceroid lipofuscinosis, which is a severe brain disorder characterized by progressive loss of brain function and early death.