title: Didemnin binds to the protein palmitoyl thioesterase responsible for infantile neuronal ceroid lipofuscinosis.
abstract: 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 EF1 alpha. 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 didemnin-binding 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 G alpha 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.
authors.affiliation: Howard Hughes Medical Institute, Department of Chemistry and Chemical Biology, Cambridge MA, USA. craig.crews@yale.edu
authors.forename: C M
authors.initials: CM
authors.lastname: Crews
authors.forename: W S
authors.initials: WS
authors.lastname: Lane
authors.forename: S L
authors.initials: SL
authors.lastname: Schreiber
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000201:enzymology* / Q000378:metabolism*; D002417:Cattle; D016384:Consensus Sequence; D017931:DNA Primers; D047630:Depsipeptides; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D007223:Infant; D008969:Molecular Sequence Data; D008970:Molecular Weight; D009472:Neuronal Ceroid-Lipofuscinoses / Q000201:enzymology*; D010456:Peptides, Cyclic / Q000096:biosynthesis / Q000302:isolation & purification / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D051381:Rats; D017386:Sequence Homology, Amino Acid; D013869:Thiolester Hydrolases / Q000737:chemistry / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D047630:Depsipeptides; D010456:Peptides, Cyclic; C030051:didemnins; D013869:Thiolester Hydrolases; C095299:palmitoyl-protein thioesterase; D019204:GTP-Binding Proteins