Didemnin binds to the protein palmitoyl thioesterase responsible for infantile neuronal ceroid lipofuscinosis.
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.
Crews
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Howard Hughes Medical Institute, Department of Chemistry and Chemical Biology, Cambridge MA, USA. craig.crews@yale.edu
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Schreiber
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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*
D017931:DNA Primers; D047630:Depsipeptides; D010456:Peptides, Cyclic; C030051:didemnins; D013869:Thiolester Hydrolases; C095299:palmitoyl-protein thioesterase; D019204:GTP-Binding Proteins