Cm. Crews et al., DIDEMNIN BINDS TO THE PROTEIN PALMITOYL THIOESTERASE RESPONSIBLE FOR INFANTILE NEURONAL CEROID-LIPOFUSCINOSIS, Proceedings of the National Academy of Sciences of the United Statesof America, 93(9), 1996, pp. 4316-4319
The marine natural product didemnin B, currently in clinical trials as
an antitumor agent, has several potent biological activities apparent
ly mediated by distinct mechanisms. Our initial investigation of didem
nin B resulted in the discovery of its GTP-dependent binding of the tr
anslation elongation factor EF1 alpha. This finding is consistent with
the protein synthesis inhibitory activity of didemnin B observed at i
ntermediate concentrations. To begin to dissect the mechanisms involve
d in the cytostatic and immunosuppressive activities of didemnin B, ob
served at low concentrations, additional didemnin-binding proteins wer
e sought. Here we report the purification of a 36-kDa glycosylated did
emnin-binding protein from bovine brain lysate. Cloning of the human c
DNA encoding this protein revealed a strong sequence similarity with p
almitoyl protein thioesterase (PPT), an enzyme that removes palmitate
from H-Ras and the G(alpha s) subunits of heterotrimeric GTP-binding p
roteins in vitro. Mutations in PPT have recently been shown to be resp
onsible for infantile neuronal ceroid lipofuscinosis, which is a sever
e brain disorder characterized by progressive loss of brain function a
nd early death.