Didemnine

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Structure of Didemnine A, B and C

Didemnins are a class of tumor-inhibiting, anti-proliferative, anti-viral and protein synthesis-inhibiting substances that were first extracted from sea ​​squirts ( Ascidiacea ) such as Trididemnum solidum . Their actual synthesis, however, is most likely due to bacteria, since the genes required for this (so-called did clusters) were detected on plasmids and didemnin synthesis in the α- Proteobacteria Tistrella mobilis and Tistrella bauzanensis .

Chemically, the didemnins belong to the depsipeptides and consist of ring-shaped, partly modified amino acids , to which further functional groups or compounds of other classes are bound. These peptides are not synthesized by ribosomes but by peptide synthases . Didemnin B probably arises from precursor molecules that are modified extracellularly.

In a study of the mechanism of action of didemnin B on protein biosynthesis, it was shown that didemnin B, in addition to other general anti-proliferative effects, effectively inhibits the translocation mechanism of eukaryotic ribosomes by forming a complex with the elongation factor EF-1 and guanosine diphosphate (GDP) which remains bound to the ribosome and thus prevents translocation and the successive protein lengthening. Because of their anti-proliferative properties, some of the didemnins have been and are being researched as cancer drugs. For example, a closely related compound of didemnin B, dehydrodidemnin B (aplidine, plitidepside), from the sea squirt Aplidium albicans is being tested by the Spanish pharmaceutical company PharmaMar SA. Investigations with didemnin B were discontinued due to the high cytotoxicity.

Individual evidence

  1. ↑ a b Y. Xu, R. Kersten u. a .: Bacterial Biosynthesis and Maturation of the Didemnin Anti-cancer Agents. In: Journal of the American Chemical Society . 134, 2012, pp. 8625-8632, doi : 10.1021 / ja301735a .
  2. ↑ a b c M. Tsukimoto, M. Nagaoka u. a .: Bacterial Production of the Tunicate-Derived Antitumor Cyclic Depsipeptide Didemnin B. In: Journal of Natural Products . 74, 2011, pp. 2329-2331, doi : 10.1021 / np200543z .
  3. ↑ B. SirDeshpande, P. Toogood: Mechanism of Protein Synthesis Inhibition by Didemnin B in Vitro. In: Biochemistry. 34, 1995, pp. 9177-9184, doi : 10.1021 / bi00028a030 .