Mechanism of Protein Synthesis Inhibition by Didemnin B in Vitro

SirDeshpande, Bhagyashri V.; Toogood, Peter L.

doi:10.1021/bi00028a030

Cited by 72 publications

(86 citation statements)

References 53 publications

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“…The activity of nordidemnin B was also studied by Dominice et al 38 who reported that nordidemnin B inhibited the growth of rat mammary WRK(1) tumor cells. The authors also reported that phosphoinositide metabolism was blocked with the same EC 50 as measured for WRK(1) cell proliferation. This dual effect on WRK(1) cells was in contrast to the earlier suggestion 35 that the antitumor effect was strictly the result of inhibited protein biosynthesis.…”

Section: Antitumor Activitymentioning

confidence: 75%

Natural products as probes of cell biology: 20 years of didemnin research

Vera

Joullié

2002

Medicinal Research Reviews

143

109

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The discovery of the didemnin family of marine depsipeptides launched an exciting and intriguing chapter in natural product chemistry. The unusual structure of the didemnin congeners has led to several total syntheses by research groups from around the world. The impressive in vitro and in vivo biological activities of the didemnins resulted in the first human clinical trials in the U.S. of a marine natural product against cancer, and additional clinical trials of a second-generation didemnin, dehydrodidemnin B (aplidine), are underway. As we mark the 20-year anniversary of the discovery of the didemnins, this class of natural products continues to stimulate active research in fields ranging from synthetic and medicinal chemistry to clinical oncology and cell biology. While some progress was made in dissecting the molecular mechanism of action and in establishing structure-activity relationships, there are still more questions than answers. This review covers the recent didemnin literature, highlighting the work directed towards understanding how this group of natural products interact with fundamental processes such as cell proliferation, protein biosynthesis, and apoptosis. The didemnin field illustrates how natural product chemistry may be used as a critical tool for the study of cell biology.

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Section: Antitumor Activitymentioning

confidence: 75%

Natural products as probes of cell biology: 20 years of didemnin research

Vera

Joullié

2002

Medicinal Research Reviews

143

109

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show abstract

“…9 This rather unusual mechanism would then be similar to that of the antibiotic kirromycin, which is known to bind to prokaryotic EF1A (previously termed EF-Tu), 15 even though DB, unlike this antibiotic, does not prevent peptide bond formation. Subsequent experimental results led to the suggestion that eEF2 binding could be prevented by inhibiting eEF1A release from the ribosomal A-site, and two alternative scenarios were then envisaged: 14 (i) direct competition of the DB‚eEF1A complex with eEF2 for the same binding site on the 27) showing the role of eEF1A and eEF1B (red arrows) in translation elongation.…”

Section: Introductionmentioning

confidence: 94%

“…Both of these mechanisms would be consistent with the observation that DB inhibition of translocation can be attenuated by increasing concentrations of eEF2. 9 Thus, although the absolute requirement for eEF1A in DB's action has been conclusively demonstrated, no structural details have been unveiled that could shed light on the way eEF2 binding to pretranslocative ribosome‚ eEF1A complexes is blocked by this natural product.…”

Section: Introductionmentioning

confidence: 99%

Structural Basis for the Binding of Didemnins to Human Elongation Factor eEF1A and Rationale for the Potent Antitumor Activity of These Marine Natural Products

et al. 2004

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Didemnins and tamandarins are closely related marine natural products with potent inhibitory effects on protein synthesis and cell viability. On the basis of available biochemical and structural evidence and results from molecular dynamics simulations, a model is proposed that accounts for the strong and selective binding of these compounds to human elongation factor eEF1A in the presence of GTP. We suggest that the p-methoxyphenyl ring of these cyclic depsipeptides is inserted into the same pocket in eEF1A that normally lodges either the 3′ terminal adenine of aminoacylated tRNA, as inferred from two prokaryotic EF-Tu‚GTP‚tRNA complexes, or the aromatic side chain of Phe/Tyr-163 from the nucleotide exchange factor eEF1BR, as observed in several X-ray crystal structures of a yeast eEF1A:eEF1BR complex. This pocket, which has a strong hydrophobic character, is formed by two protruding loops on the surface of eEF1A domain 2. Further stabilization of the bound depsipeptide is brought about by additional crucial interactions involving eEF1A domain 1 in such a way that the molecule fits snugly at the interface between these two domains. In the GDP-bound form of eEF1A, this binding site exists only as two separate halves, which accounts for the much greater affinity of didemnins for the GTP-bound form of this elongation factor. This binding mode is entirely different from those seen in the complexes of the homologous prokaryotic EF-Tu with kirromycin-type antibiotics or the cyclic thiazolyl peptide antibiotic GE2270A. Interestingly, the set of interactions used by didemnins to bind to eEF1A is also distinct from that used by eEF1BR or eEF1B , thus establishing a competition for binding to a common site that goes beyond simple molecular mimicry. The model presented here is consistent with both available biochemical evidence and known structure-activity relationships for these two classes of natural compounds and synthetic analogues and provides fertile ground for future research.

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“…tRNA-binding and translocation assays were performed essentially as described (SirDeshpande and Toogood 1995;Robert et al 2006). […”

Section: Trna-binding and Translocation Assaysmentioning

confidence: 99%

Inhibition of translation by cytotrienin A—a member of the ansamycin family

Lindqvist¹,

Robert²,

Merrick³

et al. 2010

RNA

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The ansamycins are a diverse and often physiologically active group of compounds that include geldanamycin and rifamycin, inhibitors of heat shock protein 90 and prokaryotic DNA-dependent RNA synthesis, respectively. Cytotrienin A is an ansamycintype small molecule with potent antiproliferative and proapoptotic properties. Here, we report that this compound inhibits eukaryotic protein synthesis by targeting translation elongation and interfering with eukaryotic elongation factor 1A function. We also find that cytotrienin A prevents HUVEC tube formation and diminishes microvessel formation in the chorioallantoic membrane assay. These results provide a molecular understanding into cytotrienin A's previously reported properties as an anticancer apoptosis-inducing drug.

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Mechanism of Protein Synthesis Inhibition by Didemnin B in Vitro

Cited by 72 publications

References 53 publications

Natural products as probes of cell biology: 20 years of didemnin research

Natural products as probes of cell biology: 20 years of didemnin research

Structural Basis for the Binding of Didemnins to Human Elongation Factor eEF1A and Rationale for the Potent Antitumor Activity of These Marine Natural Products

Inhibition of translation by cytotrienin A—a member of the ansamycin family

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