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Bruceantin, a novel inhibitor of peptide bond formation

1978; Elsevier BV; Volume: 518; Issue: 1 Linguagem: Inglês

10.1016/0005-2787(78)90120-x

1879-3002

Manuel Fresno, Antonio Gonzales, David Vázquez, Antonio Jiménez,

Toxin Mechanisms and Immunotoxins

The effects of bruceantin on a number of steps of the protein synthesis process have been studied using resolved model systems from both yeast and reticulocytes. Bruceantin is a potent inhibitor of polyphenylalanine synthesis as directed by poly(U). However, inhibition is less pronounced on protein synthesis as directed by endogenous mRNA and the compound inhibits the poly(U) system only poorly if added after polyphenylalanine synthesis has been initiated. Peptide bond formation as assayed in both the fragment reaction and in the puromycin reaction with a preformed initiation complex containing ribosomes and [35S]Met-tRNAF is totally blocked by bruceantin. Neither the enzymic binding of Phe-tRNA to reticulocyte ribosomes nor the formation of the 35S-labeled tRNA · ribosome initiation complex is inhibited by bruceantin. The binding of [14C]trichodermin to yeast ribosomes is strongly inhibited by bruceantin. A Klotz plot shows that both these drugs bind to ribosomes in mutually exclusive fashion and it can be calculated that bruceantin binds to the peptidyltransferase center with Kd = 0.34 μM. This high affinity is considerably lower for polyribosomes (Kd = 557 μM), which may explain the earlier finding that bruceantin only stabilizes polyribosomes at high drug concentrations.