Inhibitors of Bacterial Elongation Factor EF‐Tu

Abstract

Decoding of the genetic message occurs in a ribosomal site called A-site. Here,\ud a given amino acid is specifically recognized by the anticodon triplet of a tRNA\ud molecule carrying the corresponding amino acid. In all kingdoms of life, the\ud aminoacyl-tRNA (aa-tRNA) does not bind to the ribosomal A-site in a free form\ud but is always accompanied by an elongation factor (EF) with a bound guanosine-\ud 5-triphosphate (GTP) molecule so that a ternary complex is the molecular form\ud in which all aa-tRNAs, with the exception of the initiator tRNA, are brought to\ud the ribosome. In bacteria, the EF responsible for this activity is EF-Tu, a notable\ud representative of a widespread class of proteins called G proteins. The function of\ud EF-Tu is not restricted to that of a simple carrier insofar as this factor plays, together\ud with the ribosome, an active role in the faithful selection of the correct aa-tRNA.\ud As with other members of the GTPase switch proteins, EF-Tu also undergoes\ud important structural changes when its bound GTP molecule is hydrolyzed to GDP\ud following the activation by the ribosome of the intrinsic GTPase activity of EF-Tu.\ud Upon formation of codon–anticodon interaction, the affinity of EF-Tu·GDP for the\ud ribosome is substantially decreased so that the factor can be dissociated from the\ud ribosome. Unlike the other ribosome-dependent GTPases, IF2, and EF-G, which do\ud not require a GTP–GDP exchange factor, GDP is dissociated from the EF-Tu and\ud exchanged for GTP through the action of EF-Ts [1–3]. The translation elongation\ud steps involved in the EF-Tu-dependent decoding of aa-tRNA are schematically\ud represented in Figure 18.1.\ud EF-Tu is one of the major antibiotic targets among the protein synthesis\ud inhibitors, a property that emphasizes its central role in protein synthesis and\ud cell growth [4]. Four families of antibiotics of unrelated structures have EF-Tu as\ud target. They comprise a total of more than 30 members and have selective antibacterial\ud activities. Their prototypes are enacyloxin IIa, kirromycin, pulvomycin, and\ud GE2270A