Disease relevance of Delvomycin

• We have used electron cryomicroscopy and angular reconstitution to visualize directly the kirromycin-stalled ternary complex in the A site of the 70S ribosome of Escherichia coli [1].
• Mg2+ is not catalytically required in the intrinsic and kirromycin-stimulated GTPase action of Thermus thermophilus EF-Tu [2].
• In a previous study (C. C. Hall, J. D. Watkins, and N. H. Georgopapadakou, Antimicrob. Agents Chemother. 33:322-325, 1989), the elongation factor Tu (EF-Tu) from Staphylococcus aureus was found to be insensitive to a series of kirromycin analogs which were inhibitory to the EF-Tu from Escherichia coli [3].
• The unique tuf2 gene from the kirromycin producer Streptomyces ramocissimus encodes a minor and kirromycin-sensitive elongation factor Tu [4].
• Genetic and biochemical characterization of kirromycin resistance mutations in Bacillus subtilis [5].

High impact information on Delvomycin

• In addition, the ability of wild-type tufB to complement kirromycin resistance was determined with deletion plasmids [6].
• In the presence of kirromycin, the activated conformation of EF-Tu appears to be frozen [7].
• The steps following GTP hydrolysis--the switch of EF-Tu to the GDP-bound conformation, the release of aminoacyl-tRNA from EF-Tu to the A site, and the dissociation of EF-Tu-GDP from the ribosome--which are altogether suppressed by kirromycin, are not distinguished kinetically [7].
• Evidence is presented that kirromycin binds to this interface of wild-type EF-Tu.GTP, thereby jamming the conformational switch of EF-Tu upon GTP hydrolysis [8].
• As with the latter, poly(Phe) synthesis by EF-TuGly20 is inhibited by the antibiotic kirromycin, but differs remarkably in that it is largely independent of the presence of EF-Ts [9].

Chemical compound and disease context of Delvomycin

• Like E. coli EF-Tu, it is sensitive to modification by N-ethylmaleimide and is inhibited by the antibiotic kirromycin [10].
• A kirromycin resistant elongation factor EF-Tu from Escherichia coli contains a threonine instead of an alanine residue in position 375 [11].
• Pulvomycin and kirromycin, two antibiotics which inhibit protein biosynthesis in Escherichia coli by complex formation with the elongation factor Tu (EF-Tu), bind to different sites on the protein [12].
• A kirromycin-resistant EF-Tu species reverses streptomycin dependence of Escherichia coli strains mutated in ribosomal protein S12 [13].
• Natural kirromycin resistance of elongation factor Tu from the kirrothricin producer Streptomyces cinnamoneus [14].

Biological context of Delvomycin

• These data strongly suggest that kirromycin induces in EF-Tu.GDP an additional tRNA binding site that can bind uncharged tRNA, aminoacyl-tRNA, and N- acetylaminoacyl -tRNA [15].
• The fact that X5108 bound to EF-Tu is not in rapid equilibrium with X5108 free in solution needs to be considered in studies on the effect of X5108 and kirromycin on partial reactions of protein biosynthesis [16].
• Post-translational phosphorylation of EF-Tu had been shown to prevent its binding to amino-acylated transfer RNA as well as to kirromycin, an antibiotic known to inhibit EF-Tu function [17].
• They were selected by their kirromycin resistant phenotypes and all substitutions are in domain I at the interface between domains I and III of the EF-Tu.GTP configuration [18].
• We have isolated and sequenced a collection of kirromycin resistant tuf mutations and identified thirteen single amino acid substitutions at seven different sites in EF-Tu [19].

Anatomical context of Delvomycin

• Action of pulvomycin and kirromycin on eukaryotic cells [20].

Associations of Delvomycin with other chemical compounds

• Since both interface regions are involved in the EF-Tu switch mechanism, we propose that pulvomycin and kirromycin both act by specifically disturbing the allosteric changes required for the switch from EF-Tu-GTP to EF-Tu-GDP [21].
• The interaction of the polypeptide chain elongation factor Tu (EF-Tu) with the antibiotic kirromycin and tRNA has been studied by measuring the extent of protein modification with N-tosyl-L-phenylalanine chloromethylketone (TPCK) and N-ethylmaleimide (NEM) [15].
• The effect of guanine nucleotides and kirromycin on the conformation and stability of the chloroplast elongation factor Tu (EF-Tuchl) from Euglena gracilis has been investigated [22].
• The binding site overlaps that of kirromycin, an antibiotic with a structure that is unrelated to enacyloxin IIa but that also inhibits EF-Tu.GDP release [23].
• Aurodox is a member of the family of kirromycin antibiotics, which inhibit protein biosynthesis by binding to elongation factor Tu (EF-Tu) [24].

Gene context of Delvomycin

• These plasmids continued to express tufA, as judged by the ability to complement mocimycin resistance and by electrophoretic analysis of synthesized proteins [25].
• The deletion of the three tRNA genes does not significantly alter the in vivo expression of tufB as assessed by the kirromycin-sensitive phenotype of the transformant cells and by the synthesis of EF-Tu in mini-cells [26].
• Characterization of ftsZ gene and its protein product from Streptomyces collinus producing kirromycin [27].
• Although entry of the charged transfer messenger RNA (tmRNA) into the ribosome proceeded in the absence of elongation factor (EF-Tu) and in the presence of EF-Tu and the antibiotic kirromycin, evidence was found for the involvement of EF-Tu in trans-translation initiation [28].
• The resulting EF-TuBo kirromycin and EF-TuAr EF-Ts complexes are separated by chromatography on diethylaminoethyl-Sephadex A-50 [29].

Analytical, diagnostic and therapeutic context of Delvomycin

• Isolation, crystallization and X-ray analysis of the quaternary complex of Phe-tRNA(Phe), EF-Tu, a GTP analog and kirromycin [30].
• Western blot analysis showed that Sr.EF-Tu1 was present at all times under kirromycin production conditions in submerged and surface-grown cultures of S. ramocissimus and in germinating spores [31].

References