The Structure of Tunicamycin

Takatsuki, Akira; Kawamura, Kenji; Okina, Masao; Kodama, Yoshio; Itô, Teiichiro; Tamura, Gakuzo

doi:10.1080/00021369.1977.10862856

Cited by 46 publications

(44 citation statements)

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“…16) After the present work had been completed, the structure of tunicamycin (Fig. 5) was published by TAKATSUKI et al 17) Tunicamycin was shown to be a mixture of four homologous antibiotics which differ in the length of the carbon chain of the trans a,/3-unsaturated iso-fatty acid component (where n=8, 9, 10 or 11). The four common groups of peaks (III-VI, Fig.…”

Section: Discussionmentioning

confidence: 99%

Holomycin and an antibiotic(MM 19290) related to tunicamycin, metabolites of Streptomyces clavuligerus.

Kenig

Reading

1979

J. Antibiot.

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Streptomyces clavuligerus produces penicillin N, several cephalosporins and the /3-lactamase inhibitor clavulanic acid. The detection, isolation and properties of further metabolites of this culture, MM 21801 and MM 19290, are described. MM 21801 was identified as the antibiotic holomycin. MM 19290 was shown to be related to tunicamycin, an antibiotic complex obtained from cultures of Streptomyces lysosuperificus.Streptomyces clavuligerus ATCC 27064 (NRRL 3585) was first described as a producer of penicillin N and of a number of antibiotics structurally related to cephalosporin C, namely the 3-carbamoyloxymethyl analogue and the 7-methoxy derivative of the latter (cephamycin C), and deacetoxycephalosporin C"22,3). More recently, a potent inhibitor of /3-lactamase, clavulanic acid, was isolated from Streptomyces clavuligerus''", and shown to be a novel fused /3-lactam.1) The culture has since also been found to produce a series of clavams with antifungal activity.') We report here the detection and isolation of further antibiotics from Streptomyces clavuligerus, which have been identified as holomycin (MM 21801) and a complex (MM 19290) related to tunicamycin. Detection MethodsIn order to detect the presence of substances with antibacterial activity in cultures of Streptomyces clavuligerus, a biochromatographic procedure was used. Samples of the culture filtrate were applied to 1-cm-wide paper strips of Whatman Grade 1, and descending chromatography carried out at 4°C. The dried strips were contacted with agar plates seeded with Bacillus subtilis ATCC 6633, Sarcina lutea NCTC 8340 or Klebsiella pneumoniae ATCC 29665 as test organisms. In addition, a special bioautographic method, in which the agar contained both Klebsiella pneumoniae ATCC 29665 and benzylpenicillin, was used to locate the /3-lactamase inhibitor clavulanic acid." MM 21801Fermentation and Isolation Mycelium and spores from an agar slope of a mutant strain of Streptomyces clavuligerus , designated ITI, produced by far UV irradiation of the parent culture, were used to inoculate 50O-m1 flasks containing 100 ml of a chemically defined medium at pH 7, consisting of 1.5 glycerol , 2% sucrose, 0.25 % proline, 0.15 % sodium glutamate, 0.5 % NaCl, 0.2 % K2HPO4, 0.04 % CaCl2 , 0.01 MnCl2.4H2O, 0.01 % FeCl3.6H2O, 0.005 % ZnCl2, 0.1 % MgSO3.7H2O in deionised water. Ten ml of the seed culture were transferred after 4 days to each of a series of 2-liter flasks containing 500 ml of the same medium. The flasks were incubated at 26°C on a rotary shaker (240 rpm, 5-cm throw) for 72 hours. Three active metabolites were detected in the culture broth by biochromatography , of

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Section: Discussionmentioning

confidence: 99%

Holomycin and an antibiotic(MM 19290) related to tunicamycin, metabolites of Streptomyces clavuligerus.

Kenig

Reading

1979

J. Antibiot.

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“…Lipid groups (putative membrane anchors) are a common feature of other antibiotics which target membrane-associated steps of peptidoglycan synthesis (e.g., ramoplanin [3], moenomycin [17], amphomycin [2], tunicamycin [15], and enduracidin [7]), suggesting that these may also take advantage of the chelate effect for the enhancement of binding to membraneassociated targets. Our results show that dimerization or lipoylation of antibiotics of the vancomycin group promotes the affinity of the antibiotics for the growing cell wall, resulting in the improved antibacterial activities of these clinically important molecules.…”

Section: Vol 39 1995 Notes 783mentioning

confidence: 99%

Dimerization and membrane anchors in extracellular targeting of vancomycin group antibiotics

Beauregard¹,

Williams²,

Gwynn³

et al. 1995

Antimicrob Agents Chemother

236

193

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Antibiotics of the vancomycin group are shown to enhance their affinities for the bacterial cell wall by the devices of either dimerization (vancomycin and other glycopeptides which dimerize even more strongly) or use of a membrane anchor (teicoplanin); a chelate mechanism is suggested in both cases, as supported by antagonism experiments with the cell wall analog di-N-acetyl-L-Lys-D-Ala-D-Ala. These results may have implications for other binding processes which occur near membrane surfaces.Recent reviews of structure-activity relationships for antibiotics of the vancomycin group (10) have not considered dimerization of the antibiotics, which we now believe plays an important role in the mode of action (5,8,9,16). Here, we present results consistent with a mechanism by which dimeric (e.g., vancomycin [Fig. 1A]) and lipoylated (e.g., teicoplanin [ Fig. 1C]) glycopeptides enhance the binding affinities to their cellular targets by preferential location of the antibiotic near the site of cell wall biosynthesis.The antibacterial activities of vancomycin antibiotics result from their affinities for the Opeptidyl-D-Ala-D-Ala sequence present in the growing cell wall of gram-positive bacteria (11,14,18); bound antibiotic inhibits the transglycosylase and transpeptidase enzymes responsible for construction of the cell wall (13). While the antibiotic activity can generally be correlated with the association constant for the cell wall, as measured with the cell wall analog di-N-acetyl-L-Lys-D-Ala-D-Ala (DALAA), antibiotics which dimerize strongly show anomalously high in vitro activities (4, 6, 9).Back-to-back homodimers (Fig. 2) are formed by most antibiotics of the vancomycin group (with the exception of teicoplanin [see below]), as shown by nuclear magnetic resonance studies (4,8,16). Dimerization is promoted by structural epitopes which appear as additions to the basic heptapeptide motif, including chlorine atoms and sugars at two sites (8). Furthermore, dimerization increases the affinity for cell wall analogs by a factor of 1 to 10, as shown in nuclear magnetic resonance experiments (9); conversely, cell wall fragments enhance dimerization by factors of 2 to 100 (9).This evidence suggests that dimerization may have physiological significance in the action of antibiotics of the vancomycin group. This was investigated by determining the effects of the cell wall analog DALAA on the potencies of glycopeptide antibiotics exhibiting a range of dimerization constants by an agar diffusion assay by the methods of Rake et al. (12). Glycopeptides (1 g) and DALAA (1 to 200 g) were added as aqueous solutions to paper disks (6-mm diameter; Whatman AA), which were dried before being placed on the surfaces of agar plates (1-mm agar thickness); antibiotic medium 1 (Difco Laboratories, Detroit,) was inoculated with Bacillus subtilis ATCC 6633 (30-l spore suspension/10 ml of agar Difco Laboratories, Detroit, Mich.), which was used as the indicator organism. After incubation at 37ЊC for 18 h, inhibition zone diameters were measured. D...

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“…These substances interfere with lipid-dependent protein glycosylation [S, 13 -171 but their application as biochemical tools is limited. Tunicamycin, for instance, is highly lipophilic [18,19] and once it has been adsorbed to cellular membranes a reversal of its activity by washing the cells is not possible [2,20].…”

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confidence: 99%

Glucosamine Itself Mediates Reversible Inhibition of Protein Glycosylation

Koch

Schwarz

Scholtissek

1979

European Journal of Biochemistry

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The metabolism of glucosamine in chick embryo fibroblasts was studied at different concentrations of the amino sugar added to the culture medium.In glucose-containing medium the well-known metabolites, UDP-N-acetylglucosamine, Nacetylglucosamine 6-phosphate and N-acetylglucosamine, are detectable after inhibition of glycosylation resulting from glucosamine treatment. Especially when the cells were infected with influenza virus, high intracellular concentrations of non-metabolized glucosamine are demonstrable in addition.Removal of the inhibitor from the medium results in release of the block of influenza virus glycoprotein glycosylation within 10 min. The onset of glycosylation is paralleled by a rapid reduction of intracellular levels of glucosamine without significant changes in the concentrations of its metabolites. Furthermore, concentrations of GDP-mannose, UDP-glucose, and UDP-galactose remain constant for at least 30 min after reversal of the block.It is concluded that glucosamine as such exerts its effect on glycosylation, rather than one of its metabolites being responsible for this effect.

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The Structure of Tunicamycin

Cited by 46 publications

References 0 publications

Holomycin and an antibiotic(MM 19290) related to tunicamycin, metabolites of Streptomyces clavuligerus.

Holomycin and an antibiotic(MM 19290) related to tunicamycin, metabolites of Streptomyces clavuligerus.

Dimerization and membrane anchors in extracellular targeting of vancomycin group antibiotics

Glucosamine Itself Mediates Reversible Inhibition of Protein Glycosylation

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