Bioconversion and biosynthesis of 16-membered macrolide antibiotic, tylosin, using enzyme inhibitor: Cerulenin.

Ōmura, Satoshi; Kitao, Chiaki; Miyazawa, J.; Imai, Harumitsu; Tanaka, Hideo

doi:10.7164/antibiotics.31.254

Cited by 19 publications

(10 citation statements)

References 9 publications

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“…Although these studies established the building blocks for the ring systems of tylosin (17,18), erythromycin (11), pikromycin (20), and by analogy, other macrocyclic lactones, they provided no insight into the mechanisms of synthesis of the complex branched acyclic fatty acids. The notion that formation of the lactone ring precursor could be mechanistically analogous to fatty acid synthesis was suggested by the observation that cerulenin, an inhibitor of fatty acid biosynthesis (13), also inhibited macrolide synthesis (16,19). Recently, it was shown that the N-acetylcysteamine ester of 2-methyl-3-hydroxypentanoic acid was incorporated intact into tylactone (the lactone of tylosin) (27) and erythromycin (6).…”

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confidence: 99%

Branched-chain fatty acids produced by mutants of Streptomyces fradiae, putative precursors of the lactone ring of tylosin

Huber

Paschal

Leeds

et al. 1990

Antimicrob Agents Chemother

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Three branched-chain fatty acids (7-hydroxy-4,6-dimethylnona-2,4-dienoic acid [compound 1], its 7-epimer [compound 2], and 7-keto-4,6,-dimethylnona-2,4-dienoic acid [compound 3]) and a ketone (9-hydroxy-6,8-dimethylundeca-4,6-dien-3-one [compound 4]) were isolated from the culture broth of mutants of Streptomycesfradiae which were blocked in the biosynthesis of the macrolide antibiotic tylosin. Two phenotypic classes of mutants of this organism which were blocked in the addition of mycaminose to tylactone (compound 6) accumulated these compounds. These compounds were not produced by mutants which were blocked in lactone synthesis, in steps beyond mycaminose addition, or by the wild-type strain. Synthesis of these compounds, like synthesis of tylosin, was inhibited by the addition of cerulenin. Compounds 1, 2, and 3 were partially interconvertible by these mutants; but they were not produced from the degradation of tylactone and they were not directly incorporated into tylosin by intact cells. The structures of compounds 1 and 2 were equivalent to that of a predicted intermediate

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confidence: 99%

Branched-chain fatty acids produced by mutants of Streptomyces fradiae, putative precursors of the lactone ring of tylosin

Huber

Paschal

Leeds

et al. 1990

Antimicrob Agents Chemother

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“…Propionate was incorporated into CO2 and cells in a fashion similar to a-ketoglutarate and succinate (Fig. 6 (5,(7)(8)(9). Since the interconversion of propionyl-CoA and methylmalonyl-CoA has been demonstrated in S. fradiae (10), one can postulate common sources for these two tylactone precursors.…”

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confidence: 98%

“…Omura et al (6), using 13C enrichment, showed that tylactone was formed from five propionate molecules, two acetate molecules, and one butyrate molecule. Subsequent inhibition studies with cerulenin, an inhibitor of fatty acid synthetase, showed that tylactone and related macrolide aglycone molecules were assembled in a manner similar to fatty acid biosynthesis (5,(7)(8)(9). The data of Omura et al (5)(6)(7)(8)(9) suggested that the precursors for tylactone biosynthesis were incorporated in the following manner: propionate as one propionyl-coenzyme A (CoA) (primer) and four methylmalonyl-CoA molecules, acetate as two malonyl-CoA molecules, and butyrate as one ethylmalonylCoA molecule.…”

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Incorporation of amino acid-derived carbon into tylactone by Streptomyces fradiae GS14

Dotzlaf¹,

Metzger²,

Foglesong³

1984

Antimicrob Agents Chemother

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Washed cells from 72-h cultures of Streptomyces fradiae GS14 were used to examine the distribution of radiolabel from 14C-amino acids and related compounds into tylactone, C02, and cells. Test compounds were categorized according to products of their oxidative degradation. Those compounds known to produce propionyl-coenzyme A by direct catabolic oxidation were designated as group I. Group II included those compounds oxidized to methylmalonyl-coenzyme A via succinyl-coenzyme A and the tricarboxylic acid cycle. Group III contained compounds known to be oxidized to acetoacetyl-coenzyme A. The total amount of label recovered after 60 min ranged from 3 to 65%. Although label from all test compounds except proline (group II) and lysine (group III) was incorporated into tylactone after 60 min, label from group I and group III compounds was incorporated at levels five times greater than label from group II compounds. From 55 to 75% of the recovered label from propionate (I), asparagine (II), glutamine (II), glutamate (II), aketoglutarate (II), and succinate (II) was recovered as 14 C02. From 75 to 95% of the recovered label from the remaining compounds tested was located in the cells. Based on the data, a pathway for the role of amino acids in the biosynthesis of tylactone is proposed.Tylactone (Fig. 1) is the initial lactone precursor to tylosin, an antibiotic produced commercially by Streptomyces fradiae (1-3). Omura et al. (6), using 13C enrichment, showed that tylactone was formed from five propionate molecules, two acetate molecules, and one butyrate molecule. Subsequent inhibition studies with cerulenin, an inhibitor of fatty acid synthetase, showed that tylactone and related macrolide aglycone molecules were assembled in a manner similar to fatty acid biosynthesis (5, 7-9). The data of suggested that the precursors for tylactone biosynthesis were incorporated in the following manner: propionate as one propionyl-coenzyme A (CoA) (primer) and four methylmalonyl-CoA molecules, acetate as two malonyl-CoA molecules, and butyrate as one ethylmalonylCoA molecule.In this study, the role of amino acids as sources for the tylactone precursors was examined by using a tylA mutant of S. fradiae (1). This strain was blocked in the production of the tylosin sugars and therefore produced tylactone as its product (1, were grown in a complex medium as described previously (1).Preparation of washed cell suspensions. After 72 h of incubation, the cells from 300 ml of broth were removed by centrifugation at 16,000 x g for 5 min in a Sorvall RC-5 centrifuge. Cell pellets were washed twice with 300 ml of 0.1 M potassium phosphate buffer, pH 7.0. Approximately 6.5 g of wet cells were suspended in the buffer to a volume of 50 ml, and portions were diluted 10-fold with buffer to yield final cell suspensions containing 1.2 to 1.7 mg of dry cells per ml.Uptake and distribution reactions. Reactions were carried out in 35-ml flint glass bottles (Kimble, Toledo, Ohio) that were closed with gray butyl rubber stoppers (West Rubber Co., Phoenix...

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“…By the addition of cerulenin to the actinomycete cultures that produce polyketide-antibiotics through the pathway, such as leucomycin of Streptomyces kitasatoensis, spiramycin of S. ambofaciens and tylosin of S. fradiae, the production of these antibiotics is inhibited without growth inhibition [28][29][30] . To investigate whether the biosynthesis of fatty acid residues in the fattiviracin molecule occurs through this pathway or not, cerulenin was added to the culture, and the production of FV-8 in the culture filtrate was measured.…”

Section: Biosynthesis Of Fattiviracin 17)mentioning

confidence: 99%

Fattiviracins, Antiviral Antibiotics Produced by an Actinomycete

Uyeda

2003

Actinomycetologica

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Bioconversion and biosynthesis of 16-membered macrolide antibiotic, tylosin, using enzyme inhibitor: Cerulenin.

Cited by 19 publications

References 9 publications

Branched-chain fatty acids produced by mutants of Streptomyces fradiae, putative precursors of the lactone ring of tylosin

Branched-chain fatty acids produced by mutants of Streptomyces fradiae, putative precursors of the lactone ring of tylosin

Incorporation of amino acid-derived carbon into tylactone by Streptomyces fradiae GS14

Fattiviracins, Antiviral Antibiotics Produced by an Actinomycete

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