Macrolide biosynthesis. Tylactone formation involves the processive addition of three carbon units

Yue, Stephen; Duncan, Janice S.; Yamamoto, Yoshikuni; Hutchinson, C. Richard

doi:10.1021/ja00238a050

Cited by 131 publications

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“…No change in any of these compounds was seen when they were added to uninoculated medium and incubated for a similiar time period. The fact that this interconversion occurred indicates that the compounds are transported into the cells but are not extensively metabolized, as has been observed previously with 2-methyl-3-hydroxypentanoic acid (6,27). The fact that these compounds accumulated in cultures of mutants that were capable of tylactone synthesis supports the notion that reentry of the free acids into the biosynthetic pathway to tylosin is not favored.…”

Section: Resultssupporting

confidence: 67%

“…Those results support a pathway for biosynthesis of macrocyclic lactones (27) These branched-chain fatty acids are excreted into the culture medium, as are tylosin and tylosin precursors containing intact lactone rings (1,3), and can be transported back into the cells, but they are apparently not degraded or extensively interconverted or incorporated into tylosin. Accumulation of these fatty acids was not observed in cultures of S. fradiae mutants other than the two phenotypic classes that accumulated tylactone.…”

Section: Discussionsupporting

confidence: 57%

“…An attempt to establish antibiotic biosynthesis in a tyIG mutant of S. fradiae by the addition of the unlabeled N-acetylcysteamine ester of compound 1 (prepared as described above) was also unsuccessful. This result was not unexpected since relatively poor incorporation rates of lactone precursors are common in whole-cell experiments with macrolide-producing organisms, even when this ester is used (6,27).…”

Section: Resultsmentioning

confidence: 73%

“…Some practical difficulties encountered in the synthesis of related hydroxyacids have been noted (6,27). Furthermore, numerous natural products within the diolide class are known (14) and represent targets for synthesis (5,24); dimerizations of 7-hydroxy-a,,By,8-unsaturated fatty acids have been conducted as model systems for the synthesis of azalomycin B (elaiophylin) (21,25).…”

Section: Resultsmentioning

confidence: 99%

“…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). Those experiments provided the first direct evidence for a mechanism of chain elongation, with stepwise modification, in the synthesis of the fatty acids which ultimately cyclize to form the lactones of macrolide antibiotics and, possibly, other macrocylic * Corresponding author.…”

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confidence: 99%

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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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Section: Resultssupporting

confidence: 67%

Section: Discussionsupporting

confidence: 57%

Section: Resultsmentioning

confidence: 73%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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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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Die Thioesterase der Polyketid-Synthase von Erythromycin: Einfluß der Acylkettenstruktur auf den Abkopplungsmechanismus der Substratanaloga von der Acyl-Enzym-Zwischenstufe

et al. 1998

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Macrolides

Kirst¹

2000

Kirk-Othmer Encyclopedia of Chemical Technology

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Macrolide antibiotics are well‐established antimicrobial agents in both clinical and veterinary medicine. These agents can be administered orally and are generally used to treat infections in the respiratory tract, skin and soft tissues, and genital tract caused by gram‐positive organisms, Mycoplasma species, and certain susceptible gram‐negative and anaerobic bacteria. The macrolide class is large and structurally diverse. Macrolides are produced by fermentation of soil microorganisms. Additionally, structural modifications using both chemical and microbiological means have yielded biologically active semisynthetic derivatives. The term macrolide was introduced to denote the class of substances produced by Streptomyces species containing a macrocyclic lactone ring. Traditional macrolide antibiotics are divided into three families according to the size of the aglycone, which can be 12‐, 14‐, or 16‐membered. Naturally occurring 14‐membered macrolides include erythromycin A (C 37 H 67 NO 13 ), erythromycin B (C 37 H 67 NO 12 ), erythromycin C (C 36 H 65 NO 13 ), erythromycin D (C 36 H 65 NO 12 ), erythromycin F (C 37 H 67 NO 14 ), and erythromycin E (C 37 H 65 NO 14 ), as well as others. Erythromycin has been the principal subject of modification of 14‐membered macrolides; some of the derivatives of erythromycin and oleandomycin include 2′‐ O ‐acetylerythromycin (C 39 H 69 NO 14 ), 2′‐ O ‐propionylerythromycin (C 40 H 71 NO 14 ), erythromycin ethyl carbonate (C 40 H 71 NO 15 ), and others. 16‐Membered macrolides are divided into leucomycin‐ and tylosin‐related groups, which differ in the substitution pattern of their aglycones. Natural products include leucomycin A 1 (C 40 H 67 NO 14 ), leucomycin A 5 (C 39 H 65 NO 14 ), leucomycin A 7 (C 38 H 63 NO 14 ), midecamycin A 2 (C 42 H 69 NO 15 ), and others. A second large group of 16‐membered macrolides differs from the leucomycins in the substitution pattern of the aglycone. One difference is a methyl or hydroxymethyl group at C‐14. The most prominent member of this group is tylosin, an important veterinary antibiotic produced by S. fradiae. Tylosin and related products include tylosin (C 46 H 77 NO 17 ), relomycin (20‐dihydrotylosin) (C 46 H 79 NO 17 ), macrocin (C 45 H 75 NO 17 ), O ‐demethylmacrocin (C 44 H 73 NO 17 ), and others. Other macrolides have been made by chemical, bioconversion, or genetic manipulations which represent hybrids of structures within the 14‐membered family, within the 16‐membered family, or between the two families. The advent of molecular biology has opened new possibilities for producing hybrid macrolides. Genetic manipulations of biosynthetic pathways in macrolide‐producing microorganisms complement traditional chemical and microbiological approaches. Macrolides inhibit growth of gram‐positive bacteria, Mycoplasma species, and certain gram‐negative and anaerobic bacteria. Susceptible gram‐positive bacteria include many species of Staphylococcus and Streptococcus; susceptible gram‐negative bacteria include Bordetella pertussis, Legionella pneumophila, Moraxella catarrhalis (formerly Branhamella ), and Haemophilus ducreyi. Macrolides inhibit growth of bacteria by inhibiting protein synthesis on ribosomes. Bacterial resistance to macrolides is often accompanied by cross‐resistance to lincosamide and streptogramin B antibiotics (MLS‐resistance). Bacterial resistance to antibiotics usually results from modification of a target site, enzymatic inactivation, or reduced uptake into or increased efflux from bacterial cells. The principal side effects of macrolides are gastrointestinal problems, such as pain, indigestion, diarrhea, nausea, and vomiting. Macrolides are obtained by controlled submerged aerobic fermentations of soil microorganisms. Although species of Streptomyces have dominated, species of Saccharopolyspora, Micromonospora, and Streptoverticillium are also well represented. Macrolide antibiotics are used clinically to treat infections resulting from susceptible organisms in the upper and lower respiratory tract, skin and soft tissues, and genital tract. They are generally used orally, although they can be given intravenously. Macrolides are regarded as among the safest of antibiotics. Relatively few macrolides are used in veterinary medicine. The most important is tylosin (Tylan, Elanco Products), which is used to control chronic respiratory disease caused by Mycoplasma gallisepticum in poultry.

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Macrolide biosynthesis. Tylactone formation involves the processive addition of three carbon units

Cited by 131 publications

References 0 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

Die Thioesterase der Polyketid-Synthase von Erythromycin: Einfluß der Acylkettenstruktur auf den Abkopplungsmechanismus der Substratanaloga von der Acyl-Enzym-Zwischenstufe

Macrolides

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