The tylosin biosynthetic cluster from Streptomyces fradiae: genetic organization of the left region

Fouces, Roberto; Mellado, Encarnación; Dı́ez, Bruno; Barredo, José Luis

doi:10.1099/13500872-145-4-855

Cited by 97 publications

(82 citation statements)

References 57 publications

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“…The closest homolog of CYP154C1 identified in the data base using program BLAST (45) is a cytochrome P450 CYP154B1 from Streptomyces fradiae with 44% sequence identity (Q9XCC6) localized within the tylosin biosynthetic gene cluster (13). However, because macrolactone ring hydroxylations at C-20 and C-23 that occur during tylosin biosynthesis are catalyzed by the products of different genes, one of which encodes another cytochrome P450, CYP105L1 (Q9ZHQ1) (14), the role of the CYP154C1 homolog in S. fradiae remains unknown. CYPs with lower identity include the second member of CYP154 family in S. coelicolor A3(2), CYP154A1 (Q9KZR7) (with 42% identity), as well as CYP107B1 (B42606) and EryF, or CYP107A1 (Q00441), from S. erythraea (both with 37% identity and 54 and 51% homology, respectively).…”

Section: Resultsmentioning

confidence: 99%

“…Most of the currently identified antibiotics are produced by complex biosynthetic systems comprised of clustered gene sets located contiguously on the Streptomyces chromosome (12)(13)(14)(15)(16)(17)(18). The clustering of secondary metabolite genes has been an aid in the isolation of P450 monooxygenases involved in antibiotic biosynthesis.…”

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confidence: 99%

“…The clustering of secondary metabolite genes has been an aid in the isolation of P450 monooxygenases involved in antibiotic biosynthesis. Cytochrome P450 monooxygenases are particularly common in polyketide biosynthetic gene clusters, and they catalyze site-specific tailoring reactions leading to the macrolide antibiotics, including methymycin, neomethymycin, and pikromycin (12, 19 -22), novamethymycin (23), oleandomycin (24), amphotericin (17), and erythromycin (25,26 ally, CYPs are involved in the formation of the anticancer agent epothilone (27,28), immunosuppressant rapamycin (29,30), the growth promoter tylosin (14), and the antiparasitic agent avermectin (15). These reactions typically occur during the late stages of biosynthesis after formation of the core ring system by a polyketide synthase.…”

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confidence: 99%

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The 1.92-Å Structure of Streptomyces coelicolor A3(2) CYP154C1

Podust

Kim

Arase

et al. 2003

Journal of Biological Chemistry

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Evolutionary links between cytochrome P450 monooxygenases, a superfamily of extraordinarily divergent heme-thiolate proteins catalyzing a wide array of NADPH/NADH-and O 2 -dependent reactions, are becoming better understood because of availability of an increasing number of fully sequenced genomes. Among other reactions, P450s catalyze the site-specific oxidation of the precursors to macrolide antibiotics in the genus Streptomyces introducing regiochemical diversity into the macrolide ring system, thereby significantly increasing antibiotic activity. Developing effective uses for Streptomyces enzymes in biosynthetic processes and bioremediation requires identification and engineering of additional monooxygenases with activities toward a diverse array of small molecules. To elucidate the molecular basis for substrate specificity of oxidative enzymes toward macrolide antibiotics, the x-ray structure of CYP154C1 from Streptomyces coelicolor A3(2) was determined (Protein Data Bank code 1GWI). Relocation of certain common P450 secondary structure elements, along with a novel structural feature involving an additional ␤-strand transforming the five-stranded ␤-sheet into a six-stranded variant, creates an open cleft-shaped substrate-binding site between the two P450 domains. High sequence similarity to macrolide monooxygenases from other microbial species translates into catalytic activity of CYP154C1 toward both 12-and 14-membered ring macrolactones in vitro.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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The 1.92-Å Structure of Streptomyces coelicolor A3(2) CYP154C1

Podust

Kim

Arase

et al. 2003

Journal of Biological Chemistry

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“…They are also similar to the putative methyltransferases of the ser2 cluster in M. avium (MtfB, MtfC and MtfD), which may carry out rhamnose modification in GPL synthesis. AveBVII, MycF and TylF methylate the sugar components in the macrolides avermectin, mycinamicin and tylosin, respectively (Fouces et al, 1999 ;Ikeda et al, 1999 ;Inouye et al, 1994). If the grouping is significant then it may be used to predict that Mtf3 and Mtf4 are possible rhamnosyl methyltransferases.…”

Section: Discussionmentioning

confidence: 99%

Modification of glycopeptidolipids by an O-methyltransferase of Mycobacterium smegmatis a aThe GenBank accession number for the sequence determined in this work is AY138899.

et al. 2002

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Glycopeptidolipids (GPLs) are a major component of the outer layers of the cell walls of several non-tuberculous mycobacteria. The Mycobacterium smegmatis GPLs consist of a diglycosylated lipopeptide core which is variably modified by acetylation and methylation. Analysis of a region of the M. smegmatis chromosome, upstream of the peptide synthetase gene, mps, revealed a GPL biosynthetic locus containing genes potentially involved in glycosylation, methylation, acetylation and transport of GPLs. Methyltransferases are required to modify rhamnose and the fatty acid of GPLs. Of the four methyltransferases encoded within the locus, one methyltransferase, Mtf2, was unlike sugar methyltransferases from other species. An mtf2 mutant was created and was shown to be unable to methylate the GPL fatty acids. Direct evidence is presented that Mtf2 is a methyltransferase that modifies the GPL fatty acid.

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“…In contrast to CouO, CouP shows high similarities to known deoxysugar O-methyltransferases in the database, e.g. 57 % identity to 3-O-methyltransferase MycF catalysing the methylation at the 3-position of the deoxysugar mycinose of mycinamicin III (Inouye et al, 1994), 59 % to ElmMIII responsible for 4-O-methylation of the permethylated -rhamnose in the biosynthesis of elloramycin A (Patallo et al, 2001), and 53 % to 3-O-methyltransferase TylF converting macrocin to tylosin by O-methylation at C-3 of the deoxysugar S.-M. Li and others mycinose (Fouces et al, 1999) (Kagan & Clarke, 1994) was found in the predicted CouP from amino acid 105 to 113 (LVETGVWRG).…”

Section: Conserved Motif III [Ll(r\k)pgg(r\i\l)(l\i)(l\f\i\v)(i\l)]mentioning

confidence: 99%

Methyltransferase genes in Streptomyces rishiriensis: new coumermycin derivatives from gene-inactivation experiments b bThe GenBank accession number for the sequence reported in this paper is AF235050.

Westrich

Schmidt

et al. 2002

Microbiology

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The coumarin antibiotic coumermycin A 1 contains at least eight methyl groups, presumably derived from S-adenosylmethionine. Two putative methyltransferase genes, couO and couP, of the coumermycin A 1 biosynthetic gene cluster were inactivated by in-frame deletion. In the resulting mutants, coumermycin A 1 production was abolished. New coumermycin derivatives were accumulated instead, and were identified by HPLC-MS using selected reaction monitoring via electrospray ionization. couO mutants accumulated a coumermycin derivative lacking the methyl groups at C-8 of the characteristic aminocoumarin rings, whereas in the couP mutant a coumermycin derivative lacking the methyl groups at the 4-hydroxyl groups of the two deoxysugar moieties was identified. These results provided evidence that couO encodes a C-methyltransferase responsible for the transfer of a methyl group to C-8 of the aminocoumarin ring, and couP an O-methyltransferase for methylation of 4-OH of the sugar in the biosynthesis of coumermycin A 1 , respectively. Cmethylation of the aminocoumarin ring is considered as an early step of coumermycin biosynthesis. Nevertheless, the intermediates with the nonmethylated aminocoumarin ring were accepted by the enzymes catalysing the subsequent steps of the pathway. The new, demethylated secondary metabolites were produced in an amount at least as high as that of coumermycin A 1 in the wild-type.

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The tylosin biosynthetic cluster from Streptomyces fradiae: genetic organization of the left region

Cited by 97 publications

References 57 publications

The 1.92-Å Structure of Streptomyces coelicolor A3(2) CYP154C1

The 1.92-Å Structure of Streptomyces coelicolor A3(2) CYP154C1

Modification of glycopeptidolipids by an O-methyltransferase of Mycobacterium smegmatis a aThe GenBank accession number for the sequence determined in this work is AY138899.

Methyltransferase genes in Streptomyces rishiriensis: new coumermycin derivatives from gene-inactivation experiments b bThe GenBank accession number for the sequence reported in this paper is AF235050.

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