Biological conversion of erythronolide B,an intermediate of erythromycin biogenesis,into new "hybrid" macrolide antibiotics.

Spagnoli, Roberto; Cappelletti, Leonardo; Toscano, L.

doi:10.7164/antibiotics.36.365

Cited by 22 publications

(15 citation statements)

References 25 publications

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“…Additional C-3-appended sugars observed include 4′- O -acetyl-αL-arcanose ( 122b ) [and corresponding engineered 2′,3′-anhydro-arcanose ( 182 ) and 3′-acetylated 180 657,658 ] of the lankamycins 659 and the kujimycins [which contain a C-3 α-L-arcanose ( 122a ) or 4′- O -acetyl-α-L-arcanose ( 122b ) and a C-5 β-D-lankavose ( 181b )] 660 and α-L-oleandrose ( 184 ); found in oleandomycin 647,661 and the 3- O -oleandrosyl-5- O -desosaminyl-(8 S )-8-hydroxyerythronolide B 662 from bioconversion. Additional sugars attached to C-5 include 3-keto-4,6-dideoxy-β-D-hexopyranose 179 (CP-63693 640 ), β-D-chalcose ( 181b ; lankamycins 659 and kujimycins 654 ) and β-D-mycaminose ( 185 ; narbolide, 663 via biotransformation).…”

Section: Macrolides and Macrolactamsmentioning

confidence: 99%

A comprehensive review of glycosylated bacterial natural products

et al. 2015

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A systematic analysis of all naturally-occurring glycosylated bacterial secondary metabolites reported in the scientific literature up through early 2013 is presented. This comprehensive analysis of 15 940 bacterial natural products revealed 3426 glycosides containing 344 distinct appended carbohydrates and highlights a range of unique opportunities for future biosynthetic study and glycodiversification efforts.

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Section: Macrolides and Macrolactamsmentioning

confidence: 99%

A comprehensive review of glycosylated bacterial natural products

et al. 2015

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“…Later on, two 6-deoxysugars (L-oleandrose and D-desosamine) are attached to the aglycon. As late steps, C8 hydroxylation and epoxide formation occur after the transfer of the two sugar residues onto the macrolactone (Spagnoli et al 1983). Several genes of the oleandomycin biosynthetic pathway have been characterized.…”

Section: Introductionmentioning

confidence: 99%

Analysis of a Streptomyces antibioticus chromosomal region involved in oleandomycin biosynthesis, which encodes two glycosyltransferases responsible for glycosylation of the macrolactone ring

Olano

Rodrı́guez

Michel³

et al. 1998

Mol Gen Genet

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A 6-kb region from the chromosome of Streptomyces antibioticus, an oleandomycin producer, was cloned and sequenced. This region was located between the 3' end of the gene encoding the third subunit of the oleandomycin type I polyketide synthase and the oleP and oleB genes, which encode a cytochrome P450 monooxygenase and an oleandomycin resistance gene, respectively. Analysis of the nucleotide sequence revealed the presence of five genes encoding a cytochrome P450-like protein (oleP1), two glycosyltransferases (oleG1 and oleG2) involved in the transfer of the two 6-deoxysugars (L-oleandrose and D-desosamine) to the oleandomycin macrolactone ring, a methyltransferase (oleM1), and a gene (oleY) of unknown function. Insertional inactivation of this region by gene disruption generated an oleandomycin non-producing mutant which accumulated a compound that, according to mass spectrometry analysis, could correspond to the oleandomycin macrolactone ring (oleandolide), suggesting that the mutation affects oleandrosyl glycosyltransferase.

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“…However, as the mutant was generated by gene disruption, a polar effect preventing the expression of oleG2 could not be excluded. It has been previously demonstrated that cross‐feeding with erythronolide B, during the fermentation of an S. antibioticus mutant strain blocked in the synthesis of the macrolactone ring, resulted in the transfer of l ‐oleandrose and d ‐desosamine to the erythronolide B lactone substrate (Spagnoli et al ., 1983). These results indicated that erythronolide B was accepted as an alternative substrate by the two glycosyltransferases of S. antibioticus , and analysis of the hybrid compounds produced demonstrated that C‐8 hydroxylation and epoxide formation were taking place after the transfer of both sugars in the course of oleandomycin biosynthesis (Spagnoli et al ., 1983).…”

Section: Introductionmentioning

confidence: 99%

Interspecies complementation in Saccharopolyspora erythraea : elucidation of the function of oleP1, oleG1 and oleG2 from the oleandomycin biosynthetic gene cluster of Streptomyces antibioticus and generation of new erythromycin derivatives

Doumith¹,

Legrand²,

Lang³

et al. 1999

Molecular Microbiology

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SummaryTwo glycosyltransferase genes, oleG1 and oleG2, and a putative isomerase gene, oleP1, have previously been identified in the oleandomycin biosynthetic gene cluster of Streptomyces antibioticus. In order to identify which of these two glycosyltransferases encodes the desosaminyltransferase and which the oleandrosyltransferase, interspecies complementation has been carried out, using two mutant strains of Saccharopolyspora erythraea, one strain carrying an internal deletion in the eryCIII (desosaminyltransferase) gene and the other an internal deletion in the eryBV (mycarosyltransferase) gene. Expression of the oleG1 gene in the eryCIII deletion mutant restored the production of erythromycin A (although at a low level), demonstrating that oleG1 encodes the desosaminyltransferase required for the biosynthesis of oleandomycin and indicating that, as in erythromycin biosynthesis, the neutral sugar is transferred before the aminosugar onto the macrocyclic ring. Significantly, when an intact oleG2 gene (presumed to encode the oleandrosyltransferase) was expressed in the eryBV deletion mutant, antibiotic activity was also restored and, in addition to erythromycin A, new bioactive compounds were produced with a good yield. The neutral sugar residue present in these compounds was identified as L-rhamnose attached at position C-3 of an erythronolide B or a 6-deoxyerythronolide B lactone ring, thus indicating a relaxed specificity of the oleandrosyltransferase, OleG2, for both the activated sugar and the macrolactone substrate. The oleP1 gene located immediately upstream of oleG1 was likewise introduced into an eryCII deletion mutant of Sac. erythraea, and production of erythromycin A was again restored, demonstrating that the function of OleP1 is identical to that of EryCII in the biosynthesis of dTDP-D-desosamine, which we have previously proposed to be a dTDP-4-keto-6-deoxy-D-glucose 3,4-isomerase.

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Biological conversion of erythronolide B,an intermediate of erythromycin biogenesis,into new "hybrid" macrolide antibiotics.

Cited by 22 publications

References 25 publications

A comprehensive review of glycosylated bacterial natural products

A comprehensive review of glycosylated bacterial natural products

Analysis of a Streptomyces antibioticus chromosomal region involved in oleandomycin biosynthesis, which encodes two glycosyltransferases responsible for glycosylation of the macrolactone ring

Interspecies complementation in Saccharopolyspora erythraea : elucidation of the function of oleP1, oleG1 and oleG2 from the oleandomycin biosynthetic gene cluster of Streptomyces antibioticus and generation of new erythromycin derivatives

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