Novel octaketide macrolides related to 6-deoxyerythronolide B provide evidence for iterative operation of the erythromycin polyketide synthase

Wilkinson, Barrie; Foster, Graham; Rudd, Brian A. M.; Taylor, Nicolas L.; Blackaby, Andrew P.; Sidebottom, Philip J.; Cooper, David; Dawson, Michael J.; Buss, Anthony D; Gaisser, Sibylle; Böhm, Ines; Rowe, Christine J.; Cortés, Jesús M.; Leadlay, Peter F.; Staunton, James

doi:10.1016/s1074-5521(00)00076-4

Cited by 78 publications

(62 citation statements)

References 45 publications

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“…The programmed iteration of extension‐module 1 on the AZL PKS occurs, as with previously identified examples of programmed iteration of modules,11, 26 at a point in the assembly line where there is a protein–protein interface27 (here between AzlA and AzlB). Those previous examples all involve the same level of β‐keto processing in each of the iterative rounds of chain elongation.…”

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confidence: 53%

“…An early example is the pikromycin PKS, which produces both a 12‐membered and a 14‐membered macrolide through optional “skipping”10 of a PKS module. In other examples, a single extension module catalyzes two or more successive (and identical) rounds of polyketide carbon skeleton, either to give aberrant products11 or as part of the normal biosynthetic pathway 12, 13, 14, 15, 16. These exceptions promise to increase our understanding of the natural evolution of modular PKSs, and potentially offer lessons for the effective engineering of these systems.…”

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confidence: 99%

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An Iterative Module in the Azalomycin F Polyketide Synthase Contains a Switchable Enoylreductase Domain

Zhai

Liu

et al. 2017

Angew Chem Int Ed

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Detailed analysis of the modular Type I polyketide synthase (PKS) involved in the biosynthesis of the marginolactone azalomycin F in mangrove Streptomyces sp. 211726 has shown that only nineteen extension modules are required to accomplish twenty cycles of polyketide chain elongation. Analysis of the products of a PKS mutant specifically inactivated in the dehydratase domain of extension‐module 1 showed that this module catalyzes two successive elongations with different outcomes. Strikingly, the enoylreductase domain of this module can apparently be “toggled” off and on : it functions in only the second of these two cycles. This novel mechanism expands our understanding of PKS assembly‐line catalysis and may explain examples of apparent non‐colinearity in other modular PKS systems.

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confidence: 53%

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confidence: 99%

An Iterative Module in the Azalomycin F Polyketide Synthase Contains a Switchable Enoylreductase Domain

Zhai

Liu

et al. 2017

Angew Chem Int Ed

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“…For example, 16-membered erythromycins were isolated from Saccharopolyspora erythraea, as a result of aberrant repeated use (termed PKS stuttering) of 6-deoxyerythronolide B synthases [2]. In contrast, ringcontracted epothilone derivatives were isolated as a result of PKS skipping in addition to ring-enlarged derivatives [3].…”

Section: Introductionmentioning

confidence: 99%

Analysis of Modular-iterative Mixed Biosynthesis of Lankacidin by Heterologous Expression and Gene Fusion

2007

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Lankacidin is a unique 17-membered macrocyclic antibiotic different from usual even-membered macrolides. Based on the gene organization of the lankacidin biosynthetic cluster coded on the linear plasmid pSLA2-L in Streptomyces rochei, we previously proposed a hypothesis of modular-iterative mixed polyketide biosynthesis for lankacidin. Two experimental evidences in this paper further strengthened this hypothesis. Heterologous expression of the lankacidin cluster (lkcAlkcO) in Streptomyces lividans resulted in lankacidinol A production, indicating that the gene cluster is sufficient for the synthesis of the lankacidin skeleton. In addition, a gene fusant of lkcF and lkcG produced lankacidin at a similar level to the parent strain, suggesting that an iterative function of the LkcF protein is unlikely. These results are consistent with the hypothesis that LkcC is used four times and LkcA, LkcF and LkcG are used modularly to accomplish eight condensation reactions leading to the lankacidin skeleton.

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“…Details of the genetic engineering, product isolation, and characterization and of the insight obtained into the operation of the biosynthetic pathway are described elsewhere. The isolation of stutt-6-dEB and Ac-stutt-6-dEB has been described [13]. GlaxoSmithKline kindly provided approximately 200 mg of each of these two products (purity 85%) for use in the experiments reported.…”

Section: Methodsmentioning

confidence: 99%

“…These compounds are produced by the aberrant function of the erythromycin PKS [13] and are identical to 6-dEB except that a 3-carbon unit, (boxed in Scheme 2) has been incorporated twice. This phenomenon has been referred to as "stuttering" [13] and consequently, these compounds are referred to as stuttered 6-dEB (stutt-6-dEB) (Structure 4) and acetate starter stuttered 6-dEB (Acstutt-6-dEB) (Structure 6) and to the 3-carbon unit as the "stuttered unit". The study of these compounds was important because they have been fully characterized by 2-D NMR spectroscopy and thus provided further solid evidence upon which to predict the structure of a novel 16-membered macrolide aglycone as stutt-EB (Structure 5).…”

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confidence: 99%

Structural elucidation studies on 14- and 16-membered macrolide aglycones by accurate-mass electrospray sequential mass spectrometry

Roddis

Gates

Roddis

et al. 2002

J. Am. Soc. Mass Spectrom.

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Collision induced dissociation sequential mass spectrometry was used to investigate the fragmentation of the heptaketide macrolide aglycones, 6-deoxyerythronolide B (6-dEB), erythronolide B (EB), and acetate-starter EB (Ac-EB). The fragmentations of two previously reported octaketide analogs produced by "stuttering" of the erythromycin polyketide synthase, stuttered-6-dEB and acetate-starter stuttered-6-dEB were also studied. The accuracy with which the mass of each fragment was measured allowed it to be attributed to an unambiguous formula. Most of the experiments were repeated using samples dissolved in deuterated solvents. These data were then used to deduce plausible fragmentation pathways of the five compounds which were shown to have a high degree of similarity. Preliminary fragmentation analysis of a novel octaketide analog was performed and the structure was predicted as stuttered EB. Subsequent scale-up of the bacterial fermentations, followed by isolation and characterization by nuclear magnetic resonance spectroscopy confirmed this prediction. Further fragmentation experiments were then performed on this compound, which provided further evidence of the similarity of the fragmentation schemes. These results demonstrate the utility of collision induced dissociation sequential mass spectrometry analysis in the preliminary screening of bacterial fermentations for new polyketides. These studies were performed by electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry. (J Am Soc Mass Spectrom 2002, 13, 862-874)

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Novel octaketide macrolides related to 6-deoxyerythronolide B provide evidence for iterative operation of the erythromycin polyketide synthase

Cited by 78 publications

References 45 publications

An Iterative Module in the Azalomycin F Polyketide Synthase Contains a Switchable Enoylreductase Domain

An Iterative Module in the Azalomycin F Polyketide Synthase Contains a Switchable Enoylreductase Domain

Analysis of Modular-iterative Mixed Biosynthesis of Lankacidin by Heterologous Expression and Gene Fusion

Structural elucidation studies on 14- and 16-membered macrolide aglycones by accurate-mass electrospray sequential mass spectrometry

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