Novel Genetically Engineered Tetracenomycins

Decker, Heinrich; Haag, Sabine; Udvarnoki, Györgyi; Rohr, Jürgen

doi:10.1002/anie.199511071

Cited by 51 publications

(43 citation statements)

References 38 publications

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“…The two constructs shown in this work (pOLV and pOLE) are the first two plasmids reported capable of synthesizing dTDP-activated sugars, and so they have the potential to be used for modifying different aglycones. This will require the use of "flexible" glycosyltransferases, and in this context, a few examples of glycosyltransferase substrate flexibility have been reported (8,46,61). The S. antibioticus OleG2 glycosyltransferase has been shown to transfer L-oleandrose and L-olivose (this work) and also L-rhamnose (12).…”

Section: Discussionmentioning

confidence: 83%

Identification and Expression of Genes Involved in Biosynthesis of l -Oleandrose and Its Intermediate l -Olivose in the Oleandomycin Producer Streptomyces antibioticus

Aguirrezabalaga

Olano

Allende

et al. 2000

Antimicrob Agents Chemother

101

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A 9.8-kb DNA region from the oleandomycin gene cluster in Streptomyces antibioticus was cloned. Sequence analysis revealed the presence of 8 open reading frames encoding different enzyme activities involved in the biosynthesis of one of the two 2,6-deoxysugars attached to the oleandomycin aglycone: L-oleandrose (the oleW, oleV, oleL, and oleU genes) and D-desosamine (the oleNI and oleT genes), or of both (the oleS and oleE genes). A Streptomyces albus strain harboring the oleG2 glycosyltransferase gene integrated into the chromosome was constructed. This strain was transformed with two different plasmid constructs (pOLV and pOLE) containing a set of genes proposed to be required for the biosynthesis of dTDP-L-olivose and dTDP-L-oleandrose, respectively. Incubation of these recombinant strains with the erythromycin aglycon (erythronolide B) gave rise to two new glycosylated compounds, identified as L-3-O-olivosyl-and L-3-O-oleandrosyl-erythronolide B, indicating that pOLV and pOLE encode all enzyme activities required for the biosynthesis of these two 2,6-dideoxysugars. A pathway is proposed for the biosynthesis of these two deoxysugars in S. antibioticus.

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Section: Discussionmentioning

confidence: 83%

Identification and Expression of Genes Involved in Biosynthesis of l -Oleandrose and Its Intermediate l -Olivose in the Oleandomycin Producer Streptomyces antibioticus

Aguirrezabalaga

Olano

Allende

et al. 2000

Antimicrob Agents Chemother

101

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“…[254] The resulting Later experiments established that the substrate-flexible GT responsible for formation of 234 was ElmGT encoded on cosmid 16F4. In this work, cosmid 16F4 was transformed into a mutant of Streptomyces fradiae Tü2717, in which several genes essential for formation of the urdamycin aglycone were deleted (DPKS).…”

Section: Elloramycinmentioning

confidence: 99%

“…Consequently, more sophisticated in vivo glycodiversification strategies involving heterologous expression of genes were developed and applied in metabolic pathway engineering and combinatorial biosynthesis studies. [254][255][256] The use of cells as catalysts to carry out chemical reactions on exogenous molecules is referred as biotransformation. Precursor-directed biosynthesis [257] and mutasynthesis [258] are two well-established biotransformation processes in which a biosynthetic precursor of a natural product is replaced by a structural analogue through feeding to a wild-type strain (precursor-directed biosynthesis) or to a gene-disruption mutant (mutasynthesis).…”

Section: In Vivo Glycodiversificationmentioning

confidence: 99%

Natural‐Product Sugar Biosynthesis and Enzymatic Glycodiversification

Thibodeaux

Melançon

Liu³

2008

Angew Chem Int Ed

380

397

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Many biologically active small-molecule natural products produced by microorganisms derive their activities from sugar substituents. Changing the structures of these sugars can have a profound impact on the biological properties of the parent compounds. This realization has inspired attempts to derivatize the sugar moieties of these natural products through exploitation of the sugar biosynthetic machinery. This approach requires an understanding of the biosynthetic pathway of each target sugar and detailed mechanistic knowledge of the key enzymes. Scientists have begun to unravel the biosynthetic logic behind the assembly of many glycosylated natural products and have found that a core set of enzyme activities is mixed and matched to synthesize the diverse sugar structures observed in nature. Remarkably, many of these sugar biosynthetic enzymes and glycosyltransferases also exhibit relaxed substrate specificity. The promiscuity of these enzymes has prompted efforts to modify the sugar structures and alter the glycosylation patterns of natural products through metabolic pathway engineering and enzymatic glycodiversification. In applied biomedical research, these studies will enable the development of new glycosylation tools and generate novel glycoforms of secondary metabolites with useful biological activity.

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“…The much improved understanding of unusual sugar biosynthetic pathways and enzymes as reviewed in Section II has significantly affected pathway engineering-based glycosdiversification efforts aimed at producing natural products with altered sugar structures. More sophisticated rational approaches, in which pathways are manipulated through the replacement or alteration of the genes normally present, have replaced the classical random mutagenesis [110,143,144]. Among several methods developed recently, metabolic pathway engineering [145] and combinatorial biosynthesis [146] have garnered the most attention, due to their effectiveness in generating new chemical entities.…”

Section: Glycodiversification Via Pathway Engineeringmentioning

confidence: 99%