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Chapter 24 : Glycosylation of Secondary Metabolites To Produce Novel Compounds

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Abstract:

This chapter talks about cloning and characterizing genes involved in sugar biosynthesis and attachment. It provides an overview of the methods which are available to create novel glycosylated compounds. In many cases, genes encoding these enzymes are located in the biosynthetic gene clusters, but they are usually not clustered into one transcription unit, nor are they necessarily present in an uninterrupted linear array. The chapter provides another overview of the gene clusters cloned in the lab and discusses the functions of recently discovered genes and enzymes involved in sugar biosynthesis or attachment. The attachment of NDP-L-amicetose to O-21 is probably catalyzed by PlaA6, which resembles many natural-product glycosyltransferases (GTs). The growing importance of natural-product sugar moieties has motivated scientists to develop methods for natural-product glycosylation. The in vitro approach of glycorandomization is based on two steps. A GT catalyzes the NDP-dependent deglycosylation and coupled formation of an NDP-sugar. Different strategies have been employed to create compound libraries with nonnatural glycosylation patterns. Novel compounds have been generated by the deletion of genes of the aglycone structure and/or the expression of genes involved in modifying the aglycone structure. The introduction of whole deoxysugar biosynthetic pathways into one strain, followed by the generation of novel compounds, has been very successfully performed by Méndez et al. The most important tools for drug design in glycol biosynthesis are GTs. The first successful results in the engineering of natural-product GTs were obtained with UrdGT1b and UrdGT1c, both involved in urdamycin biosynthesis.

Citation: Bechthold A, Probst K. 2010. Glycosylation of Secondary Metabolites To Produce Novel Compounds, p 347-363. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch24

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Figures

Image of FIGURE 1
FIGURE 1

Structures of avilamycin A and evernimicin.

Citation: Bechthold A, Probst K. 2010. Glycosylation of Secondary Metabolites To Produce Novel Compounds, p 347-363. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch24
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Image of FIGURE 2
FIGURE 2

Methylation sites of the avilamycin resistance proteins AviRa and AviRb in the peptidyltransferase center.

Citation: Bechthold A, Probst K. 2010. Glycosylation of Secondary Metabolites To Produce Novel Compounds, p 347-363. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch24
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Image of FIGURE 3
FIGURE 3

Structure of saccharomicin A.

Citation: Bechthold A, Probst K. 2010. Glycosylation of Secondary Metabolites To Produce Novel Compounds, p 347-363. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch24
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Image of FIGURE 4
FIGURE 4

Structure of selected angucyclines and functions of GTs involved in their biosynthesis.

Citation: Bechthold A, Probst K. 2010. Glycosylation of Secondary Metabolites To Produce Novel Compounds, p 347-363. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch24
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Image of FIGURE 5
FIGURE 5

Structures of aranciamycin and polyketomycin.

Citation: Bechthold A, Probst K. 2010. Glycosylation of Secondary Metabolites To Produce Novel Compounds, p 347-363. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch24
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Image of FIGURE 6
FIGURE 6

Structure of a-lipomycin and organization of the a-lipomycin biosynthetic gene cluster. The GT gene is shown in white, polyketide genes are shown in light gray, sugar biosynthetic genes are shown in dark gray, and all other genes are shown in black. Nrps, nonribosomal peptide synthase gene.

Citation: Bechthold A, Probst K. 2010. Glycosylation of Secondary Metabolites To Produce Novel Compounds, p 347-363. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch24
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Image of FIGURE 7
FIGURE 7

Structure of phenalinolactone and organization of the phenalinolactone biosynthetic gene cluster. The GT gene is shown in white, sugar biosynthetic genes are shown in gray, and all other genes are shown in black.

Citation: Bechthold A, Probst K. 2010. Glycosylation of Secondary Metabolites To Produce Novel Compounds, p 347-363. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch24
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Image of FIGURE 8
FIGURE 8

Organization of the avilamycin A and saccharomicin gene clusters. Two loci which may be involved in saccharomicin biosynthesis have been identified. GT genes are shown in white, sugar biosynthetic genes are shown in gray, and all other genes are shown in black. The locations of genes for AviX12 (X12) and AviGT4 (GT4), as well as some saccharomicin genes, are shown.

Citation: Bechthold A, Probst K. 2010. Glycosylation of Secondary Metabolites To Produce Novel Compounds, p 347-363. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch24
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Image of FIGURE 9
FIGURE 9

Function of genes/enzymes involved in avilamycin A biosynthesis.

Citation: Bechthold A, Probst K. 2010. Glycosylation of Secondary Metabolites To Produce Novel Compounds, p 347-363. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch24
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Image of FIGURE 10
FIGURE 10

Organization of the landomycin A, landomycin E, urdamycin A, and saquayamycin Z biosynthetic gene clusters. GT genes are shown in white, sugar biosynthetic genes are shown in gray, and all other genes are shown in black.

Citation: Bechthold A, Probst K. 2010. Glycosylation of Secondary Metabolites To Produce Novel Compounds, p 347-363. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch24
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Image of FIGURE 11
FIGURE 11

Heterologous expression of the aranciamycin gene cluster resulted in novel aranciamycin derivatives.

Citation: Bechthold A, Probst K. 2010. Glycosylation of Secondary Metabolites To Produce Novel Compounds, p 347-363. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch24
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Image of FIGURE 12
FIGURE 12

Generation of natural products: ( ) by UrdGT2 in the wild-type strain; ( and ) by combinatorial biosynthesis was expressed in S136 a mutant lacking the GT LanGT2 [ ], and in a mutant lacking the GT MtmGIV [ ]); ( ) by mutasynthesis (1,2-dihydroxyanthraquinone was fed to XKS containing a deletion in the polyketide synthase genes); and ( and ) by manipulating the deoxysugar biosynthetic pathway (compounds were produced by a mutant lacking the dTDP-4-keto-2,6-dideoxy-D-glucose 4-ketoreductase UrdR).

Citation: Bechthold A, Probst K. 2010. Glycosylation of Secondary Metabolites To Produce Novel Compounds, p 347-363. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch24
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Tables

Generic image for table
TABLE 1

Glycosylation of compounds by biotransformation

Citation: Bechthold A, Probst K. 2010. Glycosylation of Secondary Metabolites To Produce Novel Compounds, p 347-363. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch24
Generic image for table
TABLE 2

Glycosylation of compounds

Citation: Bechthold A, Probst K. 2010. Glycosylation of Secondary Metabolites To Produce Novel Compounds, p 347-363. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch24

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