Cloning, sequencing and heterologous expression of the medermycin biosynthetic gene cluster of Streptomyces sp. AM-7161: towards comparative analysis of the benzoisochromanequinone gene clusters

Ichinose, Koji; Ozawa, Makoto; Itou, Keiko; Kunieda, Kanako; Ebizuka, Yutaka

doi:10.1099/mic.0.26310-0

Cited by 112 publications

(121 citation statements)

References 61 publications

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“…[80] Sugar 58 is also involved in the biosynthesis of the benzoisochromanequinone antibiotic medermycin. [81] The complete biosynthetic pathway for 56, starting from 21, has been elucidated through the biochemical analysis of the pathway enzymes. [82] The key intermediate 55, the substrate for glycosyltransfer in the balhimycin pathway, is derived from 60 by C-3 methylation followed by 5-epimerization.…”

Section: 22mentioning

confidence: 99%

Natural‐Product Sugar Biosynthesis and Enzymatic Glycodiversification

Thibodeaux

Melançon

Liu³

2008

Angew Chem Int Ed

390

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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Section: 22mentioning

confidence: 99%

Natural‐Product Sugar Biosynthesis and Enzymatic Glycodiversification

Thibodeaux

Melançon

Liu³

2008

Angew Chem Int Ed

390

397

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“…Interestingly, homologues of jadR1 are present in the biosynthetic clusters for several angucycline antibiotics (29,30) and for antibiotics that contain an angucycline-like structure (31,32). The amino acid sequence conservation of such JadR1 homologues may indicate that they have a similar ligandinteractive specificity.…”

Section: Jadr1mentioning

confidence: 99%

Autoregulation of antibiotic biosynthesis by binding of the end product to an atypical response regulator

Wang

Tian

Wang

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

121

147

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In bacteria, many ''atypical'' response regulators (ARRs) lack the conserved residues important for phosphorylation by which typical response regulators switch their output response, suggesting the existence of alternative regulatory mechanisms. However, such mechanisms have not been established. JadR1, an OmpR-type ARR of Streptomyces venezuelae, appears to activate the transcription of jadomycin B (JdB) biosynthetic genes while repressing its own gene. JadR1 activities were inhibited in cells induced to produce JdB, which was found to bind directly to the N-terminal receiver domain of JadR1, causing JadR1 to dissociate from target promoters. The activity of a NarL-type ARR, RedZ, that regulates production of another antibiotic was likewise modulated by the end product (undecylprodigisines), implying that end-product-mediated control of antibiotic pathway-specific ARRs may be widespread. These results could prove relevant to knowledge-based improvements in yield of commercially important antibiotics.JadR1 ͉ ligand

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“…40,41 Consequently, PnxO1 might catalyze the b-keto reduction of C11 of the nascent polyketide chain instead of PnxW described above. As another possibility, PnxO1 might catalyze the reduction at the C25 position and the subsequent lactone ring formation, which is a necessary transformation in FD-594 biosynthesis.…”

Section: Cloning Of Fd-594 Biosynthetic Gene Cluster F Kudo Et Almentioning

confidence: 99%

Cloning of the biosynthetic gene cluster for naphthoxanthene antibiotic FD-594 from Streptomyces sp. TA-0256

et al. 2010

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FD-594 is an unique pyrano [4¢,3¢:6,7]naphtho [1,2-b]xanthene polyketide with a trisaccharide of 2,6-dideoxysugars. In this study, we cloned the FD-594 biosynthetic gene cluster from the producer strain Streptomyces sp. TA-0256 to investigate its biosynthesis. The identified pnx gene cluster was 38 143 bp, consisting of 40 open reading frames, including a minimal PKS gene, TDP-olivose biosynthetic genes, two glycosyltransferase genes, two methyltransferase genes and many oxygenase/reductase genes. Most of these enzymes coded in the pnx cluster were reasonably assigned to a plausible biosynthetic pathway for FD-594, in which an unique ring opening process via Baeyer-Villiger-type oxidation catalyzed by a putative flavin adenine dinucleotide (FAD)-dependent monooxygenase, is speculated to lead to the unique xanthene structure. To clarify the involvement of pnx genes in the FD-594 biosynthesis, a glycosyltransferase, PnxGT2, and a methyltransferase, PnxMT2, were characterized enzymatically with the recombinant proteins expressed in Escherichia coli. As a result, PnxGT2 catalyzed the triple olivose transfers to the FD-594 aglycon with TDP-olivose as the glycosyl donor to afford triolivoside. Surprisingly, in the PnxGT2 enzymatic reaction, tetraolivoside and pentaolivoside were significantly detected along with the expected triolivoside. To our knowledge, PnxGT2 is the first contiguous oligosaccharide-forming glycosyltransferase in secondary metabolism. Furthermore, addition of PnxMT2 and S-adenosyl-L-methionine into the PnxGT2 reaction mixture afforded natural FD-594 to confirm that the PnxGT2 reaction product was the expected regiospecifically glycosylated compound. Consequently, the identified pnx gene cluster appears to be involved in FD-594 biosynthesis.

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Cloning, sequencing and heterologous expression of the medermycin biosynthetic gene cluster of Streptomyces sp. AM-7161: towards comparative analysis of the benzoisochromanequinone gene clusters

Cited by 112 publications

References 61 publications

Natural‐Product Sugar Biosynthesis and Enzymatic Glycodiversification

Natural‐Product Sugar Biosynthesis and Enzymatic Glycodiversification

Autoregulation of antibiotic biosynthesis by binding of the end product to an atypical response regulator

Cloning of the biosynthetic gene cluster for naphthoxanthene antibiotic FD-594 from Streptomyces sp. TA-0256

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