Novel Polyketide Metabolites from Streptomyces rimosus Mutant Strain R1059

Deseo, Myrna A; Hunter, Lain S.; Waterman, Peter G.

doi:10.1038/ja.2005.110

Cited by 7 publications

(8 citation statements)

References 7 publications

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“…[23,24] To our knowledge, this is the first isolation of glucuronidated tetracycline biosynthetic intermediates, although glucosylated, truncated tetracycline intermediates have been reported to be produced by a S. rimosus mutant. [25] In summary, by using gene disruption and heterologous reconstitution experiments, we have characterized the function of OxyE as a C-4 monooxygenase during oxytetracycline biosynthesis in S. rimosus. Our results demonstrated the power of combining gene knockout and heterologous reconstitution techniques in deciphering the functional role of enzymes in natural product biosynthesis, and provided new insight into the oxidation tailoring reactions that take place during tetracycline biosynthesis.…”

Section: Discussionmentioning

confidence: 99%

Identification of OxyE as an Ancillary Oxygenase during Tetracycline Biosynthesis

et al. 2009

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The double hydroxylation of 6-pretetramid to 4-keto-anhydrotetracycline is a key tailoring reaction during the biosynthesis of the broad-spectrum antibiotic tetracyclines. It has been shown previously by heterologous reconstitution that OxyL is a dioxygenase and is the only enzyme required to catalyze the insertion of oxygen atoms at the C-12a and C-4 positions. We report here that OxyE, a flavin adenine dinucleotide (FAD)-dependent hydroxylase homologue, is an ancillary mono-oxygenase for OxyL during oxytetracycline biosynthesis in Streptomyces rimosus. By using both gene disruption and heterologous reconstitution approaches, we demonstrated that OxyE plays a nonessential, but important role in oxytetracycline biosynthesis by serving as a more efficient C-4 hydroxylase. In addition, we demonstrated that partially oxidized biosynthetic intermediates can undergo various glycosylation modifications in S. rimosus. Our results indicate that the synergistic actions of OxyE and OxyL in the double hydroxylation step prevent accumulation of shunt products during oxytetracycline biosynthesis in S. rimosus.

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Section: Discussionmentioning

confidence: 99%

Identification of OxyE as an Ancillary Oxygenase during Tetracycline Biosynthesis

et al. 2009

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“…Glycosides of the core quinone include halawanones A and B, 376 substituted naphthalene-1-ones, 382 lactonamycins 385,386 and lomaiviticins 387 from Streptomyces and Micromonospora . Halawanones A and B are structurally related to other isochromane quinone antibiotics from Streptomyces (including exfoliamycins, granaticins and griseusins; see the lactoquinomycins, Section 4.5) and, as C-8- C -glycosides (2′-keto-β-D-oliose, 325 ) of the quinone core are unique among this class.…”

Section: Anthracyclines Tetracyclines Quinones and Tricyclinesmentioning

confidence: 99%

“…376 A product of a mutant Streptomyces , 4β,8-dihydroxy-3α- O -(α-glucopyranosyl)hydroxymetyl-4α-methyl-1,2,3,4-tetrahydron-naphthalene-1-one is a simple side chain C-9- O -α-D-glucoside( 44 ). 382 Lactonamycin, an antibiotic active against Gram-positive bacteria including MRSA and VRE, consists of a hexacyclic C-5a- O -glycoside bearing α-L-rhodinose ( 44 ). 385,386 In the related lactonamycin Z, rhodinose is replaced by α-L-digitoxose ( 68a ).…”

Section: Anthracyclines Tetracyclines Quinones and Tricyclinesmentioning

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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“…However, gene inactivation has been demonstrated to be of limited use in studying oxytetracycline biosynthesis in S. rimosus. Genomic deletions of oxyK (28) and oxyS (29) in the oxy gene cluster led to the recovery of truncated polyketides only (30), and the resulting phenotypes cannot be directly associated with the functions of the deleted genes. The exact causes for biosynthesis of these truncated compounds in S. rimosus mutants are not understood.…”

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confidence: 99%

Investigation of Early Tailoring Reactions in the Oxytetracycline Biosynthetic Pathway

Zhang

Watanabe

Wang

et al. 2007

Journal of Biological Chemistry

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Tetracyclines are aromatic polyketides biosynthesized by bacterial type II polyketide synthases. The amidated tetracycline backbone is biosynthesized by the minimal polyketide synthases and an amidotransferase homologue OxyD. Biosynthesis of the key intermediate 6-methylpretetramid requires two early tailoring steps, which are cyclization of the linearly fused tetracyclic scaffold and regioselective C-methylation of the aglycon. Using a heterologous host (CH999)/vector pair, we identified the minimum set of enzymes from the oxytetracycline biosynthetic pathway that is required to afford 6-methylpretetramid in vivo. Only two cyclases (OxyK and OxyN) are necessary to completely cyclize and aromatize the amidated tetracyclic aglycon. Formation of the last ring via C-1/C-18 aldol condensation does not require a dedicated fourth-ring cyclase, in contrast to the biosynthetic mechanism of other tetracyclic aromatic polyketides, such as daunorubicin and tetracenomycin. Acetylderived polyketides do not undergo spontaneous fourth-ring cyclization and form only anthracene carboxylic acids as demonstrated both in vivo and in vitro. OxyF was identified to be the C-6 C-methyltransferase that regioselectively methylates pretetramid to yield 6-methylpretetramid. Reconstitution of 6-methylpretetramid in a heterologous host sets the stage for a more systematic investigation of additional tetracycline downstream tailoring enzymes and is a key step toward the engineered biosynthesis of tetracycline analogs.Tetracyclines are aromatic polyketides biosynthesized by soil-borne Streptomyces bacteria (1, 2). It is well known that the carbon skeleton of an aromatic polyketide is assembled through stepwise decarboxylative condensation of malonate equivalents catalyzed by the minimal PKS, 2 which consists of a ketosynthase/chain length factor heterodimer (KS-CLF or KS ␣ -KS ␤ ), an acyl-carrier protein (ACP), and a malonyl-CoA:ACP acyltransferase (3). Dedicated tailoring enzymes transform the highly reactive poly-␤-ketone backbone into fused, richly substituted compounds (4). The biosynthesis of tetracyclines has been studied using blocked mutants of the chlorotetracycline producer Streptomyces aureofaciens (5-11). However, the underlying enzymology of several key tailoring steps that give rise to its structural features remain unresolved, including cyclization of the tetracyclic scaffold and C-methylation of C-6 to afford the key intermediate 6-methylpretetramid (Fig. 1). The oxytetracycline (oxy) biosynthetic gene cluster from Streptomyces rimosus has been completely sequenced, hence allowing a thorough investigation of the biochemical basis of these features (12-16).During tetracycline biosynthesis, the C-9 reduced decaketide backbone first undergoes C-7/C-12 intramolecular aldol condensation to fix the regioselectivity of the D ring followed by three sequential cyclization reactions to form a fully aromatized, tetracyclic intermediate pretetramid (Fig. 1). Biosynthesis of aureolic acids such as mithramycin presumably follows identical c...

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Novel Polyketide Metabolites from Streptomyces rimosus Mutant Strain R1059

Cited by 7 publications

References 7 publications

Identification of OxyE as an Ancillary Oxygenase during Tetracycline Biosynthesis

Identification of OxyE as an Ancillary Oxygenase during Tetracycline Biosynthesis

A comprehensive review of glycosylated bacterial natural products

Investigation of Early Tailoring Reactions in the Oxytetracycline Biosynthetic Pathway

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