The structure of pradimicins A, B and C: a novel family of antifungal antibiotics

Tsunakawa, Mitsuaki; Nishio, Maki; Ohkuma, Hiroaki; Tsuno, Takashi; Konishi, Masataka; Naitô, Takayuki; Oki, Taikan; Kawaguchi, Hiroshi

doi:10.1021/jo00272a013

Cited by 66 publications

(40 citation statements)

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“…This compound is biosynthetically interesting because of the unusual trans-diol present in its C ring (12,46,47). We have shown that the C-5 hydroxyl is derived from molecular oxygen and that the C-6 hydroxyl is apparently derived from water (14), indicating that the 5,6-trans-diol moiety is generated by enzymatic epoxidation of the K-region double bond followed by action of an epoxide hydrolase.…”

Section: Discussionmentioning

confidence: 99%

Cloning and heterologous expression of the entire gene clusters for PD 116740 from Streptomyces strain WP 4669 and tetrangulol and tetrangomycin from Streptomyces rimosus NRRL 3016

1997

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The genes for the complete pathways for two polycyclic aromatic polyketides of the angucyclinone class have been cloned and heterologously expressed. Genomic DNAs of Streptomyces rimosus NRRL 3016 and Streptomyces strain WP 4669 were partially digested with MboI, and libraries (ca. 40-kb fragments) in Escherichia coli XL1-Blue MR were prepared with the cosmid vector pOJ446. Hybridization with the actI probe from the actinorhodin polyketide synthase genes identified two clusters of polyketide genes from each organism. After transfer of the four clusters to Streptomyces lividans TK24, expression of one cluster from each organism was established through the identification of pathway-specific products by high-performance liquid chromatography with photodiode array detection. Peaks were identified from the S. rimosus cluster (pks RIM-1 ) for tetrangulol, tetrangomycin, and fridamycin E. Peaks were identified from the WP 4669 cluster (pks WP-2 ) for tetrangulol, 19-hydroxytetrangulol, 8-O-methyltetrangulol, 19-hydroxy-8-O-methyltetrangulol, and PD 116740. Structures were confirmed by 1 H nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.Members of the genus Streptomyces produce well over half of the known antibiotics of natural origin. Of these, polyketidederived metabolites are among the most numerous and diverse and include many clinically important members, such as erythromycin, tetracycline, and doxorubicin. Assembly of the skeletons of such compounds by oligomerization of small precursor fatty acid thioesters to form polyketide backbones is carried out by polyketide synthases (PKSs). These are made up of either large multifunctional enzymes (type I PKSs) or multienzyme complexes (type II PKSs). Molecular genetic analyses have revealed that the genes for each PKS are clustered in a relatively small region of DNA (22). The gene clusters for numerous polyketide pathways have been detected by hybridization with probes derived from genes coding for proteins that catalyze equivalent reactions in different pathways (25,29).Angucyclinones, a name recently given to naturally occurring benz [a]anthraquinones, are a rapidly growing group of polyketide natural products, involving many bioactive compounds (41). They are now the largest class of known aromatic decaketides. Two angucyclinones-tetrangulol (TET) and tetrangomycin-had been isolated from Streptomyces rimosus and were the first identified members of this class of antibiotics (26). Streptomyces strain WP 4669 produces an angucyclinone, PD 116740, which has activity against L1210 lymphocytic leukemia and HCT-8 colon adenocarcinoma cell lines (47). We have studied the biosynthesis of a number of angucyclinonederived metabolites (15, 16, 43), including PD 116740 (14). In these pathways, either dehydrorabelomycin (27, 43) or TET (13, 26), plays a key role (Fig. 1). These studies have revealed that the polyketide assembly common to both of these diverges at a prearomatic stage with an additional ketone reduction (at C-6) leading to TET. We have...

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Section: Discussionmentioning

confidence: 99%

Cloning and heterologous expression of the entire gene clusters for PD 116740 from Streptomyces strain WP 4669 and tetrangulol and tetrangomycin from Streptomyces rimosus NRRL 3016

1997

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“…Although the arenimycin biosynthetic gene cluster arn had not been identified before this study, a homologous gene cluster was previously assigned to the structurally related aromatic polyketide pradimicin (49). Pradimicin shares the benzo[α]naphthacene quinone core with arenimycins but has different oxidation patterns and different glycosylation sites and groups (50). However, the biosynthetic genes of the pradimicin benzo[α]naphtacene quinone core are conserved in the arn cluster (Fig.…”

Section: Glycogenomic Characterization Of An Arenimycin Chemotype Andmentioning

confidence: 99%

Glycogenomics as a mass spectrometry-guided genome-mining method for microbial glycosylated molecules

Kersten

Ziemert

Gonzalez³

et al. 2013

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

102

107

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Glycosyl groups are an essential mediator of molecular interactions in cells and on cellular surfaces. There are very few methods that directly relate sugar-containing molecules to their biosynthetic machineries. Here, we introduce glycogenomics as an experimentguided genome-mining approach for fast characterization of glycosylated natural products (GNPs) and their biosynthetic pathways from genome-sequenced microbes by targeting glycosyl groups in microbial metabolomes. Microbial GNPs consist of aglycone and glycosyl structure groups in which the sugar unit(s) are often critical for the GNP's bioactivity, e.g., by promoting binding to a target biomolecule. GNPs are a structurally diverse class of molecules with important pharmaceutical and agrochemical applications. Herein, O-and N-glycosyl groups are characterized in their sugar monomers by tandem mass spectrometry (MS) and matched to corresponding glycosylation genes in secondary metabolic pathways by a MS-glycogenetic code. The associated aglycone biosynthetic genes of the GNP genotype then classify the natural product to further guide structure elucidation. We highlight the glycogenomic strategy by the characterization of several bioactive glycosylated molecules and their gene clusters, including the anticancer agent cinerubin B from Streptomyces sp. SPB74 and an antibiotic, arenimycin B, from Salinispora arenicola CNB-527.secondary metabolite | drug discovery | microbial genomics | deoxysugar | polyketide

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“…XH NMR S 1.24 (1H,dt,/4'ax,4'eq=ll.l,/3',4'ax=^4'ax,5'= 12.0Hz,4'ax-H), 1.82 (1H,dd,J3',4'eq=5.1 Hz,4'eq-H), 3.13 (1H, dd, Jv r=l.l, Jr y= 9.0Hz, 2' -H), 3.47 (1H,m,3.54 (1H,dq,/5 ' Me=6.4Hz, y-O-(ll) and 2 -O-(12). (jg-D-xylopyranosyl)derivative of 9 1-O-Acetyl derivative of compound 9 methyl ester (63 mg, 0.084 mmol), obtained by a similar selective 1-0-acetylation as described above, was glycosidated with per-0-acetylated-D-xylopyranosyl bromide under the Koenigs-Knorr conditions to afford two fractions, after deblocking and purifications: Fraction 1 (ll,4.5mg,7.2%);]; MP >230°C; XH NMR S 1.16 (3H, d, /5jMe=6.0Hz, 5'-Me), 1.29 (3H,d,/17>Me=6.8Hz,2.21 (3H,s,3.07 (1H,dd,h",s"ax=9.0,J5"ax,5"eq= 12.4Hz,3.63 (1H,t,yr#r=8.1 Hz,3.70 (1H,dd,J4 >t5^q=5.6Hz,dd 4-JV-Cbz-PRMB methyl ester (D) was analogously prepared by the method reported for the corresponding PRMA derivative8*.…”

Section: -O-jg-d-galactopyranosylmentioning

confidence: 99%

Synthesis and antifungal activity of pradimicin derivatives. Modifications of the sugar part.

et al. 1993

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The structure of pradimicins A, B and C: a novel family of antifungal antibiotics

Cited by 66 publications

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Cloning and heterologous expression of the entire gene clusters for PD 116740 from Streptomyces strain WP 4669 and tetrangulol and tetrangomycin from Streptomyces rimosus NRRL 3016

Cloning and heterologous expression of the entire gene clusters for PD 116740 from Streptomyces strain WP 4669 and tetrangulol and tetrangomycin from Streptomyces rimosus NRRL 3016

Glycogenomics as a mass spectrometry-guided genome-mining method for microbial glycosylated molecules

Synthesis and antifungal activity of pradimicin derivatives. Modifications of the sugar part.

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