The biosynthesis of pederin

Cardani, Cesare; Fuganti, Claudio; Ghiringhelli, Dario; Grasselli, Piero; Pavan, M.; Valcurone, M.D.

doi:10.1016/s0040-4039(01)96058-7

Cited by 24 publications

(17 citation statements)

References 2 publications

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“…The structure of pederin and early labeling studies (13) indicate that the metabolite is largely synthesized from malonyland methylmalonyl-CoA units by a type I PKS. Such megasynthases consist of repeated modules, along which the growing polyketide chain is processed in an assembly line-like fashion (14).…”

Section: Resultsmentioning

confidence: 99%

A polyketide synthase-peptide synthetase gene cluster from an uncultured bacterial symbiont of Paederus beetles

Piel

2002

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

553

471

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Many drug candidates from marine and terrestrial invertebrates are suspected metabolites of uncultured bacterial symbionts. The antitumor polyketides of the pederin family, isolated from beetles and sponges, are an example. Drug development from such sources is commonly hampered by low yields and the difficulty of sustaining invertebrate cultures. To obtain insight into the true producer and find alternative supplies of these rare drug candidates, the putative pederin biosynthesis genes were cloned from total DNA of Paederus fuscipes beetles, which use this compound for chemical defense. Sequence analysis of the gene cluster and adjacent regions revealed the presence of ORFs with typical bacterial architecture and homologies. The ped cluster, which is present only in beetle specimens with high pederin content, is located on a 54-kb region bordered by transposase pseudogenes and encodes a mixed modular polyketide synthase͞nonribosomal peptide synthetase. Notably, none of the modules contains regions with homology to acyltransferase domains, but two copies of isolated monodomain acyltransferase genes were found at the upstream end of the cluster. In line with an involvement in pederin biosynthesis, the upstream cluster region perfectly mirrors pederin structure. The unexpected presence of additional polyketide synthase͞nonribosomal peptide synthetase modules reveals surprising insights into the evolutionary relationship between pederintype pathways in beetles and sponges.

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Section: Resultsmentioning

confidence: 99%

A polyketide synthase-peptide synthetase gene cluster from an uncultured bacterial symbiont of Paederus beetles

Piel

2002

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

553

471

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“…Cardani et al attempted to elucidate the biosynthesis of 1 by feeding radioactively labeled precursors to P. fuscipes. [24] They reported the presence of 40 % activity of administered labeled propionate in the N-acyl moiety constituting the western half of pederin (1). This seemingly suggests that the first extension unit is derived from methylmalonyl-CoA instead of malonyl-CoA and SAMdependent methylation by an MT domain.…”

Section: Sequence Analysis Of the Ps1 Regionmentioning

confidence: 99%

Unprecedented Diversity of Catalytic Domains in the First Four Modules of the Putative Pederin Polyketide Synthase

Piel¹,

Wen²,

Platzer³

et al. 2003

ChemBioChem

111

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Polyketides of the pederin group are highly potent antitumor compounds found in terrestrial beetles and marine sponges. Pederin is used by beetles of the genera Paederus and Paederidus as a chemical defense. We have recently identified a group of putative pederin biosynthesis genes and localized them to the genome of an as yet unculturable Pseudomonas sp. symbiont, the likely true pederin producer. However, this polyketide synthase cluster lacks several genes expected for pederin production. Here we report an additional polyketide synthase encoded on a separate region of the symbiont genome. It contains at least three novel catalytic domains that are predicted to be involved in pederin chain initiation and the formation of an unusual exomethylene bond. The region is bordered by mobility pseudogenes; this suggests that gene transposition led to the disjointed cluster organization. With this work, all putative pederin genes have been identified. Their heterologous expression in a culturable bacterium will provide important insights into how sustainable sources of invertebrate-derived drug candidates can be created.

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“…Isolation of the toxic substance, which was named pederin by Pavan and Bo (1953), led to the discovery of an amide with complex structure (Cardani et al 1965b;Matsumoto et al 1968). The biosynthesis of this unusual compound, which immediately became a target of scientific interest (Cardani et al 1965a), could not be re-solved in detail but is regarded as a polyketide synthesis (Cardani et al 1973). This pathway implies the presence of multifunctional proteins that biosynthesize (part of ) the substance through metabolic channeling ( Luckner 1990).…”

Section: Resultsmentioning

confidence: 99%

Brief communication. Heteroplasmy of mitochondrial DNA in the iphiuroid Astrobrachion constrictum

Steel

Trewick²,

Wallis³

2000

Journal of Heredity

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The biosynthesis of pederin

Cited by 24 publications

References 2 publications

A polyketide synthase-peptide synthetase gene cluster from an uncultured bacterial symbiont of Paederus beetles

A polyketide synthase-peptide synthetase gene cluster from an uncultured bacterial symbiont of Paederus beetles

Unprecedented Diversity of Catalytic Domains in the First Four Modules of the Putative Pederin Polyketide Synthase

Brief communication. Heteroplasmy of mitochondrial DNA in the iphiuroid Astrobrachion constrictum

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