The Pederin Family of Antitumor Agents: Structures, Synthesis and Biological Activity

Narquizian, Robert; Kocieński, Philip

doi:10.1007/978-3-662-04042-3_2

Cited by 36 publications

(34 citation statements)

References 60 publications

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“…Since pederin is a polyketide, this pseudogene could have once been a part of the ped cluster and participated in the biosynthesis of an ancestral pederin-type compound. Interestingly, the numerous members of the pederin group isolated from sponges almost always contain an additional P450-type oxygenation (15), which may be generated by an intact version of this gene.…”

Section: Resultsmentioning

confidence: 99%

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Evidence for a Symbiosis Island Involved in Horizontal Acquisition of Pederin Biosynthetic Capabilities by the Bacterial Symbiont of Paederus fuscipes Beetles

2004

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Pederin belongs to a group of antitumor compounds found in terrestrial beetles and marine sponges. It is used by apparently all members of the rove beetle genera Paederus and Paederidus as a chemical defense against predators. However, a recent analysis of the putative pederin biosynthesis (ped) gene cluster strongly suggests that pederin is produced by bacterial symbionts. We have sequenced an extended region of the symbiont genome to gain further insight into the biology of this as-yet-unculturable bacterium and the evolution of pederin symbiosis. Our data indicate that the symbiont is a very close relative of Pseudomonas aeruginosa that has acquired several foreign genetic elements by horizontal gene transfer. Besides one functional tellurite resistance operon, the region contains a genomic island spanning 71.6 kb that harbors the putative pederin biosynthetic genes. Several decayed insertion sequence elements and the mosaic-like appearance of the island suggest that the acquisition of the ped symbiosis genes was followed by further insertions and rearrangements. A horizontal transfer of genes for the biosynthesis of protective substances could explain the widespread occurrence of pederin-type compounds in unrelated animals from diverse habitats.The pederin group of natural products consists of numerous members with potent antitumor and antiviral activities ( Fig. 1) (15). Remarkably, these structurally highly similar substances have been isolated from two entirely unrelated animal groups. Pederin itself occurs in species of the beetle genera Paederus and Paederidus, while almost all other members are known only from marine sponges. In the beetles, pederin serves as a chemical defense against predators such as spiders (11). It is also the cause of Paederus dermatitis, a blistering inflammation that is contracted when the beetles are accidentally crushed on the human skin (20). In regions with a warm climate the beetles can appear in enormous numbers, resulting in notorious epidemics that have forced the evacuation of entire settlements (18,25). Interestingly, they have also been proposed as a cause for 3 of the 10 biblical plagues (16).Several lines of evidence clearly indicate that pederin is not produced by the beetles themselves but by as-yet-uncultured bacterial symbionts. Kellner and Dettner have demonstrated that within each examined beetle species pederin is synthesized in only about 90% of the females, who alone can transfer this trait to their offspring (10). According to 16S ribosomal DNA data, only these pederin-synthesizing females harbor a bacterium with the closest relationship to Pseudomonas aeruginosa (8). If eggs of such beetles are fed to nonproducing females, pederin is again synthesized in their offspring (7). Our search for the pederin biosynthesis genes, motivated by the prospect of generating an alternative biotechnological source of these rare antitumor compounds, has resulted in the isolation of a polyketide synthase cluster spanning 54 kb (19). This operon, designated the ped cluster...

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Section: Resultsmentioning

confidence: 99%

“…1) (15). Remarkably, these structurally highly similar substances have been isolated from two entirely unrelated animal groups.…”

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confidence: 95%

Evidence for a Symbiosis Island Involved in Horizontal Acquisition of Pederin Biosynthetic Capabilities by the Bacterial Symbiont of Paederus fuscipes Beetles

2004

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“…2). These compounds, with almost identical core regions but different biosynthetic starter regions and/or termini, are often highly toxic to eukaryotes and some have been considered promising candidates for anticancer drug development (38)(39)(40). Notably, this group of compounds has never been recovered from screening free-living bacteria, despite conspicuous pharmacological activities.…”

Section: Discussionmentioning

confidence: 99%

Metagenomic natural product discovery in lichen provides evidence for a family of biosynthetic pathways in diverse symbioses

Kampa

Gagunashvili

Gulder

et al. 2013

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

125

127

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Bacteria are a major source of natural products that provide rich opportunities for both chemical and biological investigation. Although the vast majority of known bacterial metabolites derive from free-living organisms, increasing evidence supports the widespread existence of chemically prolific bacteria living in symbioses. A strategy based on bioinformatic prediction, symbiont cultivation, isotopic enrichment, and advanced analytics was used to characterize a unique polyketide, nosperin, from a lichen-associated Nostoc sp. cyanobacterium. The biosynthetic gene cluster and the structure of nosperin, determined from 30 μg of compound, are related to those of the pederin group previously known only from nonphotosynthetic bacteria associated with beetles and marine sponges. The presence of this natural product family in such highly dissimilar associations suggests that some bacterial metabolites may be specific to symbioses with eukaryotes and encourages exploration of other symbioses for drug discovery and better understanding of ecological interactions mediated by complex bacterial metabolites.biosynthesis | Peltigera membranacea | trans-acyltransferase polyketide synthase | 13 C nuclear magnetic resonance

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“…The isolated genes correspond to almost the entire region of the onnamide molecule that would be needed to obtain an antitumor-active marine compound according to structure-activity relationship studies (37). The clustered architecture of these pharmacologically relevant genes has important consequences not only for the production of known and novel pederin-type anticancer agents but also for marine biotechnology and ecology in general.…”

Section: Discussionmentioning

confidence: 99%

Antitumor polyketide biosynthesis by an uncultivated bacterial symbiont of the marine sponge Theonella swinhoei

Piel

Hui

Wen

et al. 2004

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

503

405

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Bacterial symbionts have long been suspected to be the true producers of many drug candidates isolated from marine invertebrates. Sponges, the most important marine source of biologically active natural products, have been frequently hypothesized to contain compounds of bacterial origin. This symbiont hypothesis, however, remained unproven because of a general inability to cultivate the suspected producers. However, we have recently identified an uncultured Pseudomonas sp. symbiont as the most likely producer of the defensive antitumor polyketide pederin in Paederus fuscipes beetles by cloning the putative biosynthesis genes. Here we report closely related genes isolated from the highly complex metagenome of the marine sponge Theonella swinhoei, which is the source of the onnamides and theopederins, a group of polyketides that structurally resemble pederin. Sequence features of the isolated genes clearly indicate that it belongs to a prokaryotic genome and should be responsible for the biosynthesis of almost the entire portion of the polyketide structure that is correlated with antitumor activity. Besides providing further proof for the role of the related beetle symbiont-derived genes, these findings raise intriguing ecological and evolutionary questions and have important general implications for the sustainable production of otherwise inaccessible marine drugs by using biotechnological strategies. F or almost 30 years, symbiotic bacteria have been discussed as the likely true producers of numerous natural products isolated from marine invertebrates (1). Particularly suggestive of a bacterial origin is the similarity of many compounds from sponges, tunicates, or bryozoans to complex polyketides and nonribosomal peptides, two groups of metabolites that are otherwise known exclusively from microorganisms (2, 3). Into these structural families fall some of today's most promising drug candidates, such as discodermolide, bryostatin 1, aplidine, and ET-743 (4). The existence of producing symbionts could have far reaching consequences for the development of sustainable, fermentation-based sources of invertebrate-derived drug candidates, almost all of which are currently inaccessible in large amounts. Several studies have tried to pinpoint the producers by using cultivation (5), cell separation (6), immunolocalization (7), or in situ hybridization (8) approaches. However, as none of these methods have so far provided unambiguous results, the true origin of the compounds still remains an enigma. We have recently used a genetic strategy to provide insights into natural product symbiosis in terrestrial insects (9). Rove beetles of the genera Paederus and Paederidus are the source of the highly active antitumor polyketide pederin (Fig. 1), which they use as chemical defense (10). We isolated a set of putative pederin biosynthesis genes (9, 11) from the metagenome of Paederus fuscipes beetles and traced them to a bacterial symbiont with the closest relationship to Pseudomonas aeruginosa (12). The genes encode a mixed modul...

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The Pederin Family of Antitumor Agents: Structures, Synthesis and Biological Activity

Cited by 36 publications

References 60 publications

Evidence for a Symbiosis Island Involved in Horizontal Acquisition of Pederin Biosynthetic Capabilities by the Bacterial Symbiont of Paederus fuscipes Beetles

Evidence for a Symbiosis Island Involved in Horizontal Acquisition of Pederin Biosynthetic Capabilities by the Bacterial Symbiont of Paederus fuscipes Beetles

Metagenomic natural product discovery in lichen provides evidence for a family of biosynthetic pathways in diverse symbioses

Antitumor polyketide biosynthesis by an uncultivated bacterial symbiont of the marine sponge Theonella swinhoei

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