doi: 10.1073/pnas.222481399. Epub 2002 Oct 14.
A polyketide synthase-peptide synthetase gene cluster from an uncultured bacterial symbiont of Paederus beetles
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- PMID:12381784
- PMCID: PMC137826
- DOI: 10.1073/pnas.222481399
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A polyketide synthase-peptide synthetase gene cluster from an uncultured bacterial symbiont of Paederus beetles
Jörn Piel. Proc Natl Acad Sci U S A..
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Abstract
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 synthase/nonribosomal 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 synthase/nonribosomal peptide synthetase modules reveals surprising insights into the evolutionary relationship between pederin-type pathways in beetles and sponges.
Figures
Some members of the pederin family of antitumor compounds isolated fromterrestrial beetles and marine sponges.
PCR amplification of PKS gene fragments from beetle total DNA.(a) TLC analysis of the ethanolic beetle extracts.The arrow indicates the position of pederin. Small amounts of pederinfound in males and (−)-females are due to pederin transfer from(+)-females to the offspring. (b) Agarose gel of the PCRproducts obtained from total DNA of the same beetle specimens that wereused for pederin extraction. L, 1-kb DNA ladder; B, negative PCRcontrol without template DNA; 1,P. fuscipes,(+)-female, collected at Jena, Germany; 2,P. fuscipes,(−)-female, Jena; 3,P. fuscipes, male, Jena; 4,P. fuscipes, (+)-female, collected at Aydın, Turkey;5,P. fuscipes, (−)-female, Aydın; 6,P.fuscipes, male, Aydın; 7,Paederidusrubrothoracicus, (+)-female, Aydın; 8,Pd.rubrothoracicus, (−)-female, Aydın; 9,Pd.rubrothoracicus, male, Aydın; 10,P.litoralis, (+)-female, Jena; 11,P. litoralis,male, Jena. No (−)-female ofP. litoralis wasavailable.
Map of the sequencedped genes and proposed pederinbiosynthesis pathway. The product of PedF could be directly cleaved offthe enzyme (route A) or elongated further by PedH to yield anonnamide-type intermediate and subsequently cleaved (route B). TP,transposase pseudogene; MT, methyltransferase; OR, oxidoreductase; OXY,oxygenase; C, NRPS condensation domain; A, NRPS adenylation domain; T,NRPS thiolation domain; DH, putative nonfunctional dehydratasedomain.
Comparison of the first modules of PedF and the avermectin AVES2. Theshaded area in AVES2-1 indicates the AT region that is deleted inPedF1. Conserved motifs are shown as vertical bars. Motifs are: 1,EPIAIV; 2, DPQQRL; 3, CSSS; 4, HGTGTxLGD; 5, GxGGxNAHVILEE; 6,AYTLQxGR; 7, GHSxG; 8, YPF; 9, GxDS. ACP, acyl carrier protein.
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