Abstract
The complete genome of the strain Labrenzia sp. PHM005, a free-living producer of a pederin analog 18-O-demethyl pederin, hereinafter labrenzin, has been sequenced. This strain contains two replicons comprising a circular chromosome of 6,167,349 bp and a circular plasmid (named p1BIR) of 19,450 bp. A putative gene cluster responsible for the synthesis of labrenzin (lab cluster) has been identified showing that it encodes a trans-AT mixed type PKS/NRPS biosynthetic pathway that is responsible for the synthesis of pederin and possibly an onnamide analog. The putative boundaries of the lab gene cluster were determined by genetic comparisons with other related strains, suggesting that the cluster consists of a 79-kb region comprising 3 genes encoding multidomain hybrid polyketide synthase/non-ribosomal peptide synthetase (PKS/NRPS) proteins (PKS4, PKS/NRPS13, and PKS/NRPS15), and 16 auxiliary enzymes. Transcriptomic analyses suggest that all the genes of the cluster are expressed in our culture conditions (i.e., in minimal medium in the absence of any specific inducer) at detectable levels. We have developed genetic tools to facilitate the manipulation of this strain and the functional characterization of the cluster genes. We have created a site-directed mutant unable to produce pederin, demonstrating experimentally for the first time the role of the cluster in the synthesis of pederin. This work paves the way to unravel the clues of the biosynthesis of pederin family compounds and opens the door to modify and overproduce these anticancer drugs for industrial and pharmaceutical purposes.
Highlights
Pederin is a natural polyketide extracted for the first time from insect genus Paederus Curt. (Coleoptera: Staphylinidae) as non-protein insect toxin (Frank and Kanamitsu, 1987)
Culture media used to grow Labrenzia sp. strain PHM005 and to produce labrenzin were as follows: (i) Marine Broth (DIFCO 2216) (MB); (ii) Modified marine basal media (MBM) (Baumann and Baumann, 1981) containing NaCl (20 g/L) and 0.2% glucose as carbon source; (iii) MBM supplemented with vitamins (MBM + vit) [B12 (50 μg/L), panthotenic acid (50 μg/L), riboflavin (50 μg/L), pyridoxamine (10 μg/L), biotin (20 μg/L), folic acid (20 μg/L), nicotinic acid (50 μg/L), p-aminobenzoic acid (50 μg/L), thyamine (50 μg/L)]; (iv) MBM supplemented with biotin (20 μg/L) (MBM + BIOTIN); (v) MBM supplemented with thyamine (50 μg/L) (MBM + THYAMINE); (vi) MBM supplemented with biotin (20 μg/L) and thyamine (50 μg/L) (MBM + B + T)
Strain PHM005 appears to be most similar to L. alexandrii both genomes do not seem to belong to the same species since the Average nucleotide identity (ANI) value is below 95% (Goris et al, 2007)
Summary
Pederin is a natural polyketide extracted for the first time from insect genus Paederus Curt. (Coleoptera: Staphylinidae) as non-protein insect toxin (Frank and Kanamitsu, 1987). Pederin is a natural polyketide extracted for the first time from insect genus Paederus Curt. Twenty five million field-collected Paederus fuscipes were used to isolate pure pederin (Pavan and Bo, 1952) and its chemical formula was further determined (Cardani et al, 1965). It has been found that females of genera Paederus use pederin to chemically defend their offspring against predators (Kellner and Dettner, 1996). Pederin displays potent and selective bioactivities that have triggered biomedical interests (Soldati et al, 1966; Wan et al, 2011). It has a huge therapeutic potential because it is shown to be a highly potent anticancer agent (Richter et al, 1997). Related cytotoxic compounds like theopederins, mycalamides, and onnamides have been isolated from several genus
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