Production of the novel lipopeptide antibiotic trifluorosurfactin via precursor-directed biosynthesis

Biodegradation of Amphipathic Fluorinated Peptides Reveals a New Bacterial Defluorinating Activity and a New Source of Natural Organofluorine Compounds

“…For example, it was reported that incubation of 4,4,4-trifluoro- dl -valine with a Bacillus sp. resulted in the production of 4,4,4-trifluoro-2-hydroxy-3-methylbutanoic acid . Biodefluorination of fluorinated amino acids is not well known; one example was reported by Donnelly and Murphy who observed defluorination of 4-fluoroglutamic acid, which was accompanied by ammonia release.…”

“…resulted in the production of 4,4,4-trifluoro-2-hydroxy-3-methylbutanoic acid. 35 Biodefluorination of fluorinated amino acids is not well known; one example was reported by Donnelly and Murphy 36 who observed defluorination of 4-fluoroglutamic acid, which was accompanied by ammonia release. Although the enzymatic mechanism was not revealed, it is likely that the deamination of the amino acid leads to non-enzymatic fluoride release, which is supported by more recent work by Wu and Deng 37 who demonstrated that 4-fluorothreonine was defluorinated by threonine deaminase.…”

Biosynthetic incorporation of fluorinated amino acids into the nonribosomal peptide gramicidin S

“…6 Therefore, attempts have been made to biosynthetically incorporate fluorine into natural products belonging to the classes of alkaloids, nonribosomal peptides (NRPs), polyketides, and cyclic dinucleotides. [7][8][9][10][11][12][13][14][15][16][17][18][19] Notable successes have been achieved in engineering polyketide biosynthesis, bringing the biosynthesis of flurithromycin almost within reach. 17 While the similarity between a C-H and a C-F bond allows many non-natural, fluorinated analogues to slip through biosynthetic selectivity filters, designing biosynthetic enzymes with binding pockets selective for fluorinated substrates is largely unexplored.…”

“…Incorporation of fluorinated amino acids into NRPs, which are a prolific source of various drugs and antibiotics, [20][21][22] has so far relied on precursor-directed biosynthesis exploiting the natural promiscuity of biosynthetic enzymes. 9,11,[13][14][15][16]19 NRPs are produced by large multimodular enzymes called nonribosomal peptide synthetases (NRPSs). 21,23,24 These NRPSs are built from three core domains (Fig.…”

Novel fluorinated lipopeptides from Bacillus sp. CS93 via precursor-directed biosynthesis

“…The strain is known to produce the dipeptides bacilysin and chlorotetaine, plus the lipopeptides iturin A, surfactin and fengycin (Phister et al 2004;Moran et al 2010); it is likely that the antimicrobial properties of these compounds are responsible in part for the curative properties of pozol. The substrate flexibility of the biosynthetic machinery involved in lipopeptide production has enabled precursor directed incorporation of 3-fluorotyrosine and 4,4,4-trifluorovaline into iturin A and surfactin, respectively (Moran et al 2009;O'Connor et al 2012). Approximately 20 % of currently available pharmaceuticals and 30 % of agrochemicals contain fluorine, which can alter 3 compounds' properties such as lipophilicity and metabolic stability, thereby improving their biological activity (Murphy et al 2009).…”