Abstract
A fluorometabolite, 5-fluoro-5-deoxy-D-ribulose (5-FDRul), from the culture broth of the soil bacterium Streptomyces sp. MA37, was identified through a combination of genetic manipulation, chemo-enzymatic synthesis and NMR comparison. Although 5-FDRul has been chemically synthesized before, it was not an intermediate or a shunt product in previous studies of fluorometalism in S. cattleya. Our study of MA37 demonstrates that 5-FDRul is a naturally occurring fluorometabolite, rendering it a new addition to this rare collection of natural products. The genetic inactivation of key biosynthetic genes involved in the fluorometabolisms in MA37 resulted in the increased accumulation of unidentified fluorometabolites as observed from 19F-NMR spectral comparison among the wild type (WT) of MA37 and the mutated variants, providing evidence of the presence of other new biosynthetic enzymes involved in the fluorometabolite pathway in MA37.
Highlights
Fluorinated compounds have remained important in the field of lead compound discovery due to their wide therapeutic and agricultural applications [1]
MA37 wild type and the confirmed in-frame deletion variants were grown on ISP2 agar medium for 4 d before being inoculated into ISP2 liquid medium supplemented with KF (2.5 mM)
BiomoCleocunlessid20e2r0i,n1g0,txhFaOt RMPAEE3R7 RpEroVdIEuWces a broader spectrum of fluorometabolites compared to S. cat5tloeyf a11, the gene homologues of fthB and fthC in MA37 may have roles in ortohlers uinniodtehnetrifiuendidfleunotirfoiemdeftlauboorloimtese.taTbootlihtiess.eTndo,twhies genende, rwateedgetnweoraMteAd 3t7wvoaMriaAn3t7s wvahreiarentfsthwBhMeAre afnthdBfMthACManAdwftehrCeMsuAbjwecetreedstuobijne-cftreadmteo dine-lfertaiomne, rdeeslpeeticotinv,erleys. pAefctteirvefelyrm
Summary
Fluorinated compounds have remained important in the field of lead compound discovery due to their wide therapeutic and agricultural applications [1]. Compared to the vast amount of synthetic fluorinated compounds, naturally occurring fluorinated natural products are extremely rare, most of which are fluorinated fatty acids with different chain lengths discovered in sub-tropical and tropical plants [1]. The solvation tendency of fluoride ions in aqueous solutions causes fluoride to need extra energy to become a good nucleophile. Such desolvation processes elevate the difficulty of biochemically incorporating fluorine into complex organic molecules [5]. FFoorr ddeeccaaddeess,, SSttrreeppttoommyycceess ccaattttlleeyyaa rreemmaaiinneedd tthhee oonnllyy ggeenneettiiccaallllyy ttrraaccttaabbllee ssttrraaiinn pprroodduucciinngg ttwwoo flfluuoorriinnaatteedd nnaattuurraall pprroodduuccttss,, 11 aanndd 22. IInn ppaarrttiiccuullaarr,, MMAA3377 pprroodduucceess 11,, 22 aanndd aa sseerriieess ooff uunniiddeennttiififieedd flfluuoorriinnaatteedd mmeettaabboolliitteess aass oobbsseerrvveedd iinn1199FF-N-NMMRRaannaalylysissisofofthtehesuspueprenrantaatnatnotfotfhtehceuclutultruerberbortohtohfoMf AM3A73[711[]1.1I]t. HHoowweevveerr,, tthhee rreesstt ooff tthhee flfluuoorroommeettaabboolliitteess oobbsseerrvveedd iinn MMAA3377 rreemmaaiinn ttoo bbee ddeetteerrmmiinneedd. During the course of our studies, we observed that the production of several fluorinated natural products was upregulated among several MA37 fluorometabolite biosynthesis related gene inactivation variants as observed in 19F-NMR analysis, suggesting that the inactivation of genes responsible for downstream fluorometabolite biosynthesis may influence metabolic reflux and direct accumulated biosynthetic intermediates to other previously unnoticed pathways in MA37
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