Identification of a fluorometabolite from Streptomyces sp. MA37: (2R3S4S)-5-fluoro-2,3,4-trihydroxypentanoic acid

Abstract

(2R3S4S)-5-Fluoro-2,3,4-trihydroxypentanoic acid (5-FHPA) has been discovered as a new fluorometabolite in the soil bacterium Streptomyces sp. MA37.

Biosynthesis of the Fluorinated Natural Product Nucleocidin in Streptomyces calvus Is Dependent on the bldA‐Specified Leu‐tRNAUUA Molecule

“…[1,2] With the exception of 1,a ll of these compounds begin their biosynthesis from 5'-deoxy-5'-fluoroadenosine, which is produced by af luorinase-catalyzed S N 2r eaction of af luoridei on with the 5'-carbono fS-adenosylmethionine. [1,2] With the exception of 1,a ll of these compounds begin their biosynthesis from 5'-deoxy-5'-fluoroadenosine, which is produced by af luorinase-catalyzed S N 2r eaction of af luoridei on with the 5'-carbono fS-adenosylmethionine.…”

“…Nucleocidin (1,S cheme 1), an antimicrobiala nd antitrypanosomal analogue of adenosine, stands out amongst natural products as one of the few that contain fluorine and for its enigmatic history.O nly six structurally distinct organofluorine metabolitesa re known thus far:f luoroacetate, 4-fluoro-l-threonine, (2R,3R)-2-fluorocitrate, (2R,3S,4S)-5-fluoro-2,3,4-trihydroxypentanoic acid, w-fluorooleic acid (along with several congeners), and 1. [1,2] With the exception of 1,a ll of these compounds begin their biosynthesis from 5'-deoxy-5'-fluoroadenosine, which is produced by af luorinase-catalyzed S N 2r eaction of af luoridei on with the 5'-carbono fS-adenosylmethionine. [1] In contrast, the 4'-fluorine substituent in 1 demands ad ifferentf luorination mechanismt hat couplest wo demanding chemical steps;s pecifically,C ÀHb ond cleavage, followed by stereospecific glycosylationo ft he fluoridei on.…”

Natural production of fluorinated compounds and biotechnological prospects of the fluorinase enzyme

“…Also a gene cluster (fdr) has been identified involving in the biosynthesis of the novel fluorinated metabolite, 5-FHPA, and a gene (fdrC) encoding a NAD þ dependent dehydrogenase responsible for the biosynthesis of this metabolite from 5-FDR has been identified. [40] The results obtained in this work constitute an important contribution to the small list of hitherto known biogenic fluoro-organics.…”

“…To this end, the authors identified a new fluorometabolite -(2R3S4S)-5-fluoro-2,3,4-trihydroxypentanoic acid (5-FHPA)resulting from a new biosynthetic pathway derived from the fluorinase pathway leading to the production of FA and 4-FT, with 5-FDRP being the common metabolite between the two pathways. [40] Phosphorolysis of this compound produces 5-fluoro-5-deoxyribose (5-FDR), which by oxidation generates 5-fluoro-5-deoxy-D-ribono-!-lactone (5-FRL) that is subsequently hydrolyzed to 5-FHPA (Figure 3(b)). Also a gene cluster (fdr) has been identified involving in the biosynthesis of the novel fluorinated metabolite, 5-FHPA, and a gene (fdrC) encoding a NAD þ dependent dehydrogenase responsible for the biosynthesis of this metabolite from 5-FDR has been identified.…”

“…First synthesis of an [ 18 F]-radiolabeled organic molecule using the fluorinase enzyme [35] 2004 Elucidation of the fluorination mechanism catalyzed by the fluorinase enzyme [28] 2006 Sequencing of the gene cluster responsible for the synthesis of fluoroacetate and 4-fluorothreonine in S. cattleya [36] 2010 First biosynthesis of a fluorinated natural product analog (fluorosalinosporamide) through genetic engineering [37] 2014 Discovery of four additional bacterial fluorinases, one of them isolated for the first time from a marine source [38,39] 2015 Discovery of a new fluorometabolite -(2R3S4S)-5fluoro-2,3,4-trihydroxypentanoic acidproduced by Streptomyces sp. MA 37 [40] Australia, and South America, were later found to also produce this fatal compound. Examples include D. toxicarium, [48] D. stuhlmanii, [49] Figure 1.…”