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Identification of 5-Fluoro-5-Deoxy-Ribulose As A biomolecules Article Identification of 5-Fluoro-5-Deoxy-Ribulose as a Shunt Fluorometabolite in Streptomyces sp. MA37 Linrui Wu 1, Ming Him Tong 1, Kwaku Kyeremeh 2 and Hai Deng 1,* 1 Department of Chemistry, University of Aberdeen, Aberdeen AB24 3UE, UK; [email protected] (L.W.); [email protected] (M.H.T.) 2 Department of Chemistry, University of Ghana, P.O. Box LG56 Legon-Accra, Ghana; [email protected] * Correspondence: [email protected] Received: 18 June 2020; Accepted: 7 July 2020; Published: 10 July 2020 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. Keywords: fluorometabolites; 5-FDRul; Streptomyces sp. MA37; genetic manipulation; chemo-enzymatic synthesis 1. Introduction Fluorinated compounds have remained important in the field of lead compound discovery due to their wide therapeutic and agricultural applications [1]. The unmet need for a fluorine-incorporated lead compound presents an unremitting impetus for the development of selectively efficient fluorination methods. 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]. Fewer than thirty fluorinated natural products have been identified so far, including six structurally different ones of bacterial origin, such as fluoroacetate (FAc) 1, 4-fluorothreonine (4-FT) 2 [1], 5-fluoro-2,3,4-trihydroxypentanoic acid (FHPA) 3 [2], nucleocidin 4 [3] and two new glycosylated nucleocidin derivatives (5a, 5b) (Figure1A) [ 4]. Of these, 1 is a toxin that inhibits the citric acid cycle while 2 and 4 were discovered as antimicrobial metabolites. The biological function of 3 in the producing strain remains elusive. The scarcity of fluorinated compounds found in nature, compared to thousands of brominated or iodinated compounds, mainly results from the high electronegativity of fluorine, which precludes the common strategy for halogenation that involves the oxidation of fluoride ions [5]. In addition, 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]. Biomolecules 2020, 10, 1023; doi:10.3390/biom10071023 www.mdpi.com/journal/biomolecules Biomolecules 2020, 10, 1023 2 of 11 Biomolecules 2020, 10, x FOR PEER REVIEW 2 of 11 Figure 1.1. ((A)) Fluorometabolites discovered from bacteriabacteria soso far.far. ( B) The proposedproposed biosyntheticbiosynthetic pathways ofof fluoroacetate fluoroacetate 1 and1 and 4-fluorothreonine 4-fluorothreonine 2 in 2Streptomyces in Streptomyces cattleya cattleyaand Streptomyces and Streptomycessp. MA37, sp. andMA37, FHPA and 3 FHPA in Streptomyces 3 in Streptomycessp. MA37. sp. MA37. For decades, Streptomyces cattleya remained the onlyonly geneticallygenetically tractabletractable strainstrain producingproducing twotwo fluorinatedfluorinated natural products, 1 andand 22.. The The major major breakthrough was the identificationidentification of the firstfirst fluorinationfluorination enzyme,enzyme, fluorinase,fluorinase, which which converts convertsS -adenosyl-l-methionineS-adenosyl-l-methionine (SAM) (SAM)6 and6 and fluoride fluoride ions ions to generateto generate 50-fluoro-5 5′-fluoro-50-deoxy-adenosine′-deoxy-adenosine (50-FDA (5′-FDA7)[6, 7].7) Subsequent[6,7]. Subsequent studies resultedstudies inresulted the elucidation in the ofelucidation the biosynthetic of the biosynthetic pathway of pathway1 and 2 inof 1S. and cattleya 2 in S.as cattleya illustrated as illustrated in Figure 1inB[ Figure8]. Recent 1B [8]. studiesRecent demonstratedstudies demonstrated that two that genes, twofthB genes,and fthBfthC and, are fthC highly, are conserved highly conserved in the biosynthetic in the biosynthetic gene clusters gene (BGCs)clusters that (BGCs) direct that the direct production the production of 2 [9]. While of 2 the [9]. genetic While inactivation the genetic of inactivationfthB had no perturbationof fthB had no in 19 secretedperturbation2 in the in S.secreted cattleya 2variant in the as S. observed cattleya invariantF-NMR as observed analysis, biochemicalin 19F-NMR analysisanalysis, indicated biochemical that FthB,analysis an indicated aminoacyl that RNA FthB, deacylase, an aminoacyl plays anRNA essential deacylase, role inplays the an detoxification essential role of in2, the by detoxification counteracting theof 2 misacylation, by counteracting of fluorothreonyl-tRNA the misacylation which of fluorothreonyl-tRNA otherwise would be misincorporatedwhich otherwise into would protein be inmisincorporated place of L-threonine into protein [9]. While in place knocking of L out-threoninefthC significantly [9]. While reduced knocking the out concentration fthC significantly of 2 in culturereduced broth the concentration [9], the intracellular of 2 in2 culturewas accumulated broth [9], the in theintracellularS. cattleya 2variant, was accumulated indicatingthat in the FthC S. iscattleya a 4-FT variant, exporter. indicating The efforts that towards FthC is understanding a 4-FT exporter. the fluorinationThe efforts enzyme,towards fluorometabolismsunderstanding the influorinationS. cattleya enzyme,and related fluorometabolisms biotransformations in S. havecattleya off eredand related a new bio-basedbiotransformations approach have to generating offered a high-valuenew bio-based fluorinated approach chemicals to generating [10]. high-value fluorinated chemicals [10]. In thethe lastlast decade,decade, advancedadvanced genomegenome sequencingsequencing technologiestechnologies have enabled the useuse ofof genomegenome mining strategies to identify several other potential fluorometabolite-producingfluorometabolite-producing strainsstrains [[2,11].2,11]. Recent studies revealed thatthat StreptomycesStreptomyces sp.sp. MA37 MA37 (MA37), (MA37), a a soil isolate, is a talented naturalnatural productproduct producing strain [[12–15].12–15]. In particular, MA37 produces 1, 2 andand aa seriesseries ofof unidentifiedunidentified fluorinatedfluorinated 19 metabolites as observed in in 19F-NMRF-NMR analysis analysis of of the the supernatant supernatant of of the the culture culture broth broth of ofMA37 MA37 [11]. [11 It]. Ithas has been been shown shown that that 1 and1 and 2 in2 MA37in MA37 originate originate from from the thesame same biosynthetic biosynthetic pathway pathway as the as one the in one S. incattleyaS. cattleya [11,16].[11 A,16 combination]. A combination of chemical of chemical synthesis, synthesis, bioinformatic bioinformatic analysis analysis and biochemical and biochemical assays assaysallowed allowed the discovery the discovery of 3 as of 3a asnew a new fluorometabolite fluorometabolite and and the the identification identification of of the the second second fdrfdr biosynthetic gene cluster (BGC) in MA37 [[2].2]. However, the rest of the fluorometabolitesfluorometabolites observed in MA37 remain toto bebe determined.determined. Here we we describe describe the identification the identification of a natura oflly occurring a naturally fluorometabolite, occurring 5-fluoro-5-deoxy- fluorometabolite, 5-fluoro-5-deoxy-D-ribuloseD-ribulose (5-FDRul) 9, from the (5-FDRul) culture 9broth, from of theMA37, culture using broth a combination of MA37, of using genetic a combinationinactivation, 19 ofchemo-enzymatic genetic inactivation, synthesis chemo-enzymatic and 19F-NMR comparison. synthesis and AlthoughF-NMR reported comparison. before Althoughas chemical reported probes beforeduring asthe chemical previous probes fluorometabolism during the previous study in fluorometabolismS. cattleya, this is the study first in reportS. cattleya indicating, this isthat the 9 first is a naturally occurring fluorinated compound. During the course of our studies, we also observed that the production of several fluorinated natural products was upregulated among several MA37 Biomolecules 2020, 10, 1023 3 of 11 report indicating that 9 is a naturally occurring fluorinated compound. During the course of our studies, we also 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. 2. Experimental Section 2.1. Fermentation Conditions E. coli strains were grown in Luria-Bertani
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