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MetaCyc Pathway: fluoroacetate and fluorothreonine biosynthesis

This view shows enzymes only for those organisms listed below, in the list of taxa known to possess the pathway. If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.

Superclasses: Biosynthesis Secondary Metabolites Biosynthesis

Some taxa known to possess this pathway include ? : Streptomyces cattleya

Expected Taxonomic Range: Bacteria , Viridiplantae

Summary:
Despite the fact that fluorine is abundant in the earth's crust, organically bound fluorine is relatively rare in nature, owing to its low solubility and the high redox potential required for its oxidation.

Only a handful of biologically synthesized carbon-fluorine bonds are known [Harper94] . The most common natural organofluorine species is fluoroacetate, a toxin found in the leaves and seeds of a variety of tropical plants, often in high concentrations [Peters57, Basson87]. Other compounds include fluorooleate, fluoroacetone, nucleocidin (4'-fuoro-5'-O-sulphamoyladenosine), 4-fluorothreonine, and 2-fluorocitrate.

The extreme toxicity of fluoroacetate stems from its similarity to acetate. Fluoroacetate combines with coenzyme A to form fluoroacetyl-CoA, which can substitute for acetyl CoA in the tricarboxylic acid cycle. Fluoroacetyl-CoA reacts with citrate synthase to produce 2-fluorocitrate, a metabolite of which then binds very tightly to aconitase, halting the cycle. Sodium fluoroacetate was introduced as a rodenticide in the US in 1946, but its extreme toxicity limits its uses. Currently, it is licensed in the US for use against coyotes, which prey on sheep and goats, and in Australia and New Zealand to kill unwanted introduced species [Proudfoot06].

Only two bacterial strains, both actinomycetes, have been identified with the ability to synthesize organofluorine compounds. Streptomyces calvus produces nucleocidin [Thomas57, Jenkins76], while Streptomyces cattleya produces both fluoroacetate [Murphy01] and 4-fluorothreonine [Murphy01a].

Most of the current knowledge about the biosynthesis of organofluorine compounds comes from Streptomyces cattleya.

About This Pathway

The first fluorine-biochemistry enzyme to be identified was 5'-fluoro-5'-deoxyadenosine synthase. The enzyme, discovered in the bacterium Streptomyces cattleya, catalyzes the fluorination of S-adenosyl-L-methionine (SAM) to form 5'-deoxy-5'-fluoroadenosine [OHagan02]. Subsequently, the different intermediates in the pathway were detected, usually by labelled isotopes studies. fluoroacetaldehyde was shown to be the precursor of both fluoroacetate and 4-fluorothreonine [Moss00], and the enzymes responsible for its conversions to those products, fluoroacetaldehyde dehydrogenase and 4-fluorothreonine transaldolase, respectively, were identified [Murphy01, Murphy01a]. 5-fluoro-5-deoxy-D-ribose 1-phosphate was shown to be an intermediate [Cobb04], and the last intermediate to be discovered was 5-fluoro-5-deoxy-D-ribulose 1-phosphate [Onega07].

Characterization of the gene cluster for fluorometabolite biosynthesis, which included flA (the gene encoding 5'-fluoro-5'-deoxyadenosine synthase), has revealed several additional genes, including flB, the gene encoding the protein that catalyzes the second step in the pathway, 5'-fluoro-5'-deoxy-adenosine phosphorylase [Huang06a].

The only enzyme that has not been characterized from Streptomyces cattleya at this point is the aldolase that catalyzes the formation of fluoroacetaldehyde from 5-fluoro-5-deoxy-D-ribulose 1-phosphate. An in vitro assay utilizing the proteins from Streptomyces cattleya, along with a fuculose aldolase from Streptomyces coelicolor, substituting for the missing aldolase, was successful in reconstituting the biosynthesis of 4-fluorothreonine starting from the fluoride ion [Deng08].

Credits:
Created 06-Oct-2010 by Caspi R , SRI International


References

Basson87: Basson PA (1987). "Poisoning of wildlife in southern Africa." J S Afr Vet Assoc 58(4);219-28. PMID: 3334144

Cobb04: Cobb SL, Deng H, Hamilton JT, McGlinchey RP, O'Hagan D (2004). "Identification of 5-fluoro-5-deoxy-D-ribose-1-phosphate as an intermediate in fluorometabolite biosynthesis in Streptomyces cattleya." Chem Commun (Camb) (5);592-3. PMID: 14973623

Deng08: Deng H, Cross SM, McGlinchey RP, Hamilton JT, O'Hagan D (2008). "In vitro reconstituted biotransformation of 4-fluorothreonine from fluoride ion: application of the fluorinase." Chem Biol 15(12);1268-76. PMID: 19101471

Harper94: Harper DB, O'Hagan D (1994). "The fluorinated natural products." Nat Prod Rep 11(2);123-33. PMID: 15209126

Huang06a: Huang F, Haydock SF, Spiteller D, Mironenko T, Li TL, O'Hagan D, Leadlay PF, Spencer JB (2006). "The gene cluster for fluorometabolite biosynthesis in Streptomyces cattleya: a thioesterase confers resistance to fluoroacetyl-coenzyme A." Chem Biol 13(5);475-84. PMID: 16720268

Jenkins76: Jenkins ID, Verheyden JP, Moffatt JG (1976). "4'-Substituted nucleosides. 2. Synthesis of the nucleoside antibiotic nucleocidin." J Am Chem Soc 98(11);3346-57. PMID: 1262649

Moss00: Moss, S.J., Murphy, C.D., Hamilton, J.T.G., McRobert, W.C., O'Hagan, D., Schaffrath, C., Harper, D.B. (2000). "Fluoroacetaldehyde: A precursor of both fluoroacetate and 4-fluorothreonine in Streptomyces cattleya." Chemical Communications 22:2281-2282.

Murphy01: Murphy CD, Moss SJ, O'Hagan D (2001). "Isolation of an aldehyde dehydrogenase involved in the oxidation of fluoroacetaldehyde to fluoroacetate in Streptomyces cattleya." Appl Environ Microbiol 67(10);4919-21. PMID: 11571203

Murphy01a: Murphy CD, O'Hagan D, Schaffrath C (2001). "Identification of a PLP-Dependent Threonine Transaldolase: A Novel Enzyme Involved in 4-Fluorothreonine Biosynthesis in Streptomyces cattleya." Angew Chem Int Ed Engl 40(23);4479-4481. PMID: 12404452

OHagan02: O'Hagan D, Schaffrath C, Cobb SL, Hamilton JT, Murphy CD (2002). "Biochemistry: biosynthesis of an organofluorine molecule." Nature 416(6878);279. PMID: 11907567

Onega07: Onega M, McGlinchey RP, Deng H, Hamilton JT, O'Hagan D (2007). "The identification of (3R,4S)-5-fluoro-5-deoxy-D-ribulose-1-phosphate as an intermediate in fluorometabolite biosynthesis in Streptomyces cattleya." Bioorg Chem 35(5);375-85. PMID: 17574646

Peters57: Peters RA (1957). "Mechanism of the toxicity of the active constituent of Dichapetalum cymosum and related compounds." Adv Enzymol Relat Subj Biochem 18;113-59. PMID: 13444108

Proudfoot06: Proudfoot AT, Bradberry SM, Vale JA (2006). "Sodium fluoroacetate poisoning." Toxicol Rev 25(4);213-9. PMID: 17288493

Thomas57: Thomas SO, Singleton VL, Lowery JA, Sharpe RW, Pruess LM, Porter JN, Mowat JH, Bohonos N (1957). "Nucleocidin, a new antibiotic with activity against Trypanosomes." Antibiot. Annu. 1956-1957:716-721. PMID: 13425454

Other References Related to Enzymes, Genes, Subpathways, and Substrates of this Pathway

Cooper07: Cooper RG (2007). "Poisoning in ostriches following ingestion of toxic plants--field observations." Trop Anim Health Prod 39(6);439-42. PMID: 17966275

Dong03: Dong C, Deng H, Dorward M, Schaffrath C, O'Hagan D, Naismith JH (2003). "Crystallization and X-ray diffraction of 5'-fluoro-5'-deoxyadenosine synthase, a fluorination enzyme from Streptomyces cattleya." Acta Crystallogr D Biol Crystallogr 59(Pt 12);2292-3. PMID: 14646098

Dong04: Dong C, Huang F, Deng H, Schaffrath C, Spencer JB, O'Hagan D, Naismith JH (2004). "Crystal structure and mechanism of a bacterial fluorinating enzyme." Nature 427(6974);561-5. PMID: 14765200

Latendresse13: Latendresse M. (2013). "Computing Gibbs Free Energy of Compounds and Reactions in MetaCyc."

Minnaar00: Minnaar PP, McCrindle RI, Naude TW, Botha CJ (2000). "Investigation of biological samples for monofluoroacetate and Dichapetalum cymosum poisoning in southern Africa." Onderstepoort J Vet Res 67(1);27-30. PMID: 10843319

Reid95: Reid KA, Hamilton JT, Bowden RD, O'Hagan D, Dasaradhi L, Amin MR, Harper DB (1995). "Biosynthesis of fluorinated secondary metabolites by Streptomyces cattleya." Microbiology 141 ( Pt 6);1385-93. PMID: 7670640

Sanada86: Sanada M, Miyano T, Iwadare S, Williamson JM, Arison BH, Smith JL, Douglas AW, Liesch JM, Inamine E (1986). "Biosynthesis of fluorothreonine and fluoroacetic acid by the thienamycin producer, Streptomyces cattleya." J Antibiot (Tokyo) 39(2);259-65. PMID: 3082840

Schaffrath03: Schaffrath C, Deng H, O'Hagan D (2003). "Isolation and characterisation of 5'-fluorodeoxyadenosine synthase, a fluorination enzyme from Streptomyces cattleya." FEBS Lett 547(1-3);111-4. PMID: 12860396


Report Errors or Provide Feedback
Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
Page generated by SRI International Pathway Tools version 18.5 on Fri Dec 19, 2014, BIOCYC14B.