Fluoroacetate Streptomyces cattleya

Hamilton JTG, CD Murphy, MR Amin, D O Hagan, DB Harper (1998) Exploring the biosynthetic origin of fluoroacetate and 4-fluorothreonine in Streptomyces cattleya. J Chem Soc Perkin Trans 1 759-767. 

So far only a few dozen organofluorine compounds have been isolated from living organisms, for example fluoroacetic acid, 4-fluorothreonine and rw-fluoro-oleic acid [244-246], The reason that nature has not invested in fluorine chemistry could be a combination of low availability of water-dissolved fluoride in the environment due to its tendency to form insoluble fluoride salts, and the low reactivity of water-solvated fluoride ion. However, in 2002, O Hagan and collaborators [247] published the discovery of a biochemical fluorination reaction in a bacterial protein extract from Streptomyces cattleya converting S-adenosyl-L-methionine (SAM) to 5 -fluoro-5 deoxyadenosine (5 -FDA). The same protein extract contained also the necessary enzymatic activity to convert 5 -FDA into fluoroacetic acid. In 2004, the same authors published the crystal structure of the enzyme and demonstrated a nucleophilic mechanism of fluorination [248,249]. 

C. Schaffrath, S.L. Cobb, D. O Hagan, Cell-free biosynthesis of fluoroacetate and 4-fluorothreonine in Streptomyces cattleya, Angew. Chem. Int. Ed. 41 (2002) 3913-3915. 

More interestingly, the ability of a microorganism (Streptomyces cattleya) can be used to produce a 4-fluorothreonine from inorganic fluoride (KF,NaF) or any one of a number of organofluorine materials m- or p-fluorophenylalanine, fluoroacetic acid) [80]. 

The infamous fluoroacetic acid and the equally toxic naturally occurring even-numbered co-fhiorinated fatty acids were discussed in detail earlier (7), and several reviews are available (34,44, 66). Although not counted as being natural in the earlier survey (7), 4-fluorothreonine (837) is now considered to be a bona fide natural metabolite of Streptomyces cattleya (893), the stereochemistry of which has been confirmed by synthesis (894). In addition to the five oo-fluorinated fatty acids presented earlier (7), new studies of the seed oil of Dichapetalum toxicarium have uncovered 16-fluoro-palmitoleic acid (838), 18-fluorostearic acid (839), 18-fluorolinoleic acid (840), 20-fluoroarachidic acid (841), 20-fluoroeicosenoic acid (842), 18-fluoro-9,10-epoxystearic acid (843) (895), (Z)-16-fluorohexadec-7-enoic acid (844), (Z)-18-fluoroocta-dec-9-enoic acid (845), and (Z)-20-fluoroicos-9-enoic acid (846) (896). 

Tamura T, Wada M, Esaki N, Soda K (1995) Synthesis of Fluoroacetate from Fluoride, Glycerol, and P-Hydroxypyruvate by Streptomyces cattleya. J Bacteriol 177 2265... 

Hamilton JTG, Amin MR, Harper DB, O Hagan D (1997) Biosynthesis of Fluoroacetate and 4-Fhiorothreonine by Streptomyces cattleya. Glycine and Pyruvate as Precursors. Chem Commun 797... 

Moss SJ, Murphy CD, Hamilton JTG, McRoberts WC, O Hagan D, Schaffrath C, Harper DB (2000) Fluoroacetaldehyde A Precursor of Both Fluoroacetate and 4-Fluorothreonine in Streptomyces cattleya. Chem Commun 2281... 

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 4919... 

O Hagan D, Goss RJM, Meddour A, Courtieu J (2003) Assay for the Enantiomeric Analysis of I HJ-Fluoroacetic Acid Insight in the Stereochemical Course of Fluorination During Fluorometabolite Biosynthesis in Streptomyces cattleya. J Am Chem Soc 125 379... 

However, an exception to this situation is the formation of the toxin fluoroacetate, which inhibits the Krebs cycle. Moreover, O Hagan and co-workers have successfully identified the first fluorinase enzyme, in the bacterium Streptomyces cattleya, which catalyses the formation of a C-F bond [88] (Figure 1.6). 

One recently discovered example is a fluorinase enzyme that is involved in the biosynthesis of fluoroacetic acid in Streptomyces cattleya. This enzyme catalyzes the nucleophihc... 

Fluoroacetate and 4-fluorothreonine are synthesized from fluoride by Streptomyces cattleya, and analysis of supernatants was used to elucidate the details of their biosynthesis they were apparently synthesized by independent routes, and it was suggested that what is at least formally glycollate could be their precursor (Reid et al., 1995). 

Nieschalk J, Hamilton JTG, Murphy CD, Harper DB, O Hagan D. Biosynthesis of fluoroacetate and 4-fluorothreo-nine by Streptomyces cattleya. The stereochemical processing of glycerol. Chem. Common. 1997 799-800. 

Murphy, C.D., Schafifrath, C., and O Hagan, D. (2003) Fluorinated natural products the biosynthesis of fluoroacetate and 4-fluorofhreonine in Streptomyces cattleya. Chemosphere, 52, 455 161. 

Fluoroacetate. Fluoroacetate 1 is the most ubiquitous fluorine-containing natural product and has been identified in over 30 plants, principally species from Africa and Australia, and also as a secondary metabolite in the bacteria Streptomyces cattleya (see below). The compoimd was first identified by Marais (4) in South Africa as the toxic principle in plants of Dichapetalum cymosum (gifblaar). The young leaves of this plant are particularly toxic in the spring when levels of fluoroacetate of up to... 

Fluorothreonine. In 1986 a second Streptomyces species capable of the biosynthesis of fluorinated compounds was identified (24). In the course of studies with Streptomyces cattleya to improve the yield of the 6-lactam antibiotic, thienamycin, it was discovered that when fluoride was present in tiie culture medium both fluoroacetate 1 and 4-fluorothreonine 6 accumulated in millimolar concentrations during fermentation. 4-fluorothreonine is the only naturally ocurring fluorinated amino acid known. When 4-fluorothreonine was initially isolated (24) the absolute stereochemistry of 4-fluorothreonine was predicted to be analogous to L-threonine. We have recently confirmed this by asymmetric synthesis (25) and demonstrated that natural 4-fluorothreonine has the (25, 3S) configuration. The... 

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