4- Fluorothreonine 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, C.D. Murphy, J.T.G. Hamilton, D. O Hagan, Biosynthesis of fluoroace-tate and 4-fluorothreonine in Streptomyces cattleya. Incorporation of oxygen-18 from [2- H,2- 0]-glycerol and the role of serine metabolites in fluoroacetaldehyde biosynthesis, J. Chem. Soc. Perkin Trans. 1 (2001) 3100-3105. 

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). 

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, 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 40 4479... 

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). 

Organofluorines play an important role in medicinal chemistry, and estimates indicate that 20-30% of the pharmaceutical products on the market contain at least one fluorine atom [57, 58], However, natural organofluorine compounds are exceedingly rare, and the pharmaceutical industry has not yet benefited from a microbial source of such compounds. The soil bacterium Streptomyces cattleya was found to produce fluoro-acetate and 4-fluorothreonine, but the biological scope is limited to a single biological pathway that produces fluoroace-tate [58, 59], Identification of the fluorination enzyme FIA, responsible for C-F bond formation in S. cattleya, enabled the directed manipulation of biosynthetic pathways for the formation of fluorinated natural products. 

T. Tamura, Y. Sawamoto, T. Kuriyama, K. Oba, H. Tanaka, K. Inagaki, Cosynthesis of mono-fluoracetate and 4-fluorothreonine by resting cells of blocked mutants of Streptomyces cattleya NRRL8057, J. Mol. Catal. B Enzym. 23 (2003) 257-263. 

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

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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