Streptomyces cattleya

Reid KA, JTG Hamilton, RD Bowden, D O Hagan, L Dasaradhi, MR Amin, DB Harper (1995) Biosynthesis of fluorinated seeondary metabolites by Streptomyces cattleya. Microbiology (UK) 141 1385-1393. 

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. 

O Hagan, D. (2006) Recent developments on the fluorinase from Streptomyces cattleya. Journal of Fluorine Chemistry, 127, 1479-1483. 

There are several naturally occurring variations on the lactam-thiazolidine or lactam-dihydrothiazine structures, leading to other useful antibiotics or to inhibitors of the (5-lactamases, enzymes that hydrolyze the (5-lactam unit. One group, termed carbapenems 5 has a five-membered ring in which the thiazolidine sulfur is replaced with CH2- Such compounds may still contain sulfur in a thioethylamine side chain (derived from L-cysteine) as in thienamycin 6, originally isolated from Streptomyces cattleya (Scheme 2). 

Imipenem Imipenem, [5R-[5a,6a(R)]]-6-(l-hydroxyethyl)-3-[[2-[(iminomethyl)amino] ethyl]thio]-7-oxo-l-azabicyclo[3.2.0]hept-2-en-2-carboxyUc acid (32.1.3.1), is the only car-bapenem presently used in clinics. It is synthesized from thienamycin isolated from Streptomyces cattleya by reacting it with the methyl formimidate [179-182]. 

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.D. Cadicamo, J. Courtieu, H. Deng, A. Meddour, D. O Hagan, Enzymatic fluorina-tion in Streptomyces cattleya takes place with an inversion of configuration consistent with an Sn2 reaction mechanism, ChemBioChem 5 (2004) 685-690. 

H. Deng, D. O Hagan, C. Schaffrath, Fluorometabolite biosynthesis and the fluorinase from Streptomyces cattleya, Nat. Prod. Rep. 21 (2004) 773-784. 

Recent developments on research into a bacterial C-F bond forming enzyme are reviewed. The fluorinase enzyme was isolated from Streptomyces cattleya in 2002 and shown to catalyse the conversion of fluoride ion and S-adenosyl-L-methionine (SAM) to 5 -fluoro-5 -deoxyadenosine (5 -FDA) and L-methionine. Subsequently, the enzyme has been the subject of cloning, crystallisation, mechanism and substrate specificity studies. This review summarises the current status of this research. 

Fig. 1. F NMR time course of the Streptomyces cattleya cell-free extract incubation of ATP 7 and fluoride ion in buffer, monitored every hour for 17 h. Three fluorine containing products are apparent. These are 5 -FDA 5, 5 -FDI 6 and FAc 1 [6].

Fig. 7. Relative arrangement and annotation of a 10-kb gene cluster around the fluorinase gene (flA) of Streptomyces cattleya. The fIB gene codes the second step on the biosynthesis pathway to the fluormetabolites, operating directly after the fluorinase [17].

Scheme 8. The conversion of L-threonine 12 and fluoroacetaldehyde 11 to 4-FT 2 and acetaldehyde catalysed by the PLP enzyme threonine transaldolase from Streptomyces cattleya [18].

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. 

S.L. Cobb, H. Deng, A.R. McEwan, J.H. Naismith, D. O Hagan, D.A. Robinson, Substrate specificity in enzymatic fluorination. The fluorinase from Streptomyces cattleya accepts 2 -deoxyadenosine substrates, Org. Biomol. Chem. 4 (2006) 1458-1460. 

F. Huang, S.F. Haydock, D. Spiteller, T. Mironenko, T.-L. Li, D. O Hagan, P.F. Leadlay, J.B. Spencer, The gene cluster for fluorometabolite biosynthesis in Streptomyces cattleya-. A thioesterase confers resistance to fluoroacetyl-coenzyme A, Chem Biol. 13 (2006) 475-484. 

For the first time, an enzyme able to create a carbon-fluorine bond has been isolated from Streptomyces cattleya. This enzyme has been characterized and then named fluorinase. In the presence of fluoride ions, this enzyme catalyzes the conversion of 5-adenosyl methionine into 5 -fluoro-5 desoxyadenosine (Figure 4.3). ... 

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). 

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