Fluorometabolites, biosynthesis

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

Scheme 6. The reactions of the flA and fIB gene products, the fluorinase and a PNP constitute the first two steps in fluorometabolite biosynthesis.

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. 

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... 

Fluoro-5-deoxy-D-ribose-l-phosphate as an Intermediate in Fluorometabolite Biosynthesis in Streptomyces cattleya. Chem Commun 592... 

Huang F, HaydockSF, Spiteller D, Mironenko T, Li T-L, 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 13 475... 

Deng H, O Hagan D, Schaffrath C (2004) Fluorometabolite Biosynthesis and the Fluorinase from Streptomyces cattleya. Nat Prod Rep 21 773... 

Natural Products Containing Fluorine and Recent Progress in Elucidating the Pathway of Fluorometabolite Biosynthesis in Streptomyces cattleya... 

Figure 11 Labelling rationale from (i )-[l- H2]-glycerol. Fluoropropanedioi is not an intermediate in fluorometabolite biosynthesis.

It was interesting that the cell-free extract had the capacity to support the biosynthesis all the way to FAc 1, an end product of one of the fluorometabolite pathways. This observation indicates that all of the enzymes and cofactors required to support FAc biosynthesis were present and active in the cell-free extract, even though the integrity of the cells had been destroyed. This experiment showed that organic fluoride production was achievable in vitro from the S. cattleya protein extract. Subsequent purification of the fluorinase (5 -fluoro-5 -deoxyadenosine synthase), using standard purification protocols revealed that the true substrate for the enzyme was SAM 8 and not ATP 7 [8]. It transpired that ATP 7 and L-methionine (L-Met) were converted to SAM 8 in the crude cell-free extract and that the resultant SAM 8 was then processed by the fluorinase with the release of L-Met. Thus, a catalytic cycle where L-Met was regenerated to drive these two reactions had been inadvertently established (Scheme 1). The fluorinase catalyses the conversion of SAM 8 and fluoride ion to make 5 -FDA 5 as shown in Scheme 1 [8]. 

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