Some influences of fluorine in bioorganic chemistry

O’Hagan, David; S., Rzepa Henry

doi:10.1039/a604140j

Cited by 507 publications

(255 citation statements)

References 75 publications

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“…Thus, the fluorinated analogues are not entirely inert, as are azaGPP and homoLPP which yield no detectable enzymatic products. In spite of this, FGPP and FLPP would appear to be most suitable crystallization aids because binding at the active site is assured, the fluorine substituent causes only minor steric and geometric perturbation in the olefin chain [54], and the K i values are relatively low. It should be noted that FLPP employed here was racemic; thus, K i values for the respective pure enantiomers are likely to be lower with the corresponding enantioselective enzyme.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of monoterpene cyclases by inert analogues of geranyl diphosphate and linalyl diphosphate

Karp

Zhao

Santhamma

et al. 2007

Archives of Biochemistry and Biophysics

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The tightly coupled nature of the reaction sequence catalyzed by monoterpene synthases has prevented direct observation of the topologically required isomerization step leading from geranyl diphosphate to the enzyme-bound, tertiary allylic intermediate linalyl diphosphate, which then cyclizes to the various monoterpene skeletons. X-ray crystal structures of these enzymes complexed with suitable analogues of the substrate and intermediate could provide a clearer view of this universal, but cryptic, step of monoterpenoid cyclase catalysis. Toward this end, the functionally inert analogues 2-fluorogeranyl diphosphate, (±)-2-fluorolinalyl diphosphate, and (3R)-and (3S)-homolinalyl diphosphates (2,6-dimethyl-2-vinyl-5-heptenyl diphosphates) were prepared, and compared to the previously described substrate analogue 3-azageranyl diphosphate (3-aza-2,3-dihydrogeranyl diphosphate) as inhibitors and potential crystallization aids with two representative monoterpenoid cyclases, (−)-limonene synthase and (+)-bornyl diphosphate synthase. Although these enantioselective synthases readily distinguished between (3R)-and (3S)-homolinalyl diphosphates, both of which were more effective inhibitors than was 3-azageranyl diphosphate, the fluorinated analogues proved to be the most potent competitive inhibitors and have recently yielded informative liganded structures with limonene synthase.

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Section: Resultsmentioning

confidence: 99%

Inhibition of monoterpene cyclases by inert analogues of geranyl diphosphate and linalyl diphosphate

Karp

Zhao

Santhamma

et al. 2007

Archives of Biochemistry and Biophysics

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“…DFPA seems to be a good fluorinated isostere of 2-OG, because the x-ray structure of DFPA resembles that of 2-OG (data not shown), and the pK a values of DFPA (2.03 and 4.37) are also similar to those of 2-OG (2.35 and 4.85). In addition, because there are no endogenous fluorinated compounds in Anabaena, cell samples containing exogenous fluorinated molecules can be traced easily by using 19 F MAS NMR because of the fluorine spin characteristics (33). Furthermore, the technique of 19 F NMR, with a wide range of chemical shifts spanning Ϸ300 ppm, is extremely sensitive to changes in chemical structures (30).…”

Section: Synthesis Of 2-og Analoguesmentioning

confidence: 99%

Nonmetabolizable analogue of 2-oxoglutarate elicits heterocyst differentiation under repressive conditions in Anabaena sp. PCC 7120

Laurent

Chen

Bédu

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

127

168

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In response to combined nitrogen starvation in the growth medium, the filamentous cyanobacterium Anabaena sp. PCC 7120 is able to develop a particular cell type, called a heterocyst, specialized in molecular nitrogen fixation. Heterocysts are regularly intercalated among vegetative cells and represent 5-10% of all cells along each filament. In unicellular cyanobacteria, the key Krebs cycle intermediate, 2-oxoglutarate (2-OG), has been suggested as a nitrogen status signal, but in vivo evidence is still lacking. In this study we show that nitrogen starvation causes 2-OG to accumulate transiently within cells of Anabaena PCC 7120, reaching a maximal intracellular concentration of Ϸ0.1 mM 1 h after combined nitrogen starvation. A nonmetabolizable fluorinated 2-OG derivative, 2,2-difluoropentanedioic acid (DFPA), was synthesized and used to demonstrate the signaling function of 2-OG in vivo. DFPA is shown to be a structural analogue of 2-OG and the process of its uptake and accumulation in vivo can be followed by 19 F magic angle spinning NMR because of the presence of the fluorine atom and its chemical stability. DFPA at a threshold concentration of 0.3 mM triggers heterocyst differentiation under repressing conditions. The multidisciplinary approaches using synthetic fluorinated analogues, magic angle spinning NMR for their analysis in vivo, and techniques of molecular biology provide a powerful means to identify the nature of the signals that remain unknown or poorly defined in many signaling pathways.cyanobacterium ͉ Krebs cycle ͉ nitrogen metabolism ͉ nutrient starvation ͉ signal transduction

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“…Ala was used as control in position 8 and 9 as well. The fluorinated amino acids were chosen due to the widely accepted assumption that a trifluoromethyl group exhibits approximately the same size as an isopropyl group 20 and, thus, (CF 3 CH 2 )Gly resembles Leu. Interestingly, all substitutions at position 9 resulted in destabilized peptides as reflected by 15-22 K decreased melting temperatures.…”

Section: 5mentioning

confidence: 99%

“…8). 145 However, these first trials resulted only in a very inefficient substitution and the low expression yields were attributed to the increased size/van der Waals radius 20,146 of the trifluoromethyl group. Despite the low yields, it was possible to analyze the Tfm containing congener by 19 F NMR and the detected signals could be assigned.…”

mentioning

confidence: 99%

Organic fluorine as a polypeptide building element: in vivo expression of fluorinated peptides, proteins and proteomes

Merkel

Budiša

2012

Org. Biomol. Chem.

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Some influences of fluorine in bioorganic chemistry

Cited by 507 publications

References 75 publications

Inhibition of monoterpene cyclases by inert analogues of geranyl diphosphate and linalyl diphosphate

Inhibition of monoterpene cyclases by inert analogues of geranyl diphosphate and linalyl diphosphate

Nonmetabolizable analogue of 2-oxoglutarate elicits heterocyst differentiation under repressive conditions in Anabaena sp. PCC 7120

Organic fluorine as a polypeptide building element: in vivo expression of fluorinated peptides, proteins and proteomes

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