5fiu
Binding and structural studies of a 5,5-difluoromethyl adenosine nucleoside with the fluorinase enzyme
Structural highlights
FunctionFLA_STRCT Involved in the biosynthesis of fluorometabolites. Catalyzes the formation of a C-F bond by combining S-adenosyl-L-methionine (SAM) and fluoride to generate 5'-fluoro-5'-deoxyadenosine (5'-FDA) and L-methionine. It can also use 2'-deoxyadenosine in place of adenosine as substrate.[1] [2] [3] [4] [5] [6] Publication Abstract from PubMedThe investigation of a difluoromethyl-bearing nucleoside with the fluorinase enzyme is described. 5',5'-Difluoro-5'-deoxyadenosine 7 (F2DA) was synthesised from adenosine, and found to bind to the fluorinase enzyme by isothermal titration calorimetry with similar affinity compared to 5'-fluoro-5'-deoxyadenosine 2 (FDA), the natural product of the enzymatic reaction. F2DA7 was found, however, not to undergo the enzyme catalysed reaction with l-selenomethionine, unlike FDA 2, which undergoes reaction with l-selenomethionine to generate Se-adenosylselenomethionine. A co-crystal structure of the fluorinase and F2DA7 and tartrate was solved to 1.8A, and revealed that the difluoromethyl group bridges interactions known to be essential for activation of the single fluorine in FDA 2. An unusual hydrogen bonding interaction between the hydrogen of the difluoromethyl group and one of the hydroxyl oxygens of the tartrate ligand was also observed. The bridging interactions, coupled with the inherently stronger C-F bond in the difluoromethyl group, offers an explanation for why no reaction is observed. Exploration of a potential difluoromethyl-nucleoside substrate with the fluorinase enzyme.,Thompson S, McMahon SA, Naismith JH, O'Hagan D Bioorg Chem. 2015 Nov 18;64:37-41. doi: 10.1016/j.bioorg.2015.11.003. PMID:26642178[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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