The mechanism of inactivation of S-adenosylhomocysteine hydrolase by fluorinated analogs of 5'-methylthioadenosine.
5'-Deoxy-5'-difluoromethylthioadenosine (DFMTA) 1a and 5'-deoxy-5'-trifluoromethyl-thioadenosine (TFMTA) 1b are inhibitors of beef liver S-adenosyl-L-homocysteine hydrolase. DFMTA and TFMTA are time-dependent and irreversible inhibitors of the enzyme. Both 1a and 1b are oxidized by E-NAD+ to produce E-NADH and fluoride anion is formed in the inactivation reaction (2.2 mol of fluoride/mole of enzyme subunit and 3.1 fluoride/mole of enzyme subunit from DFMTA and TFMTA respectively). Using [8-3H]-1a or [8-3H]-1b no trace of labelled adenosine was detected during the inactivation reaction but adenine was formed. The mechanism of inhibition of S-adenosyl-L-homocysteine hydrolase by these two fluorinated nucleosides is discussed.
Muzard
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Laboratoire de chimie bioorganique, U.F.R. Sciences, Reims, France.
Vandenplas
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Guillerm
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Guillerm
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D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D043383:Adenosylhomocysteinase; D000818:Animals; D002417:Cattle; D003839:Deoxyadenosines / Q000494:pharmacology*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005459:Fluorides / Q000378:metabolism; D006867:Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007700:Kinetics; D013872:Thionucleosides / Q000494:pharmacology*
C116879:5'-deoxy-5'-trifluoromethylthioadenosine; D003839:Deoxyadenosines; D004791:Enzyme Inhibitors; D013872:Thionucleosides; C054301:5'-difluoromethylthioadenosine; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D000241:Adenosine; D005459:Fluorides