The Mechanism of Inactivation of S-Adenosylhomocysteine Hydrolase by Fluorinated Analogs of 5′-Methylthio Adenosine

Abstract

5′-Deoxy-5′-dilluoromethylthioadenosine (DFMTA) 1a and 5′-deoxy-5′-trifluoromethylthioadenosine (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.

Key Words:

• S-adenosyl-L-homocysteine hydrolase
• Time-dependent inhibition
• 5′-fluoromethylthioadenosines
• Enzyme-activated acylating agents