Aristeromycin-5'-carboxaldehyde: a potent inhibitor of S-adenosyl-L-homocysteine hydrolase.
In an earlier study, Liu et al. (Bioorg. Med. Chem. Lett. 1992, 2, 1741-1744) showed that both the E and Z isomers of 4',5'-didehydro-5'-fluoroaristeromycin were very potent irreversible inhibitors of S-adenosylhomocysteine (AdoHcy) hydrolase. However, it was unclear from a mechanistic standpoint whether these vinyl fluorides were themselves type-I mechanism-based inhibitors causing reduction of enzyme-bound NAD+ or whether they were prodrug for aristeromycin-5'-carboxaldehyde, which was the ultimate type-I inhibitor. To elucidate this mechanism of enzyme inhibition, (4'S)- and (4'R)-aristeromycin-5'-carboxaldehydes (1a,b) were synthesized in this study and shown to be potent type-I mechanism-based inhibitors of AdoHcy hydrolase with k2/Ki values of 4.4 x 10(6) and 8.2 x 10(4)M-1min-1, respectively. However, Using 19F NMR and HPLC, it was shown that (4'S)-4,5'-dedehydro-5'-fluoraristeromycin in the presence of AdoHcy hydrolase did not release fluoride ion or generate aristeromycin-5'-carboxaldehyde (1a,b). These results suggest that the E and Z isomers of 4',5'-didehydro-5'-fluoroaristeromycin are inactivating AdoHcy hydrolase by directly reducing NAD+ to NADH and not using the hydrolytic activity of the enzyme to generate aristeromycin-5'-carboxaldehyde.
Liu
S
S
Department of Medicinal Chemistry, University of Kansas, Lawrence 66045, USA.
Yuan
C S
CS
Borchardt
R T
RT
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D043383:Adenosylhomocysteinase; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors*; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D015394:Molecular Structure; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C100363:4',5'-didehydro-5'-fluoroaristeromycin; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; C100362:aristeromycin-5'-carboxaldehyde; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D000241:Adenosine