The effect of aliphatic adenine analogues on S-adenosylhomocysteine and S-adenosylhomocysteine hydrolase in intact rat hepatocytes.
The aliphatic adenine analogues, D-eritadenine, L-eritadenine, L-threoeritadenine, and 9-(S)-(2,3-dihydroxypropyl)adenine [(S)DHPA] function as inhibitors/inactivators of purified S-adenosylhomocysteine (AdoHcy) hydrolase, but these compounds did not induce reduction of enzyme-bound NAD+. D-Eritadenine, L-eritadenine, (S)DHPA, and L-threo-eritadenine inactivated AdoHcy hydrolase in hepatocytes, and the efficiency decreased in the order mentioned. Concurrently, there was an increase in the AdoHcy content. The accumulation of AdoHcy in the presence of (S)DHPA was more pronounced than would be expected from the inactivation of enzyme activity, suggesting that this compound may function as a reversible inhibitor as well. Furthermore, the inactivation of the intracellular enzyme by (S)DHPA is remarkable in the light of the fact that this compound induces no inactivation of purified AdoHcy hydrolase, but merely functions as an inhibitor of the enzyme. At low concentration of D-eritadenine (less than 6 microM), a distinct lag period could be demonstrated before accumulation of AdoHcy occurred. This suggests that the AdoHcy hydrolase activity must be decreased below a certain level to cause an increase in cellular AdoHcy. None of the analogues tested completely inactivated AdoHcy hydrolase and a residual enzyme activity was observed. The adenosine deaminase inhibitor, 2'-deoxycoformycin, did not potentiate the effect of these compounds on AdoHcy catabolism. The inactive enzyme formed in the presence of aliphatic adenine analogues was not reactivated under conditions where the inactivation induced by 9-beta-D-arabinofuranosyladenine was reversible.
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D043383:Adenosylhomocysteinase; D000818:Animals; D004789:Enzyme Activation; D006710:Homocysteine / Q000031:analogs & derivatives*; D006867:Hydrolases / Q000378:metabolism*; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D012435:S-Adenosylhomocysteine / Q000378:metabolism*; D013329:Structure-Activity Relationship
D006710:Homocysteine; D012435:S-Adenosylhomocysteine; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D000225:Adenine