Effects of novel anti-viral adenosine analogues on the activity of S-adenosylhomocysteine hydrolase from human liver.
Some adenosine analogues have been found previously to inhibit S-adenosylhomocysteine (SAH)-hydrolase activity in erythrocyte lysates. In this study, the enzyme was purified 500-fold from human liver and its M(r) found to be 190,000. Its kinetics in the synthase direction were studied, the Km for adenosine being determined as 32 microM. Several purine nucleoside analogues currently used in antitumour and antiviral therapy were tested for their influence on SAH-hydrolase activity. The results confirmed our previous findings for the unpurified human erythrocyte enzyme, and demonstrated that the most potent inhibitors of human liver SAH-hydrolase were neplanocin A, 7-deaza-adenosine (tubercidin), 2'-deoxyadenosine, and 9-beta-D-arabino-furanosyladenine. Analogues showing intermediate inhibition were 2'3'-dideoxyadenosine (2'3'-ddAdo), 5'-deoxy-5'-methyl-thioadenosine, 3'-deoxy-adenosine, 2-chloroadenosine, 1,2,4-triazole-3-carboxamide riboside (ribavirin), delta-adenosylornithine (sinefungin), S-adenosylmethionine, 5-amino-4-imidazole carboxamide riboside (AICAR), and 5'-iodo-5'-deoxyadenosine (5'I,5'-dAdo). Weak or no inhibition was noted with 5'-deoxyadenosine, 5-hydroxyimidazole-4-carboxamideriboside (bredinin), inosine and its deoxy analogues, and acyclovir. Our results show that drugs such as 2'3'-dideoxyadenosine (used in HIV therapy) and ribavirin (an inhibitor of inosinate dehydrogenase), in addition to their other known mechanisms of action, have an inhibitory effect on SAH-hydrolase activity, which may be of significance in their antiviral action.
Fabianowska-Majewska
K
K
Purine Research Laboratory, UMDS Guy's Hospital, London, U.K.
Duley
J A
JA
Simmonds
H A
HA
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D043383:Adenosylhomocysteinase; D000998:Antiviral Agents / Q000494:pharmacology*; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D008099:Liver / Q000201:enzymology*; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D000241:Adenosine