Adenosine analogues as substrates and inhibitors of S-adenosylhomocysteine hydrolase

Abstract

In the reaction adenosine + L-homocysteine = S-adenosyl-L-homocysteine, catalyzed by S-adenosylhomo-cysteine hydrolase from beef liver (EC 3.3.1.1), 11 nucleosides are able to substitute for adenosine to generate their corresponding S-nucleosidylhomocysteine congeners: 3-deaza-adenosine, 2-aza-3-deazaadenosine, nebularine (purine ribonucleoside), formycin, N6-methyladenosine, 8-azaadenosine, adenosine N1-oxide, pyrazomycin, 8-aminoadenosine, inosine, and the carbocyclic analogue of adenosine [(+/-)-aristeromycin]. S-Adenosylhomocysteine hydrolase from lupin seeds is able to utilize all of these nucleosides except inosine to synthesize analogues of S-adenosylhomocysteine. There is no correlation between the ability of these nucleotides to function as substrates and their inhibitory potencies, except in the case of 3-deazaadenosine. The carbocyclic analogue of adenosine is the most potent inhibitor of S-adenosylhomocysteine hydrolase with a Ki of 5 X 10(-9) M. When incubated with 3T3-L1 fibroblasts, the carbocyclic analogue of adenosine caused a 20-fold increase in the cellular concentration of S-adenosyl-homocysteine. The cellular generation of S-2-aza-3-deaza-adenosylhomocysteine was observed when 3T3-L1 fibroblasts were incubated with 2-aza-3-deazaadenosine.