Adenosine analogs as substrates and inhibitors of S-adenosylhomocysteine hydrolase

Abstract

In the reaction adenosine + L-homocysteine .dblarw. S-adenosyl-L-homocysteine, catalyzed by S-adenosylhomocysteine 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-deazaadenosine, 2-aza-3-deazaadenosine, nebularine (purine ribonucleoside), formycin, N6-methyladenosine, 8-azaadenosine, adenosine N1-oxide, pyrazomycin, 8-aminoadenosine, inosine and the carbocyclic analog of adenosine [(.+-.)-aristeromycin]. S-Adenosylhomocysteine hydrolase from lupin [Lupinus luteus] seeds is able to utilize all of these nucleosides except inosine to synthesize analogs 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 analog of adenosine is the most potent inhibitor of S-adenosylhomocysteine hydrolase with a Ki of 5 .times. 10-9 M. When incubated with 3T3-L1 fibroblasts the carbocyclic analog of adenosine caused a 10-fold increase in the cellular concentration of S-adenosylhomocysteine. The cellular generation of S-2-aza-3-deazaadenosylhomocysteine was observed when 3T3-L1 fibroblasts were incubated with 2-aza-3-deazaadenosine.