Abstract

Structural analogues of S-adenosyl-L-homocysteine with modifications in the purine, sugar, 5'-thioether linkage, and/or amino acid portion were tested as substrates and/or inhibitors of S-adenosyl-L-homocysteine hydrolase (EC 3.3.1.1). It was observed that S-3-deazaadenosyl-L-homocysteine was the only analogue that could serve as a substrate for the enzyme as well as S-adenosyl-L-homocysteine itself. When tested in the direction of S-adenosyl-L-homocysteine hydrolysis coupled with calf intestinal adenosine deaminase, the following were found to be the more potent inhibitory analogues: 5'-deoxy-5'-butylthioadenosine, N^γ-adenosyl-α,γ-diaminobutyric acid, 9-(5'-deoxy-5'-methylthio-α-D-arbinofuranosyl)adenine, 5'-deoxy-5'-aminoethylthio-2-chloroadenosine, 3-deazaadenosine, and S-3-deazaadenosyl-L-homocysteine. The inhibitory ability of 3-deazaadenosyl-L-homocysteine is probably related to its ability to serve as substrate, since its hydrolysis generates 3-deazaadenosine, which is the most potent inhibitor of S-adenosyl-L-homocysteine hydrolase as well as being resistant to adenosine deaminase. When tested in vitro in isolated rat hepatocytes, 3-deazaadenosine caused a drastic increase in the levels of S-adenosyl-L-homocysteine and S-adenosyl-L-methionine, with the formation of S-3-deazaadenosyl-L-homocysteine. 3-Deazaadenosine is thus an interesting analogue with biological potential.