Molecular Pharmacology, Vol 13, 939-947, Copyright © 1977 by the American Society for Pharmacology and Experimental Therapeutics

S-Adenosyl-L-homocysteine Hydrolase: Analogues of S-Adenosyl-L-homocysteine as Potential Inhibitors

¹ Laboratory of General and Comparative Biochemistry, National Institute of Mental Health, Bethesda, Maryland 20014

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-adenosyl-,-diaminobutyric acid, 9-(5'-deoxy-5'-methylthio--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.

Note:
ACKNOWLEDGMENTS The collaboration of Dr. N. W. Cornell in the experiments with rat hepatocytes is acknowledged. We also thank Drs. R. T. Borchardt, J. A. Montgomery, and J. Coward for their gifts of analogues, and Drug Research and Development, Chemotherapy, National Cancer Institute, for providing the majority of the analogues.

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