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

• Published in: Molecular pharmacology Vol. 13; no. 5; pp. 939 - 947
• Main Authors: Chiang, P K, Richards, H H, Cantoni, G L
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.09.1977
• Subjects: Animals; Cattle; Homocysteine - analogs & derivatives; Hydrolases - antagonists & inhibitors; In Vitro Techniques; Liver - drug effects; Liver - enzymology; Male; Rats; S-Adenosylhomocysteine - analogs & derivatives; S-Adenosylhomocysteine - metabolism; S-Adenosylhomocysteine - pharmacology; S-Adenosylmethionine - metabolism; Structure-Activity Relationship
• ISSN: 0026-895X; 1521-0111

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.