Comparison of the Inhibition of Type A and Type B S-Adenosylhomocysteine Hydrolase: Effects of Cofactor Content on Inhibition Behavior and Nucleoside Binding

Abstract

The enzyme S-adenosylhomocysteine hydrolase (E.C.3.3.1.1) occurs in two forms in bovine liver: Type A, which carries four moles of NAD⁺ per mole of enzyme tetramer, and Type B, which carries two moles of NAD⁺ per mole of tetramer.¹ The inhibition of these two forms of the enzyme with 2′,2′-difluoro-2′-deoxyadenosine has been investigated. The studies examined the binding stoichiometry and stability of the enzyme-inhibitor complexes formed from each type of the enzyme, the degree of NAD+ reduction and NAD' release, and the possibility of covalent bond formation between the enzyme and the inhibitor. Significant differences in the behavior of the two forms of the enzyme were encountered which may have important implications for the design of S-adenosylhomocysteine hydrolase inhibitors as therapeutic agents.

Key Words: :

• S-Adenosylhomocysteine hydrolase
• time-dependent inhibition
• fluorine-containing adenosine analogs