Adenosylhomocysteinase (EC 3.13.2.1, S-adenosylhomocysteine synthase, S-adenosylhomocysteine hydrolase, adenosylhomocysteine hydrolase, S-adenosylhomocysteinase, SAHase, AdoHcyase) is an enzyme that catalyzes the nicotinamide adenine dinucleotide (NAD⁺) dependent, reversible hydrolysis of S-adenosylhomocysteine to homocysteine and adenosine.^[2][3]

S-adenosyl-L-homocysteine + H₂O ⇌ L-homocysteine + adenosine

AdoHcyase is a highly conserved protein^[4] with about 430 to 470 amino acids. The family contains a glycine-rich region in the central part of AdoHcyase; a region thought to be involved in NAD-binding. AdoHcyase binds one NAD⁺ cofactor per subunit. This protein may use the morpheein model of allosteric regulation.^[5]

Overall hydrolysis begins with dehydrogenative oxidation of the 3'-OH of the ribose by NAD⁺ (forming NADH). The resulting ketone is α-deprotonated to the enol before elimination of the homocysteine thiolate. Water then adds to the a,b-unsaturated ketone, before reduction of the resultant ketone by NADH.

AdoHcyase is encoded by the AHCY gene in humans,^[6][7] which is believed to have a prognostic role in neuroblastoma.^[8] AdoHcyase is significantly associated with adenosine deaminase deficiency, which classically manifests in severe combine immunodeficiency (SCID). Accumulated adenosine derivatives, dATPs, irreversibly bind to and inhibit AdoHcyase, promoting the buildup of S-adenosyl-L-homocystine (due to equilibrium constant favors S-adenosyl-L-homocystine), a potent inhibitor of methyl transfer reactions.^[9]