InterPro domain: IPR000043

Adenosylhomocysteinase (S-adenosyl-L-homocysteine hydrolase, 3.3.1.1 ) (AdoHcyase) is an enzyme of the activated methyl cycle, responsible for the reversible hydration of S-adenosyl-L-homocysteine into adenosine and homocysteine. This enzyme is ubiquitous, highly conserved, and may play a key role in the regulation of the intracellular concentration of adenosylhomocysteine. AdoHcyase requires NAD+ as a cofactor and contains a central glycine-rich region which is thought to be involved in NAD-binding. Since AdoHyc is a potent inhibitor of S-adenosyl-L-methionine dependent methyltransferases, AdoHycase plays a critical role in the modulation of the activity of various methyltransferases. The enzyme forms homotetramers, with each monomer binding one molecule of NAD+ [ 1 , 2 , 3 , 4 ].

This family also includes S-adenosylhomocysteine hydrolase-like 1 (Ahcyl1), also known as IRBIT, and S-adenosylhomocysteine hydrolase-like protein 2 (Ahcyl2). Ahcyl1/IRBIT was shown to interact with inositol 1,4,5-trisphosphate receptors (IP3Rs), which function as intracellular Ca(2+) channels, and suppresses IP3 binding of IP3R [ 5 , 6 ]. By competing with IP3, it modulates the threshold IP3 concentration required for the activation of the receptor [ 7 ]. Further studies indicate that Ahcyl1/IRBIT is in fact a multifunctional protein that regulates several ion channels and ion transporters [ 7 , 8 ]. Despite its homology to S-adenosylhomocysteine hydrolases, Ahcyl1 has neither enzyme activity nor any effects on the enzyme activity of S-adenosylhomocysteine hydrolase [ 9 ]. Ahcyl2 lacks binding activity to IP3R [ 10 ]. Ahcyl2 upregulates NBCe1-B, which plays an important role in intracellular pH regulation [ 11 ].

1. Structure determination of selenomethionyl S-adenosylhomocysteine hydrolase using data at a single wavelength. Nat. Struct. Biol. 5, 369-76
2. Catalytic mechanism of S-adenosylhomocysteine hydrolase: roles of His 54, Asp130, Glu155, Lys185, and Aspl89. Int. J. Biochem. Cell Biol. 37, 2417-35
3. Structure and function of S-adenosylhomocysteine hydrolase. Cell Biochem. Biophys. 33, 101-25
4. S-Adenosylhomocysteine hydrolase as a target for intracellular adenosine action. Trends Pharmacol. Sci. 25, 294-7
5. IRBIT suppresses IP3 receptor activity by competing with IP3 for the common binding site on the IP3 receptor. Mol. Cell 22, 795-806
6. Binding of IRBIT to the IP3 receptor: determinants and functional effects. Biochem. Biophys. Res. Commun. 343, 49-56
7. IRBIT: a regulator of ion channels and ion transporters. Biochim. Biophys. Acta 1843, 2195-204
8. IRBIT: it is everywhere. Neurochem. Res. 36, 1166-74
9. IRBIT, a novel inositol 1,4,5-trisphosphate (IP3) receptor-binding protein, is released from the IP3 receptor upon IP3 binding to the receptor. J. Biol. Chem. 278, 10602-12
10. An IRBIT homologue lacks binding activity to inositol 1,4,5-trisphosphate receptor due to the unique N-terminal appendage. J. Neurochem. 109, 539-50
11. Ahcyl2 upregulates NBCe1-B via multiple serine residues of the PEST domain-mediated association. Korean J. Physiol. Pharmacol. 20, 433-40