Adenosylhomocysteinase
Protein-coding gene in the species Homo sapiens
From Wikipedia, the free encyclopedia
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
| S-adenosyl-L-homocysteine hydrolase | |||||||
|---|---|---|---|---|---|---|---|
 Structure of S-adenosylhomocysteine hydrolase from rat liver.[1] | |||||||
| Identifiers | |||||||
| Symbol | Ad_hcy_hydrolase | ||||||
| Pfam | PF05221 | ||||||
| InterPro | IPR000043 | ||||||
| PROSITE | PDOC00603 | ||||||
| SCOP2 | 1b3r / SCOPe / SUPFAM | ||||||
| |||||||
| AdoHcyase NAD-binding domain | |||||||
|---|---|---|---|---|---|---|---|
 d244e mutant s-adenosylhomocysteine hydrolase refined with noncrystallographic restraints | |||||||
| Identifiers | |||||||
| Symbol | AdoHcyase_NAD | ||||||
| Pfam | PF00670 | ||||||
| Pfam clan | CL0063 | ||||||
| InterPro | IPR015878 | ||||||
| PROSITE | PDOC00603 | ||||||
| SCOP2 | 1b3r / SCOPe / SUPFAM | ||||||
| |||||||
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-homocysteine (due to equilibrium constant favors S-adenosyl-L-homocystine), a potent inhibitor of methyl transfer reactions.[9]
Adenosylhomocysteinase directly converts SAH (S-Adenosyl-L-homocysteine, a potentially toxic molecule) into homocysteine and adenosine[10]. As a metabolic enzyme, AHCY has a key role in regulating the methylation potential of nucleic acids at a cellular level[11]. ACHY has also been discovered to have a role as a "metabolic gatekeeper"[12], which is involved in interactions between epigenetics and one-carbon metabolism. By controlling homocysteine levels, ACHY takes part in regulation of chromatin availability and developmental stress responses, which can have significant implications for supporting stem cell pluripotency, influencing expression of genes, differentiation of adipocytes, and regulation of normal function of the cell-cycle. The impact of alterations of these processes can have a variety of downstream effects that can have significant clinical relevance. Recent study has put AHCY regulation into a focus of therapeutic intervention. Higher levels of AHCY transcriptional upregulation are seen in patients with colorectal cancer (CRC)[13]. Pharmaceutical interventions that target AHCY have shown to reduce the related intestinal symptoms of CRC, making Adenosylhomocysteinase a therapeutic target.
