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Adenosylhomocysteinase

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S-Adenosylhomocysteine hydrolase
SAH hydrolase tetramer, Human
Identifiers
SymbolAHCY
NCBI gene191
HGNC343
OMIM180960
RefSeqNM_000687
UniProtP23526
Other data
EC number3.3.1.1
LocusChr. 20 q11.22
Search for
StructuresSwiss-model
DomainsInterPro
S-adenosyl-L-homocysteine hydrolase
Structure of S-adenosylhomocysteine hydrolase from rat liver.[1]
Identifiers
SymbolAd_hcy_hydrolase
PfamPF05221
InterProIPR000043
PROSITEPDOC00603
SCOP21b3r / SCOPe / SUPFAM
Available protein structures:
PDB  1a7a​, 1b3r​, 1d4f​, 1k0u​, 1ky4​, 1ky5​, 1li4​, 1v8b​, 1xwf​ IPR000043 PF05221 (ECOD; PDBsum)  
AlphaFold
AdoHcyase NAD-binding domain
d244e mutant s-adenosylhomocysteine hydrolase refined with noncrystallographic restraints
Identifiers
SymbolAdoHcyase_NAD
PfamPF00670
Pfam clanCL0063
InterProIPR015878
PROSITEPDOC00603
SCOP21b3r / SCOPe / SUPFAM
Available protein structures:
PDB  IPR015878 PF00670 (ECOD; PDBsum)  
AlphaFold

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-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]. AHCY 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, AHCY 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.

References

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  1. ↑ Hu Y, Komoto J, Huang Y, et al. (June 1999). "Crystal structure of S-adenosylhomocysteine hydrolase from rat liver". Biochemistry. 38 (26): 8323–33. doi:10.1021/bi990332k. PMID 10387078.
  2. ↑ De La Haba G, Cantoni GL (March 1959). "The enzymatic synthesis of S-adenosyl-L-homocysteine from adenosine and homocysteine". The Journal of Biological Chemistry. 234 (3): 603–8. doi:10.1016/S0021-9258(18)70253-6. PMID 13641268.
  3. ↑ Palmer JL, Abeles RH (February 1979). "The mechanism of action of S-adenosylhomocysteinase". The Journal of Biological Chemistry. 254 (4): 1217–26. doi:10.1016/S0021-9258(17)34190-X. PMID 762125.
  4. ↑ Sganga MW, Aksamit RR, Cantoni GL, Bauer CE (1992). "Mutational and nucleotide sequence analysis of S-adenosyl-L-homocysteine hydrolase from Rhodobacter capsulatus". Proc. Natl. Acad. Sci. U.S.A. 89 (14): 6328–6332. Bibcode:1992PNAS...89.6328S. doi:10.1073/pnas.89.14.6328. PMC 49494. PMID 1631127.
  5. ↑ T. Selwood; E. K. Jaffe. (2011). "Dynamic dissociating homo-oligomers and the control of protein function". Arch. Biochem. Biophys. 519 (2): 131–43. doi:10.1016/j.abb.2011.11.020. PMC 3298769. PMID 22182754.
  6. ↑ GeneCards.org - AHCY Gene - Adenosylhomocysteinase
  7. ↑ NLM - AHCY adenosylhomocysteinase
  8. ↑ Chicco, Davide; Sanavia, Tiziana; Jurman, Giuseppe (4 March 2023). "Signature literature review reveals AHCY, DPYSL3, and NME1 as the most recurrent prognostic genes for neuroblastoma". BioData Mining. 16 (1): 7. doi:10.1186/s13040-023-00325-1. eISSN 1756-0381. PMC 9985261. PMID 36870971.
  9. ↑ Hershfield, M S (1979). "In vivo inactivation of erythrocyte S-adenosylhomocysteine hydrolase by 2'-deoxyadenosine in adenosine deaminase-deficient patients". J Clin Invest. 63 (4): 807–811. doi:10.1172/JCI109367. PMC 372019. PMID 312296.
  10. ↑ Stanhope, Sarah C.; Weake, Vikki M. (March 2026). "AHCY: A metabolic gatekeeper at the interface of methylation, redox balance, and cellular stress response". The Journal of Biological Chemistry. 302 (3) 111220. doi:10.1016/j.jbc.2026.111220. ISSN 1083-351X. PMC 12955632. PMID 41638428.
  11. ↑ Czajewski, Ignacy (March 16, 2023). "The Role of O-Glcnacylation in Development". Development.
  12. ↑ Stanhope, Sarah C.; Weake, Vikki M. (March 2026). "AHCY: A metabolic gatekeeper at the interface of methylation, redox balance, and cellular stress response". The Journal of Biological Chemistry. 302 (3) 111220. doi:10.1016/j.jbc.2026.111220. ISSN 1083-351X. PMC 12955632. PMID 41638428.
  13. ↑ Vande Voorde, Johan; Steven, Rory T.; Najumudeen, Arafath K.; Ford, Catriona A.; Dexter, Alex; Gonzalez-Fernandez, Ariadna; Nikula, Chelsea J.; Xiang, Yuchen; Ford, Lauren; Maneta Stavrakaki, Stefania; Gilroy, Kathryn; Zeiger, Lucas B.; Pennel, Kathryn; Hatthakarnkul, Phimmada; Elia, Efstathios A. (August 2023). "Metabolic profiling stratifies colorectal cancer and reveals adenosylhomocysteinase as a therapeutic target". Nature Metabolism. 5 (8): 1303–1318. doi:10.1038/s42255-023-00857-0. ISSN 2522-5812. PMC 10447251. PMID 37580540.
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Further reading

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This article incorporates text from the public domain Pfam and InterPro: IPR000043
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