Adenosylhomocysteinase

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:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
PDB1a7a​, 1b3r​, 1d4f​, 1k0u​, 1ky4​, 1ky5​, 1li4​, 1v8b​, 1xwf​
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:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

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]

  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.