Adenosylhomocysteinase Explained

Symbol:AdoHcyase_NAD
AdoHcyase NAD-binding domain
Pfam:PF00670
Pfam Clan:CL0063
Interpro:IPR015878
Prosite:PDOC00603
Scop:1b3r

Adenosylhomocysteinase (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.[1] [2]

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

AdoHcyase is a highly conserved protein[3] 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.[4]

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,[5] [6] which is believed to have a prognostic role in neuroblastoma.[7] 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.[8]

Further reading

Notes and References

  1. De La Haba G, Cantoni GL . The enzymatic synthesis of S-adenosyl-L-homocysteine from adenosine and homocysteine . The Journal of Biological Chemistry . 234 . 3 . 603–8 . March 1959 . 10.1016/S0021-9258(18)70253-6 . 13641268 . free .
  2. Palmer JL, Abeles RH . The mechanism of action of S-adenosylhomocysteinase . The Journal of Biological Chemistry . 254 . 4 . 1217–26 . February 1979 . 10.1016/S0021-9258(17)34190-X . 762125 . free .
  3. Sganga MW, Aksamit RR, Cantoni GL, Bauer CE . 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 . 1992 . 1631127 . 10.1073/pnas.89.14.6328 . 49494. 1992PNAS...89.6328S . free .
  4. T. Selwood . E. K. Jaffe. . Dynamic dissociating homo-oligomers and the control of protein function. . Arch. Biochem. Biophys. . 519. 2. 131–43. 2011 . 22182754 . 10.1016/j.abb.2011.11.020 . 3298769.
  5. https://www.genecards.org/cgi-bin/carddisp.pl?gene=AHCY GeneCards.org - AHCY Gene - Adenosylhomocysteinase
  6. https://www.ncbi.nlm.nih.gov/gene?cmd=retrieve&dopt=default&list_uids=191&rn=1 NLM - AHCY adenosylhomocysteinase
  7. Chicco . Davide . Sanavia . Tiziana . Jurman . Giuseppe . Signature literature review reveals AHCY, DPYSL3, and NME1 as the most recurrent prognostic genes for neuroblastoma . BioData Mining . 4 March 2023 . 16 . 1 . 7 . 1756-0381 . 10.1186/s13040-023-00325-1 . 36870971 . 9985261 . free .
  8. Hershfield . M S . In vivo inactivation of erythrocyte S-adenosylhomocysteine hydrolase by 2'-deoxyadenosine in adenosine deaminase-deficient patients . J Clin Invest . 63 . 4 . 807–811 . 1979 . 312296 . 372019 . 10.1172/JCI109367 .

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