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-Adenosylhomocysteine hydrolase | |||||||
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![]() SAH hydrolase tetramer, Human | |||||||
Identifiers | |||||||
Symbol | AHCY | ||||||
NCBI gene | 191 | ||||||
HGNC | 343 | ||||||
OMIM | 180960 | ||||||
RefSeq | NM_000687 | ||||||
UniProt | P23526 | ||||||
Other data | |||||||
EC number | 3.3.1.1 | ||||||
Locus | Chr. 20 q11.22 | ||||||
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S-adenosyl-L-homocysteine hydrolase | |||||||||||
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![]() Structure of S-adenosylhomocysteine hydrolase from rat liver.[1] | |||||||||||
Identifiers | |||||||||||
Symbol | Ad_hcy_hydrolase | ||||||||||
Pfam | PF05221 | ||||||||||
InterPro | IPR000043 | ||||||||||
PROSITE | PDOC00603 | ||||||||||
SCOP2 | 1b3r / SCOPe / SUPFAM | ||||||||||
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AdoHcyase NAD-binding domain | |||||||||
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![]() 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 | ||||||||
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- 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]
References
edit- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ GeneCards.org - AHCY Gene - Adenosylhomocysteinase
- ^ NLM - AHCY adenosylhomocysteinase
- ^ 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.
External links
edit- Adenosylhomocysteinase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Further reading
edit- Vizán, Pedro; Di Croce, Luciano; Aranda, Sergi (31 March 2021). "Functional and Pathological Roles of AHCY". Frontiers in Cell and Developmental Biology. 9. doi:10.3389/fcell.2021.654344. eISSN 2296-634X. PMC 8044520. PMID 33869213.
- Vugrek, Oliver; Belužić, Robert; Nakić, Nikolina; Mudd, S. Harvey (28 January 2009). "S-adenosylhomocysteine hydrolase (AHCY) deficiency: Two novel mutations with lethal outcome". Human Mutation. 30 (4): E555–E565. doi:10.1002/humu.20985. ISSN 1059-7794. PMC 2876820. PMID 19177456.
- 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.