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Human s-adenosyl homocysteine hydrolase-like 2 protein (AHCYL2)

PDB Code 3GVP Target Class AA metabolic enzymes Target KIAA0828 Alias AHCYL2, FLJ21719, KIAA0828 Disease Area/Function metabolism, cancer Date Deposited Mar 31 2009 Authors SIPONEN, M.I., WISNIEWSKA, M., ARROWSMITH, C.H., BERGLUND, H., BOUNTRA, C., COLLINS, R., EDWARDS, A.M., FLODIN, S., FLORES, A., GRASLUND, S., HAMMARSTROM, M., JOHANSSON, A., JOHANSSON, I., KARLBERG, T., KOTENYOVA, T., MOCHE, M., NORDLUND, P., NYMAN, T., PERSSON, C., SAGEMARK, J., SCHUTZ, P., THORSELL, A.G., TRESAUGUES, L., VAN DEN BERG, S., WEIGELT, J., WELIN, M., SCHUELER, H.

About this structure

S-adenosyl-L-homocysteine (AdoHcy) is a product but also a potent feedback inhibitor of several methyltransferases which use S-adenosyl-L-methionine (AdoMet) as a methyl donor. The S-adenosyl-L-homocysteine hydrolases (SAHHs) catalyse the reversible reaction of AdoHcy to adenosine and homocysteine (1). Consequently, SAHHs play a critical role in maintaining a normal level of AdoHcy in the cell. Inhibition of SAHH results in cellular accumulation of AdoHcy, inhibiting AdoMet-dependant methyltransferases. Since methylation plays a role in a wide range of cellular processes, the inhibition of SAHHs has often been proposed as a potential drug target (2, 3)
We report the crystal structure human of SAHH-like 2 protein at a resolution of 2.25 Å. SAHH crystallized as a homotetramer in the space group P 41 21 2. Each monomer consists of two α/β domains as observed in previous SAHH structures (4). Two domains are observed, a substrate-binding catalytic domain and a co-factor binding domain, the later being a modified Rossmann fold. Each subunit is bound to a NAD and an adenosine molecule. As previously observed, this co-factor binding site is covered by a 24 amino acid, C-terminal extension from the adjacent subunit.

References

  1. Structure and function of S-adenosylhomocysteine hydrolase. (2000) Turner MA, Yang X, Yin D, Kuczera K, Borchardt RT, Howell PL. Cell Biochem Biophys. 33(2):101-25.
  2. Structure, evolution, and inhibitor interaction of S-adenosyl-L-homocysteine hydrolase from Plasmodium falciparum.(2003) Bujnicki JM, Prigge ST, Caridha D, Chiang PK. Proteins 52(4):624-32.
  3. Henderson DM, Hanson S, Allen T, Wilson K, Coulter-Karis DE, Greenberg ML, Hershfield MS, Ullman B. (1992) Cloning of the gene encoding Leishmania donovani S-adenosylhomocysteine hydrolase, a potential target for antiparasitic chemotherapy. Mol Biochem Parasitol. 53(1-2):169-83.
  4. Reddy MC, Kuppan G, Shetty ND, Owen JL, Ioerger TR, Sacchettini JC.(2008) Crystal structures of Mycobacterium tuberculosis S-adenosyl-L-homocysteine hydrolase in ternary complex with substrate and inhibitors. Protein Sci 17(12):2134-44.