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Leishmania major S-adenosylhomocysteine hydrolase

PDB Code 3G1U Target Class Miscellaneous Target LMSAH Alias n/a Disease Area/Function parasitic disease Date Deposited Jan 30 2009 Authors Siponen, M.I., Welin, M., Arrowsmith, C.H., Berglund, H., Bountra, C., Collins, R., Dahlgren, L.G., Edwards, A.M., Flodin, S., Flores, A., Graslund, S., Hammarstrom, M., Johansson, A., Johansson, I., Karlberg, T., Kotenyova, T., Lehtio, L., Moche, M., Nilsson, M.E., Nordlund, P, Nyman, T., Persson, C., Sagemark, J., Schutz, P., Thorsell, A.G., Tresaugues, L., Van Den Berg, S., Weigelt, J., Wisniewska, M., Schueler, H.

About this structure

S-adenosyl-L-homocysteine (AdoHcy) is a product but also a potent feedback inhibitor of several methyltransferases that 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 normal levels of AdoHcy in the cell. Inhibition of SAHH results in cellular accumulation of AdoHcy and inhibition of AdoMet-dependent methyltransferases. Since methylation is important in a wide range of cellular processes, SAHH has been proposed as a drug target for parasitic diseases including malaria and leishmaniasis (2, 3)

We report the crystal structure of SAHH from Leishmania major, one of the human parasites that cause leishmaniasis, at a resolution of 2.2 Å. SAHH crystallized as a homotetramer in the space group P1. Each monomer consists of two α/β domains as observed in previous SAHH structures (4). The protein consists of two domains, a substrate-binding catalytic domain and a cofactor binding domain, the latter being a modified Rossmann fold. In each monomer a NAD and an adenosine molecule was found. As previously observed, the cofactor binding site is covered by a 24 amino acid, C-terminal extension from the adjacent subunit. Owing to this interaction the observed tetramer can be described as a dimer of dimers.

References

  1. Turner MA, Yang X, Yin D, Kuczera K, Borchardt RT, Howell PL (2000) Structure and function of S-adenosylhomocysteine hydrolase. Cell. Biochem. Biophys. 33:101-125.
  2. Bujnicki JM, Prigge ST, Caridha D, Chiang PK (2003) Structure, evolution, and inhibitor interaction of S-adenosyl-L-homocysteine hydrolase from Plasmodium falciparum. Proteins 52:624-632.
  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. 53:169-183.
  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. 17:2134-2144.