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S-adenosyl homocysteine hydrolase (SAHH) from Trypanosoma brucei (Pathogen)

PDB Code 3H9U Target Class AA metabolic enzymes Target TBSAH Alias n/a Disease Area/Function parasitic disease Date Deposited Apr 30 2009 Authors SIPONEN, M.I., SCHUTZ, P. , 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., KOTZSCH, A., KRAGH NIELSEN, T., MOCHE, M., NORDLUND, P., NYMAN, T., PERSSON, C., SAGEMARK, J., THORSELL, A.G., TRESAUGUES, L., VAN DEN BERG, S., WEIGELT, J., WELIN, M., 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, leishmaniasis and trypanosomiasis (2, 3, 4)

We have previously reported the crystal structure of Leishmania major SAHH protein (PDB ID = 3GU1). In an effort to gain a better understanding of parasite SAHH proteins, we determined the crystal structure of SAHH from Trypanosoma brucei to a resolution of 1.9 Å. T. brucei SAHH crystallized as a homotetramer in the space group C 1 2 1. Each monomer consists of two α/β domains as observed in previous SAHH structures (5). Two domains are observed, a substrate-binding catalytic domain and a cofactor binding domain, the latter being a modified Rossmann fold. Each subunit is bound to a NAD molecule. As previously observed, the cofactor binding site is covered by a C-terminal extension from the adjacent subunit.

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. Parker NB, Yang X, Hanke J, Mason KA, Schowen RL, Borchardt RT, Yin DH. (2003) Trypanosoma cruzi: molecular cloning and characterization of the S-adenosylhomocysteine hydrolase. Exp Parasitol. 2:149-58.
  5. 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.