Abstract
S-Adenosylhomocysteine (AdoHcy) hydrolase regulates all adenosylmethionine-(AdoMet) dependent transmethylations by hydrolyzing the potent feedback inhibitor AdoHcy to homocysteine and adenosine. The crystallographic structure determination of a selenomethionyl-incorporated AdoHcy hydrolase inhibitor complex was accomplished using single wavelength anomalous diffraction data and the direct methods program, Snb v2.0, which produced the positions of all 30 crystallographically distinct selenium atoms. The mode of enzyme–cofactor binding is unique, requiring interactions from two protein monomers. An unusual dual role for a catalytic water molecule in the active site is revealed in the complex with the adenosine analog 2′-hydroxy, 3′-ketocyclopent-4′-enyladenine.
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References
Borchardt, R.T., Creveling, C.R. & Ueland, P.M. Biological methylation and drug design — Experimental and clinical roles of S-adenosylmethione (Humana Press, Clifton, NJ, 1986).
de la Haba, G. & Cantoni, G. The enzymatic synthesis of S-adenosyl-L-homocysteine from adenosine and homocysteine. J. Biol. Chem. 234, 603–608 (1959).
Ueland, P.M. Pharmacological and biochemical aspects of S-adenosylhomocysteine and S-adenosylhomocysteine hydrolase. Pharmacol. Rev. 34, 223–253 (1982).
Miller, M.W. et al. The mouse lethal nonagouti (Ax) mutation deletes the S-adenosylhomocysteine hydrolase (Ahcy) gene. EMBO J 13, 1806–1816 (1994).
Palmer, J.L. & Abeles, R.H. The mechanism of action of S-adenosylhomocysteinase. J. Biol. Chem. 254, 1217–1226 (1979).
Hershfield, M.S., Kredich, N.M. S-adenosylhomocysteine hydrolase is an adenosine-binding protein: a target for adenosine toxicity. Science 202, 757–760 (1978).
Hershfield, M.S. Apparent suicide inactivation of human lymphoblast S-adenosylhomocysteine hydrolase by 2′-deoxyadenosine and adenine arabinoside: A basis for direct toxic effects of analogs of adenosine. 254, 22–25 (1979).
Kredich, N.M. & Martin, D.W., Jr., Role of S-adenosylhomocysteine in adenosinemediated toxicity in cultured mouse T lymphoma cells. Cell 12, 931–938 (1977).
Hershfield, M.S., Kredich, N.M., Ownby, D.R., Ownby, H. & Buckley, R. In vivo inactivation of erythrocyte S-adenosylhomocysteine hydrolase by 2′-adeoxyadenosine in adenosine deaminase-deficient patients. J. Clin. Invest. 63, 807–811 (1979).
Wolfe, M.S., Borchardt, R.T. S-adenosyl-L-homocysteine hydrolase as a target for antiviral chemotherapy. J. Med. Chem. 34, 1521–1530 (1991).
Bitonti, A.J., Baumann, R.J., Jarvi, E.T., McCarthy, J.R. & McCann, P.P. Antimalarial activity of a 4′,5′-unsaturated 5′-fluoroadenosine mechanism-based inhibitor of S-adenosyl-L-homocysteine hydrolase. Biochem. Pharmacol. 40, 601–606 (1990).
Wolos, J.A., Frondorf, K.A. & Esser, R.E. Immunosuppression mediated by an inhibitor of S-adenosyl-L-homocysteine hydrolase. Prevention and treatment of collagen-induced arthritis. J. Immunol. 151, 526–534 (1993).
Turner, M.A. et al. Crystallization and preliminary X-ray analysis of human placental S-adenosylhomocysteine hydrolase. Acta Crystallogr. D53, 339–341 (1997).
Hendrickson, W.A. Determination of macromolecular structures from anomalous diffraction of synchrotron radiation. Science 254, 51–58 (1991).
Ault-Riche, D.B. et al. Effects of 4′-modified analogs of aristeromycin on the metabolism of S-adenosyl-L-homocysteine in murine L929 cells. Mol. Pharmacol. 43, 989–997 (1993).
Miller, R., Gallo, S.M., Khalak, H.G. & Weeks, C.M. Snb: Crystal structure determination via Shake-and-Bake. J. Appl. Crystallogr. 27, 613–621 (1994).
Smith, G.D., Nagar, B., Rini, J.M., Hauptman, H.A., Blessing, R.H. The use of Snb to determine an anomalous scattering substructure. Acta Cryst., in the press (1998).
Ramakrishnan, V. & Biou, V. Treatment of multiwavelength anomalous diffraction data as a special case of multiple isomorphous replacement. Meths Enz. 76, 538–557 (1997).
Furey, W. & Swaninathan, S. PHASES-95: A program for processing and analyzing diffraction data from macromolecules in Methods in Enzymology (eds. Carter, C.W. & Sweet, R.M.) 590–633 (Academic Press, New York, 1997).
Brünger, A.T. et al. Crystallography and NMR System (CNS): A new software system for macromolecular structure determination. Acta Crystallogr. D, submitted (1998).
Kleijwegt, G.J. & Jones, T.A. Detecting folding motifs and similarities in protein structures. Meths Enz. 277, 525–545 (1997).
Lamzin, V.S. et al. Crystal structure of NAD-dependent formate dehydrogenase. Eur. J. Biochem. 206, 441–452 (1992).
Rossman, M.J., Liljas, A., Branden, C.-I. & Banaszak, L.J., In The Enzymes (ed. Boyer, P.D.) 61–102 (Academic Press, New York; 1975).
Richardson, J.S. The anatomy and taxonomy of protein structure. Adv. Protein Chem. 34, 167–339 (1981).
Lesk, A.M. NAD-binding domains of dehydrogenases. Curr. Opin. Struct. Biol. 5, 775–783 (1995).
Buehner, M., Ford, G.C., Moras, D., Olsen, K.W. & Rossmann, M.G. D-Glyceraldehyde-3-phosphate dehydrogenase: three-dimensional structure and evolutionary significance. Proc. Natl. Acad. Sci. USA 70, 3052–3054 (1973).
Philips, C., Gover, S. & Adams, M.J. Structure of 6-phosphogluconate dehydrogenase refined at 2Å resolution. Acta Crystallogr. D51, 290–307 (1995).
Ghosh, D. et al. Three-dimensional structure of hole 3α,20β-hydroxysteroid dehydrogenase: a member of a short-chain dehydrogenase family. Proc. Natl. Acad. Sci. USA 88, 10064–10068 (1991).
Varughese, K.I., Skinner, M.M., Whiteley, J.M., Matthews, D.A. & Xuong, N.H. Crystal structure of rat liver dihydropteridine reductase. Proc. Natl. Acad. Sci. USA 89, 6080–6084 (1992).
Degano, M., Gopaul, D.N., Scapin, G., Schramm, V.L. & Sacchettini, J.C. Three-dimensional structure of the inosine-uridine nucleoside N-ribohydrolase from Crithidia fasciculata. Biochemistry 35, 5971–5981 (1996).
Ault-Riche, D.B., Yuan, C.S. & Borchardt, R.T. A single mutation at lysine 426 of human placental S-adenosylhomocysteine hydrolase inactivates the enzyme. J. Biol. Chem. 269, 31472–31478 (1994).
Goldberg, J.D., Yoshida, T. & Brick, P. Crystal structure of a NAD-dependent D-glycerate dehydrogenase at 2.4 Å resolution. J. Mol. Biol. 236, 1123–1140 (1994).
Yuan, C.-S., Liu, S., Wnuk, S.F., Robins, M.J., Borchardt, R.T. Design and synthesis of S-Adenosylhomocysteine hydrolase inhibitors as broad-spectrum antiviral agents. Adv. Antiviral Drug Des. 2, 41–88 (1996).
Abeles, R.H., Fish, S. & Lapinskas, B. S-Adenosylhomocysteinase: Mechanism of inactivation by 2′-deoxyadenosine and interaction with other nucleosides. Biochemistry 21, 5557–5562 (1982).
Cleland, W.W. & Kreevoy, M.M. Low-barrier hydrogen bonds and enzymic catalysis. Science 264, 1887–1890 (1994).
Takata, Y., Tomoharu, G. & Fujioka, M. Chemical modification of S-adenosylhomocysteinase by a water-soluble carbodiimide. Arch. Biochem. Biophys. 240, 827–835 (1985).
Gomi, T., Ogawa, H. & Fujioka, M. S-adenosylhomocysteinase from rat liver. Amino acid sequences of the peptides containing active site cysteine residues modified by treatment with 5′-p-fluorosulfonylbenzoyladenosine. J. Biol. Chem. 261, 13422–13425 (1986).
Takata, Y. & Fujioka, M. 5′-[p-(Fluorosulfonyl)benzoyl] adenosine-mediated inactivation of S-adenosylhomocysteinase. Biochemistry 23, 4357–4362 (1984).
Gomi, T. & Fujioka, M. Evidence for an essential histidine residue in S-adenosylhomocysteinase from rat liver. Biochemistry 22, 137–143 (1983).
Yuan, C.-S., Yeh, J., Squier, T.C., Rawitch, A. & Borchardt, R.T. Ligand-dependent changes in intrinsic fluorescence of S-adenosylhomocysteine hydrolase: implications for the mechanism of inhibitor-induced inhibition. Biochemistry 32, 10414–10422 (1993).
Doublié, S., Carter, C.W. in Crystallization of nucleic acids and proteins: a practical approach (eds Ducruix, A. & Giegé, R.) 311–317 (Oxford University Press, New York; 1992).
Yuan, C.S., Wnuk, S.F., Liu, S., Robins, M.J. & Borchardt, R.T. (E)-5′,6′-didehydro-6′-deoxy-6′-flurohomoadenosine: a substrate that measures the hydrolytic activity ofS-adenosylhomocysteine hydrolase. Biochemistry 33, 12305–12311 (1994).
Otwinowski, Z. & Minor, W. Processing of X-ray diffraction data collected in oscillation mode. Meths Enz. 276, 307–326 (1997).
Blessing, R.H. Data reduction and error analysis for accurate single crystal diffraction intensities. Crystallogr. Rev. 1, 3–58 (1987).
French, S. & Wilson, K. On the treatment of negative intensity observations. Acta Crystallogr. A34, 517–525 (1978).
Blessing, R.H. J. Appl. Crystallogr. 30, 176–178 (1997).
Jones, T.A., Zou, J.Y., Cowan, S.W., Kjeldgaard, M. Improved methods for building protein models in electron density maps and the location of errors in these models. Acta Crystallogr. A47, 110–119 (1991).
Kleijwegt, G.J. & Jones, T.A. In From first map to final model (eds. Bailey, S., Hubbard, R. & Waller, D.) 59–66 (SERC Daresbury, Warrington; 1994).
Brünger, A.T. The free R value: a novel statistical quantity for assessing the accuracy of crystal structures. Nature 355, 472–474 (1992).
Laskowski, R.A., MacArthur, M.W., Moss, D.S. & Thornton, J.M. PROCHECK: a program to check the stereochemical quality of protein structures. J. Appl. Crystallogr. 26, 283–291 (1993).
Kraulis, P.J. MOLSCRIPT: A program to produce both detailed and schematic plots of protein structures. J. Appl. Crystallogr. 24, 946–950 (1991)
Hutchinson, E.G. & Thornton, J.M. PROMOTIF-a program to identify and analyze structural motifs in proteins. Protein Sci. 5, 212–220 (1996).
Flores, T.P., Moss, D.S. & Thornton, J.M. An algorithm for automatically generating protein topology cartoons. Protein Engng. 7, 31–37 (1994).
Brünger, A.T. XPLOR Version 3.1 (Yale University Press, New Haven, Connecticut; 1993).
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Turner, M., Yuan, CS., Borchardt, R. et al. Structure determination of selenomethionyl S-adenosylhomocysteine hydrolase using data at a single wavelength. Nat Struct Mol Biol 5, 369–376 (1998). https://doi.org/10.1038/nsb0598-369
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DOI: https://doi.org/10.1038/nsb0598-369
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