S. cerevisiae Glutamate Cysteine Ligase Inhibition
22. Lu¨ersen, K., Walter, R. D., and Mu¨ller, S. (2000) Biochem. J. 346, 545–552
23. Campbell, E. B., Hayward, M. L., and Griffith, O. W. (1991) Anal. Biochem.
194, 268–277
alkyl sulfoximine-based inhibitors are excellent transition state
mimics that dramatically reduce enzymatic activity. Examina-
tion of the ScGCL-BSO complex suggests that additional func-
tionalities may be engineered to increase selectivity. ScGCL and
human GCL share Ͼ40% sequence identity, with nearly com-
plete conservation of active site architecture (24), suggesting
that the insights garnered from the study of ScGCL will facili-
tate the development of improved therapeutics that modulate
glutathione production in mammalian systems.
24. Biterova, E. I., and Barycki, J. J. (2009) J. Biol. Chem. 284, 32700–32708
25. Jez, J. M., Cahoon, R. E., and Chen, S. (2004) J. Biol. Chem. 279,
33463–33470
26. Rodgers, D. W. (1994) Structure 2, 1135–1140
27. Otwinowski, Z., and Minor, W. (1997) Methods Enzymol. 276, 307–326
28. Adams, P. D., Grosse-Kunstleve, R. W., Hung, L. W., Ioerger, T. R., Mc-
Coy, A. J., Moriarty, N. W., Read, R. J., Sacchettini, J. C., Sauter, N. K., and
Terwilliger, T. C. (2002) Acta. Crystallogr. D Biol. Crystallogr. 58,
1948–1954
Acknowledgments—We thank the BioCARS staff for assistance in
x-ray data collection, Dr. Mark Wilson (University of Nebraska) for
helpful discussions, and Dr. Melanie Simpson (University of
Nebraska) for thoughtful insights and review of the manuscript.
29. Emsley, P., and Cowtan, K. (2004) Acta. Crystallogr. D Biol. Crystallogr. 60,
2126–2132
30. Murshudov, G. N., Vagin, A. A., and Dodson, E. J. (1997) Acta. Crystallogr.
D Biol. Crystallogr. 53, 240–255
31. Davis, I. W., Leaver-Fay, A., Chen, V. B., Block, J. N., Kapral, G. J., Wang,
X., Murray, L. W., Arendall, W. B., 3rd, Snoeyink, J., Richardson, J. S., and
Richardson, D. C. (2007) Nucleic Acids Res. 35, W375–W383
32. Pettersen, E. F., Goddard, T. D., Huang, C. C., Couch, G. S., Greenblatt,
D. M., Meng, E. C., and Ferrin, T. E. (2004) J. Comput. Chem. 25,
1605–1612
REFERENCES
1. Griffith, O. W., and Mulcahy, R. T. (1999) Adv. Enzymol. Relat. Areas Mol.
Biol. 73, 209–267, xii
2. Orlowski, M., and Meister, A. (1971) J. Biol. Chem. 246, 7095–7105
3. Strumeyer, D. H., and Bloch, K. (1960) J. Biol. Chem. 235, PC27
4. Yip, B., and Rudolph, F. B. (1976) J. Biol. Chem. 251, 3563–3568
5. Copley, S. D., and Dhillon, J. K. (2002) Genome Biol. 3, research0025
6. Tateishi, N., Higashi, T., Shinya, S., Naruse, A., and Sakamoto, Y. (1974)
J. Biochem. 75, 93–103
33. Huang, C. S., Moore, W. R., and Meister, A. (1988) Proc. Natl. Acad. Sci.
U.S.A. 85, 2464–2468
34. Mårtensson, J., Jain, A., Stole, E., Frayer, W., Auld, P. A., and Meister, A.
(1991) Proc. Natl. Acad. Sci. U.S.A. 88, 9360–9364
35. Brekken, D. L., and Phillips, M. A. (1998) J. Biol. Chem. 273, 26317–26322
36. Griffith, O. W., and Meister, A. (1979) J. Biol. Chem. 254, 7558–7560
37. Griffith, O. W. (1999) Free Radic. Biol. Med. 27, 922–935
38. Rappa, G., Gamcsik, M. P., Mitina, R. L., Baum, C., Fodstad, O., and Lorico,
A. (2003) Eur. J. Cancer 39, 120–128
7. Wild, A. C., and Mulcahy, R. T. (1999) Biochem. J. 338, 659–665
8. Lu, S. C. (2009) Mol. Aspects Med. 30, 42–59
9. Richman, P. G., and Meister, A. (1975) J. Biol. Chem. 250, 1422–1426
10. Huang, C. S., Anderson, M. E., and Meister, A. (1993) J. Biol. Chem. 268,
20578–20583
39. Abbott, J. J., Ford, J. L., and Phillips, M. A. (2002) Biochemistry 41,
2741–2750
11. Huang, C. S., Chang, L. S., Anderson, M. E., and Meister, A. (1993) J. Biol.
Chem. 268, 19675–19680
40. Hibi, T., Nii, H., Nakatsu, T., Kimura, A., Kato, H., Hiratake, J., and Oda, J.
(2004) Proc. Natl. Acad. Sci. U.S.A. 101, 15052–15057
41. Hothorn, M., Wachter, A., Gromes, R., Stuwe, T., Rausch, T., and Schef-
fzek, K. (2006) J. Biol. Chem. 281, 27557–27565
12. Fraser, J. A., Saunders, R. D., and McLellan, L. I. (2002) J. Biol. Chem. 277,
1158–1165
13. Misra, I., and Griffith, O. W. (1998) Protein Expr. Purif. 13, 268–276
14. Godwin, A. K., Meister, A., O’Dwyer, P. J., Huang, C. S., Hamilton, T. C.,
and Anderson, M. E. (1992) Proc. Natl. Acad. Sci. U.S.A. 89, 3070–3074
15. Mulcahy, R. T., Bailey, H. H., and Gipp, J. J. (1994) Cancer Chemother.
Pharmacol. 34, 67–71
42. Abbott, J. J., Pei, J., Ford, J. L., Qi, Y., Grishin, V. N., Pitcher, L. A., Phillips,
M. A., and Grishin, N. V. (2001) J. Biol. Chem. 276, 42099–42107
43. Liaw, S. H., and Eisenberg, D. (1994) Biochemistry 33, 675–681
44. Krajewski, W. W., Jones, T. A., and Mowbray, S. L. (2005) Proc. Natl. Acad.
Sci. U.S.A. 102, 10499–10504
16. Mulcahy, R. T., Bailey, H. H., and Gipp, J. J. (1995) Cancer Res. 55,
4771–4775
45. Herrera, K., Cahoon, R. E., Kumaran, S., and Jez, J. (2007) J. Biol. Chem.
282, 17157–17165
17. Anderson, M. E. (1998) Chem. Biol. Interact 111–112, 1–14
18. Meister, A., and Anderson, M. E. (1983) Annu. Rev. Biochem. 52, 711–760 46. Gogos, A., and Shapiro, L. (2002) Structure 10, 1669–1676
19. Townsend, D. M., and Tew, K. D. (2003) Oncogene 22, 7369–7375
20. Griffith, O. W. (1982) J. Biol. Chem. 257, 13704–13712
47. Polekhina, G., Board, P. G., Gali, R. R., Rossjohn, J., and Parker, M. W.
(1999) EMBO J. 18, 3204–3213
21. Arrick, B. A., Griffith, O. W., and Cerami, A. (1981) J. Exp. Med. 153, 48. Galant, A., Arkus, K. A., Zubieta, C., Cahoon, R. E., and Jez, J. M. (2009)
720–725
Plant Cell 21, 3450–3458
14466 JOURNAL OF BIOLOGICAL CHEMISTRY
VOLUME 285•NUMBER 19•MAY 7, 2010