O-alkyl hydroxamates as metaphors of enzyme-bound enolate intermediates in hydroxy acid dehydrogenases. Inhibitors of isopropylmalate dehydrogenase, isocitrate dehydrogenase, and tartrate dehydrogenase

Journal of Organic Chemistry

Volumn 61, Issue 14, 1996, Pages 4527-4531

  Pirrung, Michael C ^a,b   Han, Hyunsoo ^a   Chen, Jrlung ^a  

^a DUKE UNIVERSITY   (United States)

^b John Simon Guggenheim Memorial Foundation   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 0000793346     PISSN: 00223263     EISSN: None     Source Type: Journal    
DOI: 10.1021/jo952090+     Document Type: Article

References (61)

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22. A significant discussion has arisen concerning the stabilization of high energy intermediates like enolates in enzyme active sites by short, strong hydrogen bonds (Cleland, W. W.; Kreevoy, M. M. Science 1994, 264, 1887. Warshel, A.; Papazyan, A.; Kollman, P. A. Science 1995, 269, 102), and questions about even the existence of enolates in enzymes have been raised (Gassman, P. G.; Gerlt, J. A. J. Am. Chem. Soc. 1993, 115, 11552-68. Gerlt, J. A.; Kozarich, J. W.; Kenyon, G. L.; Gassman, P. G. J. Am. Chem. Soc. 1991, 113, 9667). The hydroxy acid dehydrogenases, as metalloenzymes, have a different mechanism of enolate stabilization available to them.
23. A significant discussion has arisen concerning the stabilization of high energy intermediates like enolates in enzyme active sites by short, strong hydrogen bonds (Cleland, W. W.; Kreevoy, M. M. Science 1994, 264, 1887. Warshel, A.; Papazyan, A.; Kollman, P. A. Science 1995, 269, 102), and questions about even the existence of enolates in enzymes have been raised (Gassman, P. G.; Gerlt, J. A. J. Am. Chem. Soc. 1993, 115, 11552-68. Gerlt, J. A.; Kozarich, J. W.; Kenyon, G. L.; Gassman, P. G. J. Am. Chem. Soc. 1991, 113, 9667). The hydroxy acid dehydrogenases, as metalloenzymes, have a different mechanism of enolate stabilization available to them.
24. A significant discussion has arisen concerning the stabilization of high energy intermediates like enolates in enzyme active sites by short, strong hydrogen bonds (Cleland, W. W.; Kreevoy, M. M. Science 1994, 264, 1887. Warshel, A.; Papazyan, A.; Kollman, P. A. Science 1995, 269, 102), and questions about even the existence of enolates in enzymes have been raised (Gassman, P. G.; Gerlt, J. A. J. Am. Chem. Soc. 1993, 115, 11552-68. Gerlt, J. A.; Kozarich, J. W.; Kenyon, G. L.; Gassman, P. G. J. Am. Chem. Soc. 1991, 113, 9667). The hydroxy acid dehydrogenases, as metalloenzymes, have a different mechanism of enolate stabilization available to them.
25. A significant discussion has arisen concerning the stabilization of high energy intermediates like enolates in enzyme active sites by short, strong hydrogen bonds (Cleland, W. W.; Kreevoy, M. M. Science 1994, 264, 1887. Warshel, A.; Papazyan, A.; Kollman, P. A. Science 1995, 269, 102), and questions about even the existence of enolates in enzymes have been raised (Gassman, P. G.; Gerlt, J. A. J. Am. Chem. Soc. 1993, 115, 11552-68. Gerlt, J. A.; Kozarich, J. W.; Kenyon, G. L.; Gassman, P. G. J. Am. Chem. Soc. 1991, 113, 9667). The hydroxy acid dehydrogenases, as metalloenzymes, have a different mechanism of enolate stabilization available to them.
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39. i of 2 against the porcine enzyme is 1 μM.
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41. Hurley, J. H.; Dean, A. M.; Sohl, J. L.; Koshland, D. E., Jr.; Stroud, R. M. Science 1990, 249, 1012-1016. Hurley, J. H.; Dean, A. M.; Koshland, D. E., Jr.; Stroud, R. M. Biochemistry 1991, 30, 8671-8677. Hurley, J. H.; Thorsness, P. E.; Ramalingam, V.; Helmers, N. H.; Koshland, D. E., Jr.; Stroud, R. M. Proc. Natl. Acad. Sci. U.S.A. 1989, 86, 8635-8639. Dean, A. M.; Koshland, D. E., Jr. Science 1990, 249, 1044-1046.
42. Hurley, J. H.; Dean, A. M.; Sohl, J. L.; Koshland, D. E., Jr.; Stroud, R. M. Science 1990, 249, 1012-1016. Hurley, J. H.; Dean, A. M.; Koshland, D. E., Jr.; Stroud, R. M. Biochemistry 1991, 30, 8671-8677. Hurley, J. H.; Thorsness, P. E.; Ramalingam, V.; Helmers, N. H.; Koshland, D. E., Jr.; Stroud, R. M. Proc. Natl. Acad. Sci. U.S.A. 1989, 86, 8635-8639. Dean, A. M.; Koshland, D. E., Jr. Science 1990, 249, 1044-1046.
43. Hurley, J. H.; Dean, A. M.; Sohl, J. L.; Koshland, D. E., Jr.; Stroud, R. M. Science 1990, 249, 1012-1016. Hurley, J. H.; Dean, A. M.; Koshland, D. E., Jr.; Stroud, R. M. Biochemistry 1991, 30, 8671-8677. Hurley, J. H.; Thorsness, P. E.; Ramalingam, V.; Helmers, N. H.; Koshland, D. E., Jr.; Stroud, R. M. Proc. Natl. Acad. Sci. U.S.A. 1989, 86, 8635-8639. Dean, A. M.; Koshland, D. E., Jr. Science 1990, 249, 1044-1046.
44. A vinyl fluoride enol analogue i (Pirrung, M. C.; Rowley, E. G.; Holmes, C. P. J. Org. Chem. 1993, 58, 5683) has also been studied with the bacterial enzyme. It shows only moderate, competitive inhibition, further supporting the idea that an enolate, not the enol, is the intermediate in the IDH reaction. (Equation Presented)
45. i study because of the loss of divalent metal to insoluble complexes at higher pH.
46. Tietze, L. F.; Arlt, M.; Beller, M.; Glusenkamp, K.-H.; Jahde, E.; Rajewsky, M. F. Chem. Ber. 1991, 124, 1215-1221.
47. 1 data were obtained from a Dixon plot.
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