Electronic substituent effects on the cleavage specificity of a non-heme Fe2+-dependent β-diketone dioxygenase and their mechanistic implications

Journal of the American Chemical Society

Volumn 126, Issue 39, 2004, Pages 12202-12203

  Straganz, Grit D ^a   Hofer, Hannes ^a   Steiner, Walter ^a   Nidetzky, Bernd ^a  

^a GRAZ UNIVERSITY OF TECHNOLOGY   (Austria)

Author keywords

[No Author keywords available]

Indexed keywords

ACETIC ACID; ACETYLACETONE; BETA DIKETONE DIOXYGENASE; IRON; METHYLGLYOXAL; OXYGENASE; UNCLASSIFIED DRUG;

AEROBIC METABOLISM; ARTICLE; CHEMICAL BOND; GAS CHROMATOGRAPHY; MASS SPECTROMETRY; QUANTITATIVE STRUCTURE ACTIVITY RELATION; REACTION ANALYSIS; THERMODYNAMICS;

CHROMATOGRAPHY, HIGH PRESSURE LIQUID; FERROUS COMPOUNDS; KETONES; NONHEME IRON PROTEINS; OXYGENASES; SUBSTRATE SPECIFICITY;

EID: 4644294915     PISSN: 00027863     EISSN: None     Source Type: Journal    
DOI: 10.1021/ja0460918     Document Type: Article

References (17)

1. (a) Costas, M.; Mehn, M. P.; Jensen, M. P.; Que, L., Jr. Chem. Rev. 2004, 104, 939-986.
2. (b) Solomon, E. I.; Brunold, T. C.; Davis, M. I.; Kemsley, J. N.; Lee, S. K.; Lehnert, N.; Neese, F.; Skulan, A. J.; Yang, Y. S.; Zhou, J. Chem. Rev. 2000, 100, 235-349.
3. (c) Bugg, T. D. H. Tetrahedron 2003, 59, 7075-7101.
4. (d) Groce, S. L.; Lipscomb, J. D. J. Am. Chem. Soc. 2003, 125, 11780-11781.
5. (a) Dai, Y.; Pochapsky, T. C.; Abeles, R. H. Biochemistry 2001, 40, 6379-6387.
6. (b) Steiner, R. A.; Kalk, K. H.; Dijkstra, B. W. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 16625-16630.
7. (c) Leuenberger, M. G.; Engeloch-Jarret, C.; Woggon, W. D. Angew. Chem., Int. Ed. 2001, 16, 2613-2617.
8. Straganz, G. D.; Glieder, A.; Brecker, L.; Ribbons, D. W.; Steiner, W. Biochem. J. 2003, 369, 573-581.
9. Bugg, T. D. H.; Linn, G. Chem. Commun. 2001, 11, 941-952.
10. 2+-dependent NHMCDs are thought to activate molecular oxygen through electron transfer from the deprotonated, metal bound substrate.1,2 We perform Hartee-Fock calculations of the electronic state of monoanionic acetylacetone and find that the HOMO is centered at C-3 and oxygen. Nucleophilic attack by C-3 of the substrate would directly lead to the peroxide intermediate. Single electron transfer from the substrate via the metal yields a conjugated radical that is located both on C-3 and the two oxygen atoms. The resulting activated oxygen species will subsequently add to C-3 (see (II) and (III), Scheme 1). Therefore, irrespective of the exact mechanism of oxygen activation in Dke1, the same central peroxide intermediate will occur and is the point of departure for our mechanistic considerations.
11. (a) Sanvoisin, J.; Langley, G. J.; Bugg, T. D. H. J. Am. Chem. Soc. 1995, 117, 7836-7837.
12. (b) Mayer, R. J.; Que, L., Jr. J. Biol. Chem. 1984, 259, 13056-13060.
13. Hansch, C.; Leo, A.; Hoekman, D. H. In Exploring Qsar: Hydrophobic, Electronic, & Steric Constants; Heller, S. R., Ed.; American Chemical Society: Washington, DC, 1995.
14. (a) Crudden, C. M.; Chen, A. C.; Calhoun, L. A. Angew. Chem., Int. Ed. 2000, 39, 2851-2855.
15. (b) Goodman, R. M.; Kishi, Y. J. Am. Chem. Soc. 1998, 120, 9392-9393.
16. Geraldes, C. F. G. C.; Barros, M. T.; Maycock, C. D.; Silva, M. I. J. Mol. Struct. 1990, 238, 335-346.
17. Considering that conversion of a dioxetane ring is a highly exothermic reaction, we looked at the occurrence of luminescence during the Dke1-catalyzed cleavage of pentanedione at 25 °C and pH 7.5. We did not observe any, even at high enzyme concentrations of 200 μM. However, we emphasize that the nature of the rate-limit ing step in the reaction of Dke1 is not known and the fraction of enzyme-bound dioxetane intermediate may be too small to allow detection of luminescence.