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Off-pathway, oxygen-dependent thiamine radical in the Krebs cycle.
- Source :
-
Journal of the American Chemical Society [J Am Chem Soc] 2008 Feb 06; Vol. 130 (5), pp. 1662-8. Date of Electronic Publication: 2008 Jan 10. - Publication Year :
- 2008
-
Abstract
- The catalytic cofactor thiamine diphosphate is found in many enzymes of central metabolism and is essential in all extant forms of life. We demonstrate the presence of an oxygen-dependent free radical in the thiamine diphosphate-dependent Escherichia coli 2-oxoglutarate dehydrogenase, which is a key component of the tricarboxylic acid (Krebs) cycle. The radical was sufficiently long-lived to be trapped by freezing in liquid nitrogen, and its electronic structure was investigated by electron paramagnetic resonance (EPR) and electron-nuclear double resonance (ENDOR). Taken together, the spectroscopic results revealed a delocalized pi radical on the enamine-thiazolium intermediate within the enzyme active site. The radical is generated as an intermediate during substrate turnover by a side reaction with molecular oxygen, resulting in the continuous production of reactive oxygen species under aerobic conditions. This off-pathway reaction may account for metabolic dysfunction associated with several neurodegenerative diseases. The possibility that the on-pathway reaction may proceed via a radical mechanism is discussed.
Details
- Language :
- English
- ISSN :
- 1520-5126
- Volume :
- 130
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Journal of the American Chemical Society
- Publication Type :
- Academic Journal
- Accession number :
- 18183975
- Full Text :
- https://doi.org/10.1021/ja076468k