3-Nitropropionic Acid is a Suicide Inhibitor of MitochondrialRespiration that, Upon Oxidation by Complex II, Forms a Covalent AdductWith a Catalytic Base Arginine in the Active Site of the Enzyme
We report three new structures of mitochondrial respiratory Complex II (succinate ubiquinone oxidoreductase, E.C. 1.3.5.1) at up to 2.1 {angstrom} resolution, with various inhibitors. The structures define the conformation of the bound inhibitors and suggest the residues involved in substrate binding and catalysis at the dicarboxylate site. In particular they support the role of Arg297 as a general base catalyst accepting a proton in the dehydrogenation of succinate. The dicarboxylate ligand in oxaloacetate-containing crystals appears to be the same as that reported for Shewanella flavocytochrome c treated with fumarate. The plant and fungal toxin 3-nitropropionic acid, an irreversible inactivator of succinate dehydrogenase, forms a covalent adduct with the side chain of Arg297. The modification eliminates a trypsin cleavage site in the flavoprotein, and tandem mass spectroscopic analysis of the new fragment shows the mass of Arg 297 to be increased by 83 Da and to have potential of losing 44 Da, consistent with decarboxylation, during fragmentation.
- Research Organization:
- Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
- Sponsoring Organization:
- USDOE Director, Office of Science. Office of Basic EnergySciences; National Institutes of Health (NIH)
- DOE Contract Number:
- DE-AC02-05CH11231; NIHR01GM62563
- OSTI ID:
- 891223
- Report Number(s):
- LBNL-59358; JBCHA3; R&D Project: 864U1E; BnR: 400412000; TRN: US0605325
- Journal Information:
- Journal of Biological Chemistry, Vol. 281, Issue 9; Related Information: Journal Publication Date: 03/03/2006; ISSN 0021-9258
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
72 PHYSICS OF ELEMENTARY PARTICLES AND FIELDS
ADDUCTS
ARGININE
CATALYSIS
CATALYSTS
CLEAVAGE
DECARBOXYLATION
DEHYDROGENATION
ENZYMES
FRAGMENTATION
MODIFICATIONS
OXIDATION
PROTONS
RESIDUES
RESOLUTION
RESPIRATION
SUBSTRATES
TOXINS
TRYPSIN
UBIQUINONE
Complex II succinate dehydrogenase respiratory chain bindingsite suicide inhibitor 3-nitropropionic acid nitroalkene