Oxidative metabolites of 5-S-cysteinylnorepinephrine are irreversible inhibitors of mitochondrial complex I and the alpha-ketoglutarate dehydrogenase and pyruvate dehydrogenase complexes: possible implications for neurodegenerative brain disorders.
The major initial product of the oxidation of norepinephrine (NE) in the presence of L-cysteine is 5-S-cysteinylnorepinephrine which is then further easily oxidized to the dihydrobenzothiazine (DHBT) 7-(1-hydroxy-2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1, 4-benzothiazine-3-carboxylic acid (DHBT-NE-1). When incubated with intact rat brain mitochondria, DHBT-NE-1 evokes rapid inhibition of complex I respiration without affecting complex II respiration. DHBT-NE-1 also evokes time- and concentration-dependent irreversible inhibition of NADH-coenzyme Q(1) (CoQ(1)) reductase, the pyruvate dehydrogenase complex (PDHC), and alpha-ketoglutarate dehydrogenase (alpha-KGDH) when incubated with frozen and thawed rat brain mitochondria (mitochondrial membranes). The time dependence of the inhibition of NADH-CoQ(1) reductase, PDHC, and alpha-KGDH by DHBT-NE-1 appears to be related to its oxidation, catalyzed by an unknown component of the inner mitochondrial membrane, to electrophilic intermediates which bind covalently to active site cysteinyl residues of these enzyme complexes. The latter conclusion is based on the ability of glutathione to block inhibition of NADH-CoQ(1) reductase, PDHC, and alpha-KGDH by scavenging electrophilic intermediates, generated by the mitochondrial membrane-catalyzed oxidation of DHBT-NE-1, forming glutathionyl conjugates, several of which have been isolated and spectroscopically identified. The possible implications of these results to the degeneration of neuromelanin-pigmented noradrenergic neurons in the locus ceruleus in Parkinson's disease are discussed.
Xin
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Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma 73019, USA.
Shen
X M
XM
Li
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Dryhurst
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D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D007655:Ketoglutarate Dehydrogenase Complex / Q000037:antagonists & inhibitors / Q000187:drug effects; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000187:drug effects*; D009638:Norepinephrine / Q000031:analogs & derivatives* / Q000378:metabolism; D010084:Oxidation-Reduction; D010300:Parkinson Disease / Q000378:metabolism*; D011768:Pyruvate Dehydrogenase Complex / Q000037:antagonists & inhibitors / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013843:Thiazines / Q000494:pharmacology*
C413502:5-cysteinylnorepinephrine; C413503:DHBT-NE-1; D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D011768:Pyruvate Dehydrogenase Complex; D013843:Thiazines; D007655:Ketoglutarate Dehydrogenase Complex; D014450:Electron Transport Complex III; D009638:Norepinephrine