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Brain Mitochondria Catalyze the Oxidation of 7‐(2‐Aminoethyl)‐3,4‐Dihydro‐5‐Hydroxy‐2 H ‐1,4‐Benzothiazine‐3‐Carboxylic Acid (DHBT‐1) to Intermediates that Irreversibly Inhibit Complex I and Scavenge Glutathione: Potential Relevance to the Pathogenesis of Parkinson's Disease
Author(s) -
Li Hong,
Shen XueMing,
Dryhurst Glenn
Publication year - 1998
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1998.71052049.x
Subject(s) - chemistry , neuromelanin , quinone , mitochondrion , benzothiazine , thioredoxin reductase , stereochemistry , imine , biochemistry , dopamine , glutathione , dopaminergic , enzyme , medicinal chemistry , substantia nigra , catalysis , biology , neuroscience
We have proposed that a very early step in the pathogenesis of idiopathic Parkinson's disease is the elevated translocation of l ‐cysteine into neuromelanin‐pigmented dopaminergic neurons in the substantia nigra. This influx of l ‐cysteine was proposed to divert the normal neuromelanin pathway by scavenging dopamine‐ o ‐quinone, formed by autoxidation of cytoplasmic dopamine, to give initially 5‐ S ‐cysteinyldopamine, which is further oxidized to 7 ‐ (2 ‐ aminoethyl) ‐ 3,4 ‐ dihydro ‐ 5 ‐ hydroxy ‐ 2 H ‐ 1,4 ‐ benzothiazine‐3‐carboxylic acid (DHBT‐1). In a recent report, it was demonstrated that DHBT‐1 evokes inhibition of complex I respiration when incubated with intact rat brain mitochondria and a time‐dependent irreversible inhibition of NADH‐coenzyme Q 1 (CoQ 1 ) reductase when incubated with mitochondrial membranes. In this study, it is established that the time dependence of NADH‐CoQ 1 reductase inhibition reflects the oxidation of DHBT‐1, catalyzed by an unknown constituent of the inner mitochondrial membrane, to an o ‐quinone imine intermediate that rearranges to 7‐(2‐aminoethyl) ‐ 5 ‐ hydroxy ‐ 1,4 ‐ benzothiazine ‐ 3 ‐ carboxylic acid (BT‐1) and decarboxylates to 7‐(2‐aminoethyl)‐5‐hydroxy‐1,4‐benzothiazine (BT‐2), which are further catalytically oxidized to o ‐quinone imine intermediates. The electrophilic o ‐quinone imine intermediates formed in these mitochondria‐catalyzed oxidations of DHBT‐1, BT‐1, and BT‐2 are proposed to bind covalently to key sulfhydryl residues at the complex I site, thus evoking irreversible inhibition of NADH‐CoQ 1 reductase. Evidence for this mechanism derives from the fact that greater than equimolar concentrations of glutathione completely block inhibition of NADH‐CoQ 1 reductase by DHBT‐1, BT‐1, and BT‐2 by scavenging their electrophilic o ‐quinone imine metabolites to form glutathionyl conjugates. The results of this investigation may provide insights into the irreversible loss of glutathione and decreased mitochondrial complex I activity, which are both anatomically specific to the substantia nigra and exclusive to Parkinson's disease.