115331-10-7Relevant academic research and scientific papers
Oxidative metabolites of 5-S-cysteinylnorepinephrine are irreversible inhibitors of mitochondrial complex I and the α-ketoglutarate dehydrogenase and pyruvate dehydrogenase complexes: Possible implications for neurodegenerative brain disorders
Xin,Shen,Li,Dryhurst
, p. 749 - 760 (2000)
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-benzothia zine-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 Q1 (CoQ1) reductase, the pyruvate dehydrogenase complex (PDHC), and α-ketoglutarate dehydrogenase (α-KGDH) when incubated with frozen and thawed rat brain mitochondria (mitochondrial membranes). The time dependence of the inhibition of NADH-CoQ1 reductase, PDHC, and α-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-CoQ1 reductase, PDHC, and α-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.
Oxidation chemistry of (-)-norepinephrine in the presence of L-cysteine
Shen, Xue-Ming,Dryhurst, Glenn
, p. 2018 - 2029 (2007/10/03)
The noradrenergic neurotransmitter (-)-norepinephrine (1) is very easily oxidized at physiological pH to an o-quinone (2) that normally cyclizes and subsequently oxidatively polymerizes to black melanin. In this investigation it is demonstrated that L-cysteine (CySH) can divert the melanin pathway by efficiently scavenging o-quinone 2 to give, initially, 5-S- cysteinylnorepinephrine (6) and 2-S-cysteinylnorepinephrine (7). These cysteinyl conjugates are appreciably more easily oxidized than 1 to o- quinones that, in part, are further attacked by CySH to give 2,5-bi-S- cysteinylnorepinephrine (8), an even more easily oxidized compound. The o- quinone intermediates formed upon oxidation of 6-8 can also undergo facile intramolecular cyclizations to bicyclic o-quinone imines that oxidize the cysteinyl conjugates from which they are derived in a reaction sequence that leads initially to a number of dihydrobenzothiazines. At least two of these compounds, 7-(1-hydroxy-2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4- benzothiazine-3-carboxylic acid (9) and 8-(1-hydroxy-2-aminoethy])-3,4- dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid (10) are lethal when administered into the brains of mice. The in vitro chemical pathways elucidated in this investigation might be of relevance to the depigmentation and degeneration of neuromelanin-pigmented noradrenergic cell bodies in the locus ceruleus in Parkinson's Disease and to the degeneration of noradrenergic nerve terminals in Alzheimer's Disease and following transient cerebral ischemia (stroke).
