99558-89-1Relevant academic research and scientific papers
Kinetic evidence that cysteine reacts with dopaminoquinone via reversible adduct formation to yield 5-cysteinyl-dopamine: An important precursor of neuromelanin
Jameson, Guy N.L.,Zhang, Jie,Jameson, Reginald F.,Linert, Wolfgang
, p. 777 - 782 (2004)
The reaction of cysteine (cys) with dopaminoquinone (DQ) to form (mainly) 5-cysteinyl-dopamine (5-cys-DA) is of interest because it is known to play a role in the production of melanin in the mammalian brain. To gain insight into this important reaction, an in vitro detailed kinetic study was undertaken. It has been established that cys reacts with DQ via the initial reversible formation of an intermediate adduct or complex and that this adduct then decomposes to form 5-cys-DA. A little 2-cys-DA, is almost certainly formed at the same time but its presence could not be kinetically investigated. Clarification of the kinetic data was aided by following the reaction of DQ with a cys analogue, mercaptoacetic acid (maa). Maa was found to react in a similar fashion, but also forms, reversibly, a bis-complex. This bis-complex, 2,5-(maa)2-dopaminoquinone, is in equilibrium with the di-protonated compound but neither of these species reacts further over the timescale employed in these kinetic studies. Equilibrium constants and first-order rate constants have been extracted from the data and the cys complex is found to be weaker than its maa analogue by an order of magnitude (Kcys = (1.09 ± 0.02) × 10-3; K1,maa = (7.45 ± 0.11) × 10-3). (Note that the possibility that cys also forms a bis-complex at much higher cys concentrations cannot be excluded.) The rates of decomposition differ markedly - the cys complex has the value kcys = 1830 ± 50 s-1 whereas the rate constant for the decomposition of the maa complex is kmaa = 69.3 ± 0.02 s-1 and we attribute this difference to the effect of the positive charge carried by the amino-group on cys. Finally, the constants obtained are used to compare the reactivity of thiol addition with ring cyclization (U. El-Ayaan, E. Herlinger, R. F. Jameson, and W. Linert, J. Chem. Soc., Dalton Trans., 1997, 2813-2818) and we show how this has important implications concerning the production of neuromelanin.
Oxidation of dopamine in the presence of cysteine: Characterization of new toxic products
Shen, Xue-Ming,Zhang, Fa,Dryhurst, Glenn
, p. 147 - 155 (2007/10/03)
Previous studies demonstrated that oxidation of dopamine (DA) in the presence of L-cysteine (CySH) at pH 7.4 gives a complex mixture of cysteinyl conjugates of the neurotransmitter that can be easily further oxidized to a number of dihydrobenzothiazines (DHBTs) along with unidentified yellow products. In this investigation, three of these products have been identified. 7-(2-Aminoethyl)-5-hydroxy-1,4-benzothiazine-3-carboxylic acid (BT-1) is formed as a result of oxidation of 5-S-cysteinyldopamine (5-S-CyS- DA) and 7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3- carboxylic acid (DHBT-1). Regioisomers 6-(2-aminoethyl)1,8,9,10- tetrahydrobenzo[1,2-b:4,3-b']bis[1,4]thiazine-9-carboxylic acid (12) and 6- 2-aminoethyl)1,2,3,10-tetrahydrobenzo[1,2-b:4,3-b']bis[1,4]thiazine-2- carboxylic acid (13) are formed by oxidation of 2,5-bi-S-cysteinyldopamine (2,5-bi-S-CyS-DA), 6-S-cysteinyl-7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H- 1,4-benzothiazine-3-carboxylic acid (DHBT-2), and 6-S-cysteinyl-8-(2- aminoethyl)-3,4-dihydro-5-hydroxy-2H- 1,4-benzothiazine-3-carboxylic acid (DHBT-6). 2,5-Bi-S-CyS-DA, DHBT-2, and DHBT-6 are major early products of DA oxidation in the presence of CySH. However, because these three compounds are the most easily oxidized products formed in this reaction, they are subsequently transformed into 12 and 13, the latter regioisomer always being the major product. Both 12 (LD50 = 18.5 μg) and 13 (LD50 = 1.5 μg) are lethal when administered into the brains of mice and evoke hyperactivity and tremor. The potential relevance of the in vitro chemistry described in this and earlier reports to reactions that might occur in neuromelanin-pigmented dopaminergic neurons in Parkinson's disease is discussed.
Further insights into the influence of L-cysteine on the oxidation chemistry of dopamine: Reaction pathways of potential relevance to Parkinson's disease
Shen, Xue-Ming,Dryhurst, Glenn
, p. 751 - 763 (2007/10/03)
The initial step in the genesis of neuromelanin, a black polymeric pigment normally found in the cytoplasm of dopaminergic cell bodies in the substantia nigra (SN), is the autoxidation of dopamine (DA) to DA-o-quninone (1). In this investigation, it is demonstrated that in the presence of L-cysteine (CySH) o-quinone 1 is scavenged to give 5-S-cysteinyldopamine (5-S-CyS-DA, major product) and 2-S-cysteinyldopamine (2-S-CyS-DA, minor product). These cysteinyl conjugates are more easily oxidized than DA. The relative yields of the resulting products are dependent on the concentration of free CySH. These products include 2,5-bi-S-cysteinyldopamine (2,5-bi-S-CyS-DA) and 2,5,6-tri- S-cysteinyldopamine (2,5,6-tri-S-CyS-DA), 7-(2-aminoethyl)-3,4-dihydro-5- hydroxy-2H-1,4-benzothiazine-3-carboxylic acid (DHBT-1), 8-(2-aminoethyl)- 3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid (DHBT-5), and a number of cysteinyl conjugates of these dihydrobenzothiazines (DHBTs). 2,5- Bi-S-CyS-DA, DHBT-1, the 6-S-cysteinyl conjugate of DHBT-1, DHBT-5, and the 6-S-cysteinyl conjugate of DHBT-5 were lethal when administered into the brains of laboratory mice and evoke a very characteristic hyperactivity syndrome and episodes of sever tremor. These and related results provide support for the hypothesis that the massive, irreversible loss of glutathione (GSH), increased 5-S-CyS-DA/DA concentration ratio, and depigmentation of dopaminergic neurons in the SN that all occur in Parkinson's disease (PD) might be caused by the γ-glutamyl transpeptidase-mediated translocation of CySH (and/or GSH) into these cells. Furthermore, the resulting cysteinyldopamines and DHBTs might include endotoxic metabolites responsible for the selective degeneration of nigrostriatal dopaminergic neurons and PD.
Reactions of Cysteine and Cysteinyl Derivatives with Dopamine-o-quinone and Further Insights into the Oxidation Chemistry of 5-S-Cysteinyldopamine: Potential Relevance to Idiopathic Parkinson's Disease
Zhang, Fa,Dryhurst, Glenn
, p. 193 - 216 (2007/10/03)
Recent studies suggest that elevated rates of autoxidation of dopamine (DA) in the cytoplasm of neuromelanin-pigmented dopaminergic cell bodies in the substantia nigra (SN) and/or reactions of its proximate oxidation product, DA-o-quinone, with glutathione (GSH) or L-cysteine (CySH) might yield endotoxins that play roles in the pathogenesis of idiopathic Parkinson's Diseease (PD).In this study the reactions between DA-o-quinone and CySH and some cysteine derivatives have been studied.The reactions between DA-o-quinone and CySH or cysteine methyl ester are rapid and give the corresponding 5-D-cysteinyl conjugates of DA as the predominant products.By contrast, the reaction between the sterically hindered D-penicillamine methyl ester (PME) and DA-ο-quinone is much slower to give, initially, a mixture of the 2-S-, 5-S-, and 6-S-PME conjugates of DA.These conjugates are then further oxidized by unreacted DA-o-quinone to give a complex mixture of products which include 7-(aminoethyl)-5-hydroxy-2,2-dimethyl-1,4-benzothiazine-3-carboxylic acid methyl ester (13).Large increases in the 5-S-cysteinyldopamine (5-S-CyS-DA)/DA concentration ratio have been measured in the Parkinsonian SN and have been interpreted to reflect elevated rates of DA autoxidation in this structure that degenerates in PD.However, the present study reveals that at physiological pH 5-S-CyS-DA is not only more easily oxidized than DA but a bicyclic o-quinone imine (5) intermediate is formed that can chemically oxidize the former conjugate in a reaction that leads to 7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid (6).Compound 6 is lethal when administered into the brains of mice.However, this putative dihydrobenzothiazine endotoxin is even more easily oxidized than 5-S-CyS-DA in a rather complex reaction that ultimately forms 7-(2-aminoethyl)-5-hydroxy-1,4-benzothiazine-3-carboxylic acid (15).Although this benzothiazine could not be isolated it was identified by comparison of its electrochemical and spectroscopic properties in solution with those of 13.The results of this study suggest that benzothiazine 15 might serve as a better analytical marker molecule than 5-S-CyS-DA for either elevated rates of DA autoxidation and/or for roles of GSH and CySH in the neurodegenerative mechanisms in the SN that contribute to PD.
Effects of L-Cysteine on the Oxidation Chemistry of Dopamine: New Reaction Pathways of Potential Relevance to Idiopathic Parkinson's Disease
Zhang, Fa,Dryhurst, Glenn
, p. 1084 - 1098 (2007/10/02)
Oxidation of the catecholaminergic neurotransmitter dopamine (1) at physiological pH normally results in formation of black, insoluble melanin polymer.In this study, it is demonstrated that L-cysteine (CySH) can divert the melanin pathway by scavenging the proximate o-quinone oxidation product of 1 to give 5-S-cysteinyldopamine (8).This cysteinyl conjugate is further oxidized in the presence of free CySH to give 7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid (11) and its 6-S-cysteinyl (12), 8-S-cysteinyl (14), and 6,8-di-S-cysteinyl (16)conjugates in addition to many other unidentified compounds. 5-S-Cysteinyldopamine (8) and dihydrobenzothiazines 11, 12, 14, and 16 are all more easily oxidized than 1.With increasing molar excesses of CySH, the formation of melanin is decreased and, ultimately, completely blocked.Preliminary experiments have revealed than when injected into the brains of laboratory mice, dihydrobenzothiazine 11 and its cysteinyl conjugates 12 and 14 are lethal and evoke profound behavioral responses including hyperactivity and tremor.On the basis of these results and other recent observations, a new hypothesis has been advanced which might help explain the selective degeneration of nigrostriatal dopaminergic neurons which occurs in idiopathic Parkinson's Disease (PD).This hypothesis proposes that in response to some form of chronic brain insult, the activity of γ-glutamyltranspeptidase is upregulated leading to an increased rate of translocation of glutathione (GSH) into the cytoplasm of dopaminergic cell bodies in the substantia nigra (SN) pars compacta.The results of this in vitro study predict that such an elevated translocation of GSH intoheavily pigmented dopaminergic neurons would cause a diversion of the neuromelanin pathway with consequent depigmentation of these cells and formation of 8, all of which occur in the Parkinsonian SN.The further very facile oxidation of 8 which must occur under intraneuronal conditions where 1 is autoxidized, i.e., in neuromelanin-pigmented cells, would lead to dihydrobenzothiazine 11 and its cysteinyl conjugates which could be the endotoxins responsible for the selective degeneration of dopaminergic SN neurons in PD.The ease of autoxidation of 8 is suggested to account for the low levels of this conjugate found in the degenerating and Parkinsonian SN.The latter reaction and the intraneuronal autoxidation/redox cycling of 11 and its cysteinyl conjugates would be expected to result in greatly increased rates of intraneuronal formation of O2-radical anion which could (a) catalyze the oxidation of 1 by molecular oxygen, hence accounting for the significantly elevated 8/1 ratio observed in the Parkinsonian SN, and (b) lead to increased production of H2O2 and HO-radical, resulting in the extensive peroxidative damage which occurs in the SN in PD.
