Bioorganic Chemistry p. 193 - 216 (1995)
Update date:2022-08-25
Topics:
Zhang, Fa
Dryhurst, Glenn
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.
View MoreChangsha Goomoo Chemical Technology Co.Ltd
Contact:+86-731-82197655
Address:No.649,Chezhan Rd.(N),Changsha,Hunan,China
Nanjing Zelang Medical Technology Co. Ltd
Contact:86-25-83063290/13770714480
Address:Ganjiabian 108# 01 Unit,701-702 room,Yao Hua Street,Qixia District,Nanjing,Jiangsu,China
Contact:+86-0311-84455288-844
Address:Mayu Industrial Park, Jinzhou, Hebei, China.
Shanghai Yuantai Chemical Products Co., Ltd
Contact:021--66129803
Address:Chengyin Road,Shanghai,China
Landz International Company Ltd.
Contact:0086-21-58891610
Address:985 Dongfang Road, Pudong, Shanghai 200122 China
Doi:10.1016/S0040-4020(01)90839-7
(1964)Doi:10.1007/s00044-016-1773-x
(2017)Doi:10.1002/hlca.19570400125
(1957)Doi:10.1039/c8nj03181a
(2018)Doi:10.1016/0040-6031(81)80240-7
(1981)Doi:10.1021/bi00845a017
(1968)