Abstract
ortho-Quinones are produced in vivo through the oxidation of catecholic substrates by enzymes such as tyrosinase or by transition metal ions. Neuromelanin, a dark pigment present in the substantia nigra and locus coeruleus of the brain, is produced from dopamine (DA) and norepinephrine (NE) via an interaction with cysteine, but it also incorporates their alcoholic and acidic metabolites. In this study we examined the metabolic fate of ortho-quinones derived from the catecholamine metabolites, 3,4-dihydroxyphenylethanol (DOPE), 3,4-dihydroxyphenylethylene glycol (DOPEG), 3,4-dihydroxyphenylacetic acid (DOPAC) and 3,4-dihydroxyphenylmandelic acid (DOMA). The oxidation of catecholic substrates by mushroom tyrosinase was followed by UV-visible spectrophotometry. HPLC analysis after reduction with NaBH4 or ascorbic acid enabled measurement of the half-lives of ortho-quinones and the identification of their reaction products. Spectrophotometric examination showed that the ortho-quinones initially formed underwent extensive degradation at pH 6.8. HPLC analysis showed that DOPE-quinone and DOPEG-quinone degraded with half-lives of 15 and 30 min at pH 6.8, respectively, and >100 min at pH 5.3. The major product from DOPE-quinone was DOPEG which was produced through the addition of a water molecule to the quinone methide intermediate. DOPEG-quinone yielded a ketone, 2-oxo-DOPE, through the quinone methide intermediate. DOPAC-quinone and DOMA-quinone degraded immediately with decarboxylation of the ortho-quinone intermediates to form 3,4-dihydroxybenzylalcohol (DHBAlc) and 3,4-dihydroxybenzaldehyde (DHBAld), respectively. DHBAlc-quinone was converted to DHBAld with a half-life of 9 min, while DHBAld-quinone degraded rapidly with a half-life of 3 min. This study confirmed the fact that ortho-quinones from DOPE, DOPEG, DOPAC and DOMA are converted to quinone methide tautomers as common intermediates, through proton rearrangement or decarboxylation. The unstable quinone methides afford stable alcoholic or carbonyl products.
Highlights
Neuromelanin is a complex polymeric compound present in the human central nervous system which is synthesized mainly in dopaminergic neurons of the substantia nigra and in noradrenergic neurons of the locus coeruleus [1,2]
STphecetrUoVph-ovtiosmibelteriscpEexcatrmoipnhaotitoonms etric examinations were performed at a 100 μM concentration of the four catecholamine metabolites in 50 mM sodium phosphate buffer, pH 6.8 or 5.3, at 37 °C
We identified the ketone metabolite of dihydroxyphenylethylene glycol (DOPEG) (2), 2-oxo-DOPE (5), in the oxidation mixture when the oxidation was stopped by ascorbic acid
Summary
Neuromelanin is a complex polymeric compound present in the human central nervous system which is synthesized mainly in dopaminergic neurons of the substantia nigra and in noradrenergic neurons of the locus coeruleus [1,2]. The substantia nigra and locus coeruleus are the areas in the brain with the highest concentration of neuromelanin pigment [6]. Our degradative aapppprrooaacchh ssuuggggeesstteedd tthhaatt tthhee ppiiggmmeenntteedd ppaarrtt ooff ssuubbssttaannttiiaa nniiggrraa nneeuurroommeellaanniinn iiss ddeerriivveedd ffrroomm ddooppaammiinnee ((DDAA)) aannddccyyssteteinineeininaammoloalrarrartaiotioofo2f:12:[17,[87],.8I]n. AIdndaidtidonit,ioitnw, iatswreacsenretclyenstulyggseusgtegdesttheadt tvhaartiovuasricoautescchaotelicchmoleictamboeltiatebsoalirteesinacroeripnocorartpeodraintetod ninetuoronmeuerloamninelafrnoimn ftrhoemsuthbsetasnutbisatannigtiraanaingdraloacnuds lcooceurus lceouesr,ulienucsl,uidncinlugd3in,4g-d3,i4h-yddihroyxdyropxhyepnhyelanlyalnailnanein(De O(DPOAP)A, 3),,43-,4d-idhiyhdyrdorxoyxpyhpehnenylyeltehthananool l((DDOOPPEE,, 11)),, 33,,44--ddiihhyyddrrooxxyypphheennyylleetthhyylleennee ggllyyccooll ((DDOOPPEEGG,, 22)),, 33,,44--ddiihhyyddrrooxxyypphheennyyllaacceettiicc aacciidd ((DDOOPPAACC,, 33)) aanndd 33,,44--ddiihhyyddrrooxxyymmaannddeelliiccacaidci(dDO(MDOAM, 4A),,wh4i)c, h warheimchetaabroelitemseotfadboopliatems inoef(DdAo)paanmdinnoerep(DinAe)phrainnde (nNoEre)pfionrempehdribnye t(hNeEo)xifdoramtiveeddbeyamthineaotixoindabtyivme odneoaammininaetiooxnidbaysemfoolnloowamedinbeyorxeidduacsteiofno/llooxwideadtiobny (rFeidguucrteio1n)/[o9x–i1d1a]t.ion (Figure 1) [9,10,11]. IInn tthhiiss ssttuuddyy, ,wweecocmompapraerdedthtehreearcetaicvtiitvieitsieosf tohfotsheoosrethoor-tqhuo-iqnuonineosnreesgarredgianrgditnhgeirthheailrf-hliavlef-sliavneds danedgrdadegartiaodnatpiorondpurcotsd.uocrttsh. oo-rQthuoi-nQouniensoanrees parroedpurcoeddubcyedoxbiydaotxioidnatwioitnhwmituhshmrouosmhrotyormostiynraossei.nTashee. fTahteesfaotfeosrtohfoo-qrtuhion-oqnueinsowneersewexearme einxeadmbinyetdwboymtwetohomdest[h1o5d,1s6[]1: 5U,1V6-]v:iUsiVbl-evsispiebcletrosppehcottroomphetortyomtoedtreytetcot odrettheoc-tquorinthoon-qesuiwnoitnheasnwaibtshorapntioanbsmorapxtiimonummaaxroimunudm40a0ronumndan4d00HPnLmC atnodfoHlloPwLCthetodefoglrlaodwatitohne odfegorrathdoa-tqiouninoofnoersthaon-qdutihneonaepspaenadratnhceeaopfpperaordanuccetsoaf fpterrodreudctuscatifotenr troedthuecticoonrrteospthoendcoinrrgescpaotencdhionlgs bcayteNchaoBlHs 4boyr aNsacBorHb4icoarcidas.coTrhbeicreascuildts. sTuhgegersetsuthltast osrutghgo-eqsut inthoante oprrtohdo-uqcutisnfornoempcraotdecuhcotslamfroinme mcaetetachboollaitmesinmeamyentaobt obleiteins cmorapyonraottedbeinintoconrepuorroamtedelainntion,nbeuutroemxeerltannienu,rboutotxeixcietryt anseusurocthoxbieccitayuases osurtchho-bqeucianuosneesoratrheo-hqiughinlyonreesacatriveehciogmhlpyoruenacdtsivtehactolmeapdotuoncdystothtoaxtilceitaydtthorocuygtohtothxeiciritybinthdrionuggtho tthheioirl ebninzdyimngestoanthdiothleenpzroydmuecstiaonndotfhreeapcrtoivdeucotxioyngeonf srpeaecctiievse[1o7x–y1g9e]n. species [17,18,19]
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