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Reactivities of Quinone Methides Versus O-Quinones in Catecholamine Metabolism and Eumelanin Biosynthesis

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Reactivities of Quinone Methides Versus O-Quinones in Catecholamine Metabolism and Eumelanin Biosynthesis International Journal of Molecular Sciences Review Reactivities of Quinone Methides versus o-Quinones in Catecholamine Metabolism and Eumelanin Biosynthesis Manickam Sugumaran Department of Biology, University of Massachusetts Boston, Boston, MA 02125, USA; [email protected]; Tel.: +1-617-287-6598 Academic Editor: David Arráez-Román Received: 18 August 2016; Accepted: 12 September 2016; Published: 20 September 2016 Abstract: Melanin is an important biopolymeric pigment produced in a vast majority of organisms. Tyrosine and its hydroxylated product, dopa, form the starting material for melanin biosynthesis. Earlier studies by Raper and Mason resulted in the identification of dopachrome and dihydroxyindoles as important intermediates and paved way for the establishment of well-known Raper–Mason pathway for the biogenesis of brown to black eumelanins. Tyrosinase catalyzes the oxidation of tyrosine as well as dopa to dopaquinone. Dopaquinone thus formed, undergoes intramolecular cyclization to form leucochrome, which is further oxidized to dopachrome. Dopachrome is either converted into 5,6-dihydroxyindole by decarboxylative aromatization or isomerized into 5,6-dihydroxyindole-2-carboxylic acid. Oxidative polymerization of these two dihydroxyindoles eventually produces eumelanin pigments via melanochrome. While the role of quinones in the biosynthetic pathway is very well acknowledged, that of isomeric quinone methides, however, remained marginalized. This review article summarizes the key role of quinone methides during the oxidative transformation of a vast array of catecholamine derivatives and brings out the importance of these transient reactive species during the melanogenic process. In addition, possible reactions of quinone methides at various stages of melanogenesis are discussed. Keywords: catecholamine metabolism; quinone methides; quinone isomerization; eumelanin biosynthesis; dihydroxyindole polymers; quinone reactivity 1. Introduction Tyrosine and its hydroxylated product dopa constitute major precursors for cellular catecholamines in practically all organisms. They serve as the starting point for the biosynthesis of crucial hormones, neurotransmitters, alkaloids, coenzymes, and a plethora of pigments. Melanin is an important phenolic pigment formed from the amino acid tyrosine and its derivatives in nature. It is widely distributed in practically all organisms and is extensively used by animals for pigmentation, camouflage, mimicry, UV protection and thermoregulation [1–5]. There are two kinds of melanins biosynthesized in animals. The yellow to red pheomelanin arises by the oxidative polymerization of cysteinyldopa derivatives formed by the condensation of the amino acid, cysteine and dopaquinone (or its derivatives). The brown to black eumelanin is generated by the oxidative polymerization of 5,6-dihydroxyindoles, which in turn arise by intramolecular cyclization and further transformation of dopaquinone [1–5]. The focus of this review is on eumelanin. Raper–Mason pathway for the biosynthesis of eumelanin was established in early 1930s–1940s by the pioneering work of Raper and Mason [6–10]. They studied the enzymatic oxidation of tyrosine and dopa systematically and delineated a pathway for the biosynthesis of eumelanin, which is depicted in Figure1. According to this pathway, tyrosinase converts tyrosine to dopaquinone via dopa. Int. J. Mol. Sci. 2016, 17, 1576; doi:10.3390/ijms17091576 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2016, 17, 1576 2 of 23 Int. J. Mol. Sci. 2016, 17, 1576 2 of 23 However, dopa is not directly formed but indirectly produced by the reduction of dopaquinone to dopa. However, dopa is not directly formed but indirectly produced by the reduction of dopa.dopaquinone Dopaquinone to dopa. exhibits Dopaquinon a rapid nonenzymatice exhibits a intramolecularrapid nonenzymatic cyclization intramolecular producing leucochrome,cyclization whichproducing reduces leucochrome, dopaquinone which to dopa reduces and gets dopaquinone oxidized toto dopachrome dopa and gets (Figure oxidized1). After to dopachrome the formation of(Figure dopaquinone, 1). After most the formation of the reaction of dopaquinone, leading to most melanin of the biosynthesis reaction leading can to occur melanin with biosynthesis out the need forcan any occur enzyme. with Thus,out the the need common for any beliefenzyme. was Thus, that the tyrosinase common is belief the sole was enzyme that tyrosinase responsible is the forsole the productionenzyme responsible of eumelanin for the pigment production in nature. of eumelanin pigment in nature. FigureFigure 1. 1.Raper–Mason Raper–Mason PathwayPathway for for the the biosynthesis biosynthesis ofof eumelanin. eumelanin. Tyrosinase Tyrosinase converts converts tyrosine tyrosine to dopaquinone via dopa However, dopa is not formed directly from tyrosine but indirectly by the to dopaquinone via dopa However, dopa is not formed directly from tyrosine but indirectly by the reduction of dopaquinone. Dopaquinone undergoes intrmolecular cyclization producing reduction of dopaquinone. Dopaquinone undergoes intrmolecular cyclization producing leucochrome leucochrome nonenzymatically, which is further oxidized to dopachrome by dopaquinone. nonenzymatically, which is further oxidized to dopachrome by dopaquinone. Dopachrome is converted Dopachrome is converted to 5,6-dihydroxyindole (DHI) as the major product and to 5,6-dihydroxyindole (DHI) as the major product and 5,6-dihydroxyindole-2-carboxylic acid (DHICA) 5,6-dihydroxyindole-2-carboxylic acid (DHICA) as the minor product. Further oxidation of DHI to as the minor product. Further oxidation of DHI to melanochrome and its eventual polymerization melanochrome and its eventual polymerization leads to melanin pigment. leads to melanin pigment. Dopachrome was initially believed to undergo transformation to produce 5,6-dihydroxyindole (DHI),Dopachrome as the major was initiallyproduct believedwith small to undergoamounts transformationof DHICA. The todihydroxyindoles produce 5,6-dihydroxyindole are further (DHI),oxidized as the to major melanochrome product with and smalleventually amounts produces of DHICA. dark Thecolored dihydroxyindoles melanin polymer. are However, further oxidized this tosimple melanochrome scheme was and modified eventually with produces the discovery dark of colored two new melanin enzymes polymer. associated However, with melanogenic this simple schemepathway. was An modified enzyme with converting the discovery dopachrome of two newto 5,6-dihydroxyindole-2-carboxylic enzymes associated with melanogenic acid (DHICA) pathway. Anwas enzyme first discovered converting in dopachromemammalian systems to 5,6-dihydroxyindole-2-carboxylic [11–16]. Subsequently a sister enzyme acid (DHICA) catalyzing was the first discoveredconversion in of mammalian dopachrome systems to DHI [ 11was–16 characterized]. Subsequently from a insects sister enzyme [17–19]. catalyzingAlthough the the mammalian conversion of dopachromeenzyme was to initially DHI was named characterized as dopachrome from isomerase, insects [17 the–19 current]. Although accepted the mammalianname for this enzymeenzyme is was initiallydopachrome named tautomerase as dopachrome (DCT) isomerase, [13,14]. The the sister current enzyme accepted in insects name forconverts this enzyme dopachrome is dopachrome to DHI and hence should be called dopachrome decarboxylase. However, it also converts dopachrome tautomerase (DCT) [13,14]. The sister enzyme in insects converts dopachrome to DHI and hence methyl ester to DHICA methyl ester thus catalyzing a perfect tautomerization reaction [19]. should be called dopachrome decarboxylase. However, it also converts dopachrome methyl ester to Therefore, this enzyme will be referred to as dopachrome decarboxylase/tautomerase (DCDT). DHICA methyl ester thus catalyzing a perfect tautomerization reaction [19]. Therefore, this enzyme Another enzyme named DHICA oxidase that catalyzed the oxidation of DHICA to its corresponding will be referred to as dopachrome decarboxylase/tautomerase (DCDT). Another enzyme named quinone was discovered in mouse [20,21]. With the help of these enzymes, DHI melanin, DHICA DHICAmelanin oxidase and mixed that catalyzed DHI/DHICA the oxidation eumelanins of DHICAare formed to its in correspondingvarious animal quinone systems. was Thus, discovered melanin in mousebiosynthesis [20,21]. Within animals the help seems of these to occur enzymes, with the DHI he melanin,lp of three DHICA (or more) melanin enzymes and as mixed opposed DHI/DHICA to one. eumelaninsAs shown arein Figure formed 1, inquinone various reactivity animal systems.plays a central Thus, role melanin in eumelanin biosynthesis biosynthesis. in animals However, seems to occurless withknown the and help more of three reactive (or more) quinone enzymes methides, as opposed which toare one. isomers As shown of 4-alkylquinones, in Figure1, quinone also reactivityparticipates plays in a key central conversions role in eumelanin and contributes biosynthesis. to the However,reactivity lessof different known andcatecholamines more reactive quinoneassociated methides, with eumelanogenic which are isomers pathway. of 4-alkylquinones, This review summarizes also participates the importance in key conversions of quinone and contributesmethides during to the reactivitythe oxidative of differenttransformation catecholamines of a variety associated of catecholamines with eumelanogenic related to eumelanin pathway. Thisand review serves summarizes to illustrate
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