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Chemical Reactivities of Ortho-Quinones Produced in Living Organisms: Fate of Quinonoid Products Formed by Tyrosinase and Phenol

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Chemical Reactivities of Ortho-Quinones Produced in Living Organisms: Fate of Quinonoid Products Formed by Tyrosinase and Phenol International Journal of Molecular Sciences Review Chemical Reactivities of ortho-Quinones Produced in Living Organisms: Fate of Quinonoid Products Formed by Tyrosinase and Phenoloxidase Action on Phenols and Catechols Shosuke Ito 1,* , Manickam Sugumaran 2 and Kazumasa Wakamatsu 1,* 1 Department of Chemistry, Fujita Health University School of Medical Sciences, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi 470-1192, Japan 2 Department of Biology, University of Massachusetts, Boston, MA 02125, USA; [email protected] * Correspondence: [email protected] (S.I.); [email protected] (K.W.); Tel.: +81-562-93-9849 (S.I. & K.W.); Fax: +81-562-93-4595 (S.I. & K.W.) Received: 30 July 2020; Accepted: 20 August 2020; Published: 24 August 2020 Abstract: Tyrosinase catalyzes the oxidation of phenols and catechols (o-diphenols) to o-quinones. The reactivities of o-quinones thus generated are responsible for oxidative browning of plant products, sclerotization of insect cuticle, defense reaction in arthropods, tunichrome biochemistry in tunicates, production of mussel glue, and most importantly melanin biosynthesis in all organisms. These reactions also form a set of major reactions that are of nonenzymatic origin in nature. In this review, we summarized the chemical fates of o-quinones. Many of the reactions of o-quinones proceed extremely fast with a half-life of less than a second. As a result, the corresponding quinone production can only be detected through rapid scanning spectrophotometry. Michael-1,6-addition with thiols, intramolecular cyclization reaction with side chain amino groups, and the redox regeneration to original catechol represent some of the fast reactions exhibited by o-quinones, while, nucleophilic addition of carboxyl group, alcoholic group, and water are mostly slow reactions. A variety of catecholamines also exhibit side chain desaturation through tautomeric quinone methide formation. Therefore, quinone methide tautomers also play a pivotal role in the fate of numerous o-quinones. Armed with such wide and dangerous reactivity, o-quinones are capable of modifying the structure of important cellular components especially proteins and DNA and causing severe cytotoxicity and carcinogenic effects. The reactivities of different o-quinones involved in these processes along with special emphasis on mechanism of melanogenesis are discussed. Keywords: o-quinones; quinone methides; phenols; catechols; tyrosinase; thiols; amines; dopaquinone; sclerotization; melanization 1. Introduction ortho-Quinones are ubiquitous in nature. Plants especially produce a wide variety of o-quinones as secondary metabolites. It is not possible to cover all naturally occurring quinones and their reactions in a short review. Therefore, only quinones arising from catecholamine derivatives and few other related molecules will be considered in this review. Unlike the related p-quinones that are reasonably stable towards isolation and characterization, several of the o-quinones are extremely reactive and difficult to isolate. Often, they are present in the transient form in a reaction thus even avoiding detection. A most important and prominent example of the o-quinones is dopaquinone that plays pivotal roles in melanogenesis, the process of production of eumelanin and pheomelanin [1]. Due to its Int. J. Mol. Sci. 2020, 21, 6080; doi:10.3390/ijms21176080 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 2 of 35 Int. J. Mol. Sci. 2020, 21, 6080 2 of 36 plays pivotal roles in melanogenesis, the process of production of eumelanin and pheomelanin [1]. Due to its inherent high reactivity dopaquinone can easily undergo both Michael 1,6- and 1,4- additionsinherent highwith reactivity nucleophiles dopaquinone such as thiols can easily and amines. undergo These both Michaelreactions 1,6- lead and to 1,4-additionsthe production with of melaninnucleophiles pigment such found as thiols in andthe amines.skin, hair, These and reactions eyes of leadall animals. to the production The reactivity of melanin of the pigment related dopaminequinonefound in the skin, hair, produces and eyes neuromelanin of all animals. in the The brain reactivity [2,3]. of Protein the related dopaquinones dopaminequinone formed in produces mussel proteinsneuromelanin are responsible in the brain for [2 ,3gluing]. Protein of mussels dopaquinones to rocks formed and other in mussel hard proteins surfaces are [4]. responsible The defense for reactiongluing of exhibited mussels toby rocks tunichromes and other found hard surfacesin the blood [4]. The of defensetunicates reaction are due exhibited to the reactivities by tunichromes of o- quinonesfound in the[5]. bloodIn insects, of tunicates catecholamine are due derivates to the reactivities such as N of-acetyldopamineo-quinones [5]. and In insects, N-β-alanyldopamine catecholamine formderivates key components such as N-acetyldopamine of hardened exoskeleton and N-β -alanyldopaminethat protects the soft form bodied key componentsanimals [6]. In of plants hardened and fungi,exoskeleton oxidative that browning protects the reactions soft bodied that animalsare part [of6]. their In plants defense and mechanism fungi, oxidative against browning invading reactions insects, isthat caused are part by the of theirreactivities defense of mechanismenzymatically against generated invading o-quinones. insects, While is caused some by of the the reactivities reactions are of beneficialenzymatically to the generated organisms,o-quinones. several While of the some reactions of the reactions of o-quinones are beneficial especially to the binding organisms, to macromoleculesseveral of the reactions such as of proteinso-quinones and especially DNA through binding the to sulfhydryl macromolecules and/or such amino as proteinsgroups, andresults DNA in deterioratingthrough the sulfhydryl biological and consequences/or amino groups, such resultsas cytotoxicity in deteriorating and carcinogenesis. biological consequences Therefore, such it asis importantcytotoxicity to and understand carcinogenesis. the biological Therefore, activities it is important of these to transient understand compounds. the biological o-Quinones activities are of mostlythese transient produced compounds. in biologicalo-Quinones systems by are th mostlye oxidation produced of the in corresponding biological systems catechols by the (o oxidation-diphenols) of bythe two corresponding electron removal. catechols However, (o-diphenols) tyrosinase by two and electron related removal. phenoloxidases However, tyrosinasepresent in andmammals, related plants,phenoloxidases fungi, and present insects in are mammals, capable plants,of oxidizing fungi, andsimple insects phenols are capable to the corresponding of oxidizing simple quinones phenols [7] (Figureto the corresponding 1). This review quinones summarizes [7] (Figure briefly1). the This function review summarizes of tyrosinase briefly and the the chemical function ofreactivity tyrosinase of oand-quinones the chemical with various reactivity nucleophiles of o-quinones. Special with emphasis various is nucleophiles. given to the mechanisms Special emphasis of melanogenesis. is given to Atthe this mechanisms point, we want of melanogenesis. to point out that At practically this point, weall biological want to point reactions out that are practicallyenzyme-catalyzed, all biological with thereactions exception are enzyme-catalyzed, of ribozymes, which with theare exceptionRNA catalysts. of ribozymes, Without which enzymatic are RNA intervention, catalysts. Without some reactionsenzymatic can intervention, proceed, but some for reactions them to canbe useful proceed, for butthe forbiological them to system, be useful enzymatic for the biological intervention system, is absolutelyenzymatic interventionnecessary. An is example absolutely is necessary.hydration Anof carbon example dioxide is hydration to carbonic of carbon acid which dioxide can to carbonicproceed quiteacid whichrapidly can without proceed the quiteneed rapidlyfor an enzyme, without but the in need biological for an systems, enzyme, ca butrbonic in biological anhydrase systems, makes thiscarbonic hydration anhydrase go faster. makes However, this hydration a very go small faster. set However, of reactions, a very form small a group set of of reactions, nonenzymatic form a reactionsgroup of that nonenzymatic often occur reactions in biological that systems. often occur Glycation in biological of hemoglobin systems. is Glycationone such example. of hemoglobin While itis is one a useful such example. index to Whiledetermine it is athe useful seriousness index to of determine diabetic conditions, the seriousness the glycation of diabetic is conditions,entirely of nonenzymaticthe glycation is origin. entirely In of nonenzymaticthe case of o-quinone origin. In chemistry, the case of oonce-quinone these chemistry, reactive onceintermediates these reactive are generatedintermediates by enzyme are generated assisted by reactions, enzyme assistedthe rest of reactions, the reactions the rest seem of theto proceed reactions nonenzymatically seem to proceed withoutnonenzymatically the need for without any enzymatic the need assistance. for any enzymatic These nonenzymatic assistance. These reactions nonenzymatic are absolutely reactions essential are forabsolutely parts of essential melanin for biosynthesis, parts of melanin insect biosynthesis, cuticular sclerotization, insect cuticular innate sclerotization, immunity innate in invertebrate immunity animalsin
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