An Updated Review of Tyrosinase Inhibitors
TL;DR: This article surveys tyrosinase inhibitors newly discovered from natural and synthetic sources and the inhibitory strength is compared with that of a standard inhibitor, kojic acid, and their inhibitory mechanisms are discussed.
Abstract: Tyrosinase is a multifunctional, glycosylated, and copper-containing oxidase, which catalyzes the first two steps in mammalian melanogenesis and is responsible for enzymatic browning reactions in damaged fruits during post-harvest handling and processing. Neither hyperpigmentation in human skin nor enzymatic browning in fruits are desirable. These phenomena have encouraged researchers to seek new potent tyrosinase inhibitors for use in foods and cosmetics. This article surveys tyrosinase inhibitors newly discovered from natural and synthetic sources. The inhibitory strength is compared with that of a standard inhibitor, kojic acid, and their inhibitory mechanisms are discussed.
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TL;DR: The sequencing and assembly of the oyster genome using short reads and a fosmid-pooling strategy and transcriptomes of development and stress response and the proteome of the shell are reported, showing that shell formation in molluscs is more complex than currently understood and involves extensive participation of cells and their exosomes.
Abstract: The Pacific oyster Crassostrea gigas belongs to one of the most species-rich but genomically poorly explored phyla, the Mollusca. Here we report the sequencing and assembly of the oyster genome using short reads and a fosmid-pooling strategy, along with transcriptomes of development and stress response and the proteome of the shell. The oyster genome is highly polymorphic and rich in repetitive sequences, with some transposable elements still actively shaping variation. Transcriptome studies reveal an extensive set of genes responding to environmental stress. The expansion of genes coding for heat shock protein 70 and inhibitors of apoptosis is probably central to the oyster's adaptation to sessile life in the highly stressful intertidal zone. Our analyses also show that shell formation in molluscs is more complex than currently understood and involves extensive participation of cells and their exosomes. The oyster genome sequence fills a void in our understanding of the Lophotrochozoa.
1,806 citations
TL;DR: This review presents in depth discussions of all these classes of Cu enzymes and the correlations within and among these classes, as well as the present understanding of the enzymology, kinetics, geometric structures, electronic structures and the reaction mechanisms these have elucidated.
Abstract: Based on its generally accessible I/II redox couple and bioavailability, copper plays a wide variety of roles in nature that mostly involve electron transfer (ET), O2 binding, activation and reduction, NO2− and N2O reduction and substrate activation. Copper sites that perform ET are the mononuclear blue Cu site that has a highly covalent CuII-S(Cys) bond and the binuclear CuA site that has a Cu2S(Cys)2 core with a Cu-Cu bond that keeps the site delocalized (Cu(1.5)2) in its oxidized state. In contrast to inorganic Cu complexes, these metalloprotein sites transfer electrons rapidly often over long distances, as has been previously reviewed.1–4 Blue Cu and CuA sites will only be considered here in their relation to intramolecular ET in multi-center enzymes. The focus of this review is on the Cu enzymes (Figure 1). Many are involved in O2 activation and reduction, which has mostly been thought to involve at least two electrons to overcome spin forbiddenness and the low potential of the one electron reduction to superoxide (Figure 2).5,6 Since the Cu(III) redox state has not been observed in biology, this requires either more than one Cu center or one copper and an additional redox active organic cofactor. The latter is formed in a biogenesis reaction of a residue (Tyr) that is also Cu catalyzed in the first turnover of the protein. Recently, however, there have been a number of enzymes suggested to utilize one Cu to activate O2 by 1e− reduction to form a Cu(II)-O2•− intermediate (an innersphere redox process) and it is important to understand the active site requirements to drive this reaction. The oxidases that catalyze the 4e−reduction of O2 to H2O are unique in that they effectively perform this reaction in one step indicating that the free energy barrier for the second two-electron reduction of the peroxide product of the first two-electron step is very low. In nature this requires either a trinuclear Cu cluster (in the multicopper oxidases) or a Cu/Tyr/Heme Fe cluster (in the cytochrome oxidases). The former accomplishes this with almost no overpotential maximizing its ability to oxidize substrates and its utility in biofuel cells, while the latter class of enzymes uses the excess energy to pump protons for ATP synthesis. In bacterial denitrification, a mononuclear Cu center catalyzes the 1e- reduction of nitrite to NO while a unique µ4S2−Cu4 cluster catalyzes the reduction of N2O to N2 and H2O, a 2e− process yet requiring 4Cu’s. Finally there are now several classes of enzymes that utilize an oxidized Cu(II) center to activate a covalently bound substrate to react with O2.
Figure 1
Copper active sites in biology.
Figure 2
Latimer Diagram for Oxygen Reduction at pH = 7.0 Adapted from References 5 and 6.
This review presents in depth discussions of all these classes of Cu enzymes and the correlations within and among these classes. For each class we review our present understanding of the enzymology, kinetics, geometric structures, electronic structures and the reaction mechanisms these have elucidated. While the emphasis here is on the enzymology, model studies have significantly contributed to our understanding of O2 activation by a number of Cu enzymes and are included in appropriate subsections of this review. In general we will consider how the covalency of a Cu(II)–substrate bond can activate the substrate for its spin forbidden reaction with O2, how in binuclear Cu enzymes the exchange coupling between Cu’s overcomes the spin forbiddenness of O2 binding and controls electron transfer to O2 to direct catalysis either to perform two e− electrophilic aromatic substitution or 1e− H-atom abstraction, the type of oxygen intermediate that is required for H-atom abstraction from the strong C-H bond of methane (104 kcal/mol) and how the trinuclear Cu cluster and the Cu/Tyr/Heme Fe cluster achieve their very low barriers for the reductive cleavage of the O-O bond.
Much of the insight available into these mechanisms in Cu biochemistry has come from the application of a wide range of spectroscopies and the correlation of spectroscopic results to electronic structure calculations. Thus we start with a tutorial on the different spectroscopic methods utilized to study mononuclear and multinuclear Cu enzymes and their correlations to different levels of electronic structure calculations.
1,181 citations
TL;DR: The first structure of the full fungal tyrosinase complex from the mushroom Agaricus bisporus is presented, explaining how calcium ions stabilize the tetrameric state of the enzyme.
Abstract: Tyrosinase catalyzes the conversion of phenolic compounds into their quinone derivatives, which are precursors for the formation of melanin, a ubiquitous pigment in living organisms. Because of its importance for browning reactions in the food industry, the tyrosinase from the mushroom Agaricus bisporus has been investigated in depth. In previous studies the tyrosinase enzyme complex was shown to be a H(2)L(2) tetramer, but no clues were obtained of the identities of the subunits, their mode of association, and the 3D structure of the complex. Here we unravel this tetramer at the molecular level. Its 2.3 A resolution crystal structure is the first structure of the full fungal tyrosinase complex. The complex comprises two H subunits of ∼392 residues and two L subunits of ∼150 residues. The H subunit originates from the ppo3 gene and has a fold similar to other tyrosinases, but it is ∼100 residues larger. The L subunit appeared to be the product of orf239342 and has a lectin-like fold. The H subunit contains a binuclear copper-binding site in the deoxy-state, in which three histidine residues coordinate each copper ion. The side chains of these histidines have their orientation fixed by hydrogen bonds or, in the case of His85, by a thioether bridge with the side chain of Cys83. The specific tyrosinase inhibitor tropolone forms a pre-Michaelis complex with the enzyme. It binds near the binuclear copper site without directly coordinating the copper ions. The function of the ORF239342 subunits is not known. Carbohydrate binding sites identified in other lectins are not conserved in ORF239342, and the subunits are over 25 A away from the active site, making a role in activity unlikely. The structures explain how calcium ions stabilize the tetrameric state of the enzyme.
612 citations
TL;DR: This review has focused on the tyrosinase inhibitors discovered from all sources and biochemically characterised in the last four decades.
Abstract: Tyrosinase is a multi-copper enzyme which is widely distributed in different organisms and plays an important role in the melanogenesis and enzymatic browning. Therefore, its inhibitors can be attractive in cosmetics and medicinal industries as depigmentation agents and also in food and agriculture industries as antibrowning compounds. For this purpose, many natural, semi-synthetic and synthetic inhibitors have been developed by different screening methods to date. This review has focused on the tyrosinase inhibitors discovered from all sources and biochemically characterised in the last four decades.
546 citations
TL;DR: A review of tyrosinase inhibitors of natural and synthetic origins can be found in this paper, where the information offered here should help food industry in developing and using potential tyrosinsase inhibitors desirable efficacy and safety, and for improving food quality.
Abstract: Tyrosinase (EC 1.14.18.1), a copper-containing enzyme, can cause enzymatic browning in raw fruits, vegetables, and beverages. Browning is an undesirable reaction that is responsible for less attractive appearance and loss in nutritional quality. These phenomena have encouraged researchers to seek new potent tyrosinase inhibitors for use in the food industry. This article reviews recent studies on tyrosinase inhibitors of natural and synthetic origins. The information offered here should help food industry in developing and using potential tyrosinase inhibitors desirable efficacy and safety, and for improving food quality.
256 citations
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TL;DR: Some of the recent advances in flavonoid research are reviewed and the role of anthocyanins and flavones in providing stable blue flower colours in the angiosperms is outlined.
3,465 citations
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TL;DR: This article overviews the various inhibitors obtained from natural and synthetic sources with their industrial importance, and examines the role of tyrosinase in melanin biosynthesis and its role in dermatological disorders.
Abstract: Tyrosinase is known to be a key enzyme in melanin biosynthesis, involved in determining the color of mammalian skin and hair. Various dermatological disorders, such as melasma, age spots and sites of actinic damage, arise from the accumulation of an excessive level of epidermal pigmentation. In addition, unfavorable enzymatic browning of plant-derived foods by tyrosinase causes a decrease in nutritional quality and economic loss of food products. The inadequacy of current conventional techniques to prevent tyrosinase action encourages us to seek new potent tyrosinase inhibitors. This article overviews the various inhibitors obtained from natural and synthetic sources with their industrial importance.
913 citations
"An Updated Review of Tyrosinase Inh..." refers background in this paper
...Some tyrosinase inhibitors have been discovered and reviewed before [7-9]; this article surveys tyrosinase inhibitors newly discovered from natural and synthetic sources....
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TL;DR: This review describes the different approaches to obtain depigmentation, suggests a classification of whitening molecules on the basis of the mechanism by which they interfere with melanogenesis, and confirms the necessity to apply standardized protocols to evaluate depigmenting treatments.
Abstract: Many modalities of treatment for acquired skin hyperpigmentation are available including chemical agents or physical therapies, but none are completely satisfactory. Depigmenting compounds should act selectively on hyperactivated melanocytes, without short- or long-term side-effects, and induce a permanent removal of undesired pigment. Since 1961 hydroquinone, a tyrosinase inhibitor, has been introduced and its therapeutic efficacy demonstrated, and other whitening agents specifically acting on tyrosinase by different mechanisms have been proposed. Compounds with depigmenting activity are now numerous and the classification of molecules, based on their mechanism of action, has become difficult. Systematic studies to assess both the efficacy and the safety of such molecules are necessary. Moreover, the evidence that bleaching compounds are fairly ineffective on dermal accumulation of melanin has prompted investigations on the effectiveness of physical therapies, such as lasers. This review which describes the different approaches to obtain depigmentation, suggests a classification of whitening molecules on the basis of the mechanism by which they interfere with melanogenesis, and confirms the necessity to apply standardized protocols to evaluate depigmenting treatments.
734 citations
"An Updated Review of Tyrosinase Inh..." refers background in this paper
...Accordingly, a huge number of depigmenting agents or whitening agents developed by those alternative approaches have been successfully identified and deeply reviewed in many articles [10-16]....
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TL;DR: A study on the importance of tyrosinase, especially that derived from mushroom, and describes its biochemical character and inhibition and activation by the various chemicals obtained from natural and synthetic origins with its clinical and industrial importance in the recent prospects.
Abstract: Tyrosinase, also known as polyphenol oxidase, is a copper-containing enzyme, which is widely distributed in microorganisms, animals, and plants. Nowadays mushroom tyrosinase has become popular because it is readily available and useful in a number of applications. This work presents a study on the importance of tyrosinase, especially that derived from mushroom, and describes its biochemical character and inhibition and activation by the various chemicals obtained from natural and synthetic origins with its clinical and industrial importance in the recent prospects.
729 citations
"An Updated Review of Tyrosinase Inh..." refers background in this paper
...A number of research papers and reviews have already been published on the structural and kinetic aspects of the enzyme tyrosinase [17-22]; therefore, under this section I will briefly discuss tyrosinase’s biochemical characteristics and reaction mechanism....
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