A perspective on the biotechnological applications of the versatile tyrosinase

Bioresource Technology 289 (2019) 121730

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Review

A perspective on the biotechnological applications of the versatile tyrosinase a

a

b

Kyoungseon Min , Gwon Woo Park , Young Je Yoo , Jin-Suk Lee a b

a,⁎

T

Bio/Energy R&D Center, Korea Institute of Energy Research (KIER), Gwangju 61003, Republic of Korea School of Chemical and Biological Engineering, Seoul National University, Seoul 08826, Republic of Korea

A R T I C LE I N FO

A B S T R A C T

Keywords: Tyrosinase Versatility Industrial application

Tyrosinase (E.C. 1.14.18. 1) is a type of Cu-containing oxidoreductase which has bifunctional activity for various phenolic substrates: ortho-hydroxylation of monophenols to diphenols (a cresolase activity) and oxidation of diphenols to quinones (a catecholase activity). Based on the broad substrate spectrum, tyrosinase has been used in bioremediation of phenolic pollutants, constructing biosensors for identifying phenolic compounds, and LDOPA synthesis. Furthermore, not only tyrosinase has been used to produce useful polyphenol derivatives, but also it is recently revealed that the promiscuous activity of tyrosinase is closely related with delignification in the biorefinery. Accordingly, tyrosinase might be a potential biocatalyst for industrial applications (e.g., electroenzymatic L-DOPA production, but its long-term stability and reusability should be further explored. In this review, we emphasize the versatility of tyrosinase, which includes conventional applications, and suggest new perspectives as an industrial biocatalyst (e.g., electroenzymatic L-DOPA production). Especially, this review focuses on and comprehensively discusses recent innovative studies.

1. Introduction

by a cresolase activity and sequential oxidation of diphenols to quinones by a catecholase activity with concomitant reduction of molecular oxygen (O2) to water (Faccio et al., 2012). In addition, tyrosinase is widely distributed in nature including in fungi, plants, bacteria, and animals and also has a broad substrate spectrum for diverse phenolic compounds (e.g., L-tyrosine, L-DOPA, catechol, caffeic acid, tyramine, phenol, p-aminophenol, cresol, p-cresol, dopamine, 4-hydroxyanisole, L-isoproterenol, 4-ethoxyphenpl, 4-butylcatechol, and pyrogallol) (Espín et al., 2000). Because of its bifunctionality and broad substrate spectrum, tyrosinase can be versatile in various fields. For example, tyrosinase has been studied for bioremediation of phenolic contaminants (Durán and Esposito, 2000), construction of biosensors for use in medical diagnoses (Min and Yoo, 2009) and detection of aromatic compounds in food (da Silva et al., 2019). Furthermore, tyrosinase has been used in medical applications for producing L-3,4-dihyroxyphenyl alanine (L-DOPA), which is a common drug for Parkinson’s disease (Min et al., 2010), and synthesizing functional biocompounds (Lee et al., 2019). In accordance with recent research, the catalytic promiscuity of tyrosinase is able to function on the phenolic moiety of lignin, and making it capable of delignification, which implies that the application of tyrosinase could be used in the biorefinery. Herein, we aim to review the versatility of tyrosinase including both conventional applications (e.g. the bioremediation of phenolic

An enzyme is a biocatalyst that catalyzes chemical reactions in living systems and usually functions under mild operational conditions (e.g., ambient temperature and atmospheric pressure). High specificity enables an enzyme to be dominant over a chemical catalyst in organic chemistry (Lee et al., 2018), pharmaceuticals (Min et al., 2010), and biorefineries (Mishra et al., 2017). For example, biorefineries utilizing biomasses as sustainable feedstocks have recently emerged due to recent concerns about the depletion of fossil fuels and climate change. Cellulase, which is a type of hydrolase that breaks down cellulose to low molecular weight saccharides, has been commercially used for obtaining fermentable sugars from a biomass in the field of biorefineries (Hasunuma et al., 2013). Additionally, oxidoreductases such as hemecontaining peroxidases (e.g., lignin peroxidase), flavin-containing dehydrogenases (e.g., glucose dehydrogenase), and copper-containing oxidoreductases (e.g., laccase and tyrosinase) might contribute to shift the paradigm from petroleum-based to enzyme-based industries in the production of polymer building blocks and value-added materials (Martínez et al., 2017). Among enzymes with high potential for industrial applications, tyrosinase (E.C. 1.14.18.1) is of our interest. Tyrosinase is a member of the type III copper-containing oxidoreductases and has the following bifunctional activity: ortho-hydroxylation of monophenols to diphenols

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Corresponding author. E-mail address: [email protected] (J.-S. Lee).

https://doi.org/10.1016/j.biortech.2019.121730 Received 27 May 2019; Received in revised form 26 June 2019; Accepted 28 June 2019 Available online 29 June 2019 0960-8524/ © 2019 Published by Elsevier Ltd.

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in the insect cells Trichoplusia ni. They achieved a yield of ∼1.6 mg of HmTyr from a 10 g larval biomass (Dolinska et al., 2014). In addition, Fogal et al. (2015) expressed HmTyr in insect cells (i.e., Spodoptera frugiperda ovary cells [Sf9]). The expression system was optimized as follows: Sf9 cell density was 2 × 106 cell mL−1, infected by 1 multiplicity of infection (MOI, i.e., the number of virus particles per cell) grown at 21 °C with 2 mM copper(II) sulfate (CuSO4), and a culture time of 96 h. Under the optimum conditions, 8 mg of HmTyr were obtained from a 1 L culture. They determined the kinetic constants for diverse substrates (L-tyrosine, L-DOPA, 4-tert-butylcatechol, L-DOPA methyl ester, 4-methyl catechol, dopamine, 3,4-dihydroxyphenylacetic acid, catechol, L-isoproterenol, and 3-[3,5-dihyroxyphenyl]-1-propionic acid) and the inhibition constants for various inhibitors (phenylthiourea, L-mimosine, cinnamic acid, kojic acid, caffeic acid, benzoic acid, and aesculetin) of the recombinant HmTyr (Fogal et al., 2015). Lai et al. (2016) also expressed the recombinant HmTyr and its mutants in insect High five cells on a large-scale, resulting in an expression yield of ∼4–6 mgL−1. The recombinants were purified and concentrated up to ∼10 mg mL−1 for crystallization and characterization to determine the crystal structure of HmTyr (Lai et al., 2016). The results on the HmTyr expression described above might contribute to develop an indispensable paradigm for pharmaceuticals and cosmetics, especially for the discovery of compounds that could treat OCA1. Even though the fungal tyrosinase from Agaricus bisporus (AbTyr) has been the most widely used for a long time, researches on structural information and heterologous expression have only been recently published. Pretzler et al. (2017) recently attempted the heterologous expression of AbTyr in E. coli BL21 (DE3). The initial expression by adding IPTG as an inducer produced quite an amount of inclusion bodies, and thus, they cultured the strain in auto-inducing medium including 500 mM of sodium chloride (NaCl) at 20 °C for 20 h, achieving 140 mg L−1 of soluble latent tyrosinase. In order to activate the latent AbTyr, the recombinant AbTyr was treated with protease K to cleave the C-terminal domain that blocked the active site, and the activated recombinant AbTyr showed a broad substrate spectrum for tyrosol, chlorogenic acid, p-coumaric acid, 4-tert-butylcatechol, octopamine, 4-methylcatechol, resorcinol, hydroquinone, protocatechuic acid, 3,4-dihydroxyphenylacetic acid, pyrogallol, and 3-methoxyphenol. In addition, the crystal structure revealed that both the active center and the surrounding amino acids of the recombinant AbTyr were identical to the tyrosinase isolated from the natural source (Pretzler et al., 2017). Recently, Kampatsikas et al. (2017) heterologously expressed plant tyrosinase from Malus domestica (MdTyr) in E. coli. To avoid insoluble expression, glutathione-S-transferase (GST) was used as a fusion partner as well as expression temperature was retained at 20 °C, resulting in a remarkably higher production yield than other plant tyrosinases, up to 26.5–225 mg L−1. Additionally, activating method for the latent recombinant, characterization including substrate specificity, and homology modeling were performed. Based on the results of the activity assay, sequence alignment and homology modeling, they proposed the concept of an activity controller: the catecholase and cresolase activity can be manipulated by the combination of two amino acids. The proposed activity controller might give an insight for structure-based engineering to control the catalytic activity as well as shift the substrate specificity (Kampatsikas et al., 2017).

contaminants, detection of phenolic compounds, L-DOPA synthesis) and new perspectives related to lignin refinery (e.g., promiscuous activity for lignin decomposition) Especially, the newly discovered promiscuous activity of tyrosinase will contribute to produce catechol-like polyphenols from aromatic compounds that can be obtained from lignin decomposition. 2. Recent progress for producing recombinant tyrosinase Even though tyrosinase has been researched for a long time, commercial tyrosinase has been prepared by extraction from mushroom until now. Many researchers have made great efforts to obtain a highly concentrated recombinant tyrosinase, but there is not enough information available on the recombinant expression of tyrosinase. Nonetheless, the high level production of a recombinant tyrosinase is important for various applications; thus, we reviewed recombinant tyrosinase in terms of the expression protocol, production yield, and physicochemical properties. For example, Selinheimo et al. (2006) identified the tyrosinase gene tyr2 from the filamentous fungus Trichoderma reesei (TrTyr) and homologously overexpressed it under the strong cbh1 promoter. TrTyr was secreted into the culture media with a yield of 1 g L−1 in a batch fermentation and exhibited a broad substrate spectrum for L-tyrosine, L-DOPA, phenol, p-cresol, 4-aminophenol, tyramine, p-coumaric acid, aniline, (−)-epicatechin, (+)-catechin hydrate, pyrocatechol, and pyrogallol (Selinheimo et al., 2006). Duarte et al. (2012) attempted to homologously express tyrosinase from Pycnoporous sanguineus CCT4518 (PsTyr). Intracellular PsTyr expression was optimized by 0.15% Ltyrosine as an inducer in 2% malt extract broth at 30 °C with constant agitation of 150 rpm and the culture was performed for 2 days in the presence of light. The optimum condition for the intracellular PsTyr was determined as pH 6.6 and 45 °C with L-DOPA as the substrate; however, PsTyr was not stable at 45 °C: the half-life was about only 15 min and thus not suitable for further applications (Duarte et al., 2012). Additionally, heterologous expressions of tyrosinase have been studied. Westerholm-Parvinen et al. (2007) expressed TrTyr in Pichia pastoris and acheived a production yield of 24 mg L−1 by optimizing copper concentration and expression conditions. The heterologously expressed TrTyr had not only similar activities with the homologously expressed TrTyr in T. reesei using L-DOPA and L-tyrosine as the substrates, but also the same physicochemical properties such as secondary structure, thermal stability, and chemical denaturation (WesterholmParvinen et al., 2007). In accordance with Halaouli et al. (2006), the tyrosinase-encoding gene from the white-rot fungus Pycnoporus sanguineus BRFM49 (PsTyr) was cloned and overexpressed in Aspergillus niger by controlling the glyceraldehyde-3-phophate-dehydrogenase promoter. The recombinant PsTyr was secreted into the extracellular medium and fully active with a molecular weight of 45 kDa. The extracellular PsTyr exhibited 534 and 1668 U L−1 of cresolase and catecholase activity, respectively, corresponding to a protein yield of 20 mg L−1 (Halaouli et al., 2006). Ren et al. (2013) expressed tyrosinase from Verrucomicrobium spinosum (VsTyr) in E. coli. In a batch culture, 0.76 Um L−1 of the recombinant VsTyr was produced in the late induction phase with 1 mM of IPTG as the inducer at 32 °C. To achieve high cell density by prolonging the exponential growth, a fedbatch culture was performed and then a cell density of 37 g L−1 and a tyrosinase activity of 13 U mL−1 were achieved within 28 h, resulting in 3 g L−1 of active tyrosinase and 103 mg L-1 h−1 of overall volumetric productivity corresponding to 464 mU L-1h−1 (Ren et al., 2013). Because human tyrosinase (Hmtyr) is responsible for the first two steps in melanin biosynthesis, there have been many efforts to express Hmtyr on a large-scale to perform a structure-based study for discovering compounds to treat oculocutaneous albinism (OCA1) which is the most severe form of albinism. For instance, Dolinska et al. (2014) expressed HmTyr and two OCA1-related mutants (R422Q and R422W)

3. Conventional application of tyrosinase based on broad substrate spectrum Tyrosinase is capable of utilizing various phenolic compounds as the substrate. Based on the broad substrate spectrum, tyrosinase has been widely used in both bioremediation of phenolic pollutants and biosensor construction for analyzing phenolic compounds. In this section, we summarize recent progress of tyrosinase-driven conventional applications. 2

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pollutants in industrial waste water from dying process. Laccase (Lonappan et al., 2017) and peroxidase (Sun et al., 2017) are the most widely used enzymes to decolorize dye-containing waste water. Additionally, tyrosinase has been utilized for dye-decolorization, even if some azo dyes inhibit the catecholase activity of tyrosinase (Shiv Kumar Dubey, 2007). According to da Silva et al. (2013), mushroom tyrosinase is capable of decolorizing dyes such as reactive yellow 15 (RY15) and reactive blue 114 (RB114). They optimized decolorizing condition using a response surface methodology, and tyrosinase decolorized over 90% of RY15 and RB 114 at 25 °C and pH 7.0 with aeration (da Silva et al., 2013). Franciscon et al. (2012) isolated Brevibacterium sp. strain VN-15 from an activated sludge of a textile company and then utilized the strain for decolorization and detoxification of azo dyes such as RY107, Reactive Black 5 (RB5), Reactive Red 198 (RR198), and Direct Blue 71 (DB71), resulting in over 99% decolorization. During the process, tyrosinase activity was observed, whereas laccase and peroxidase activities were not detected at all, thereby suggesting the major role of tyrosinase in the decolorization and detoxification of azo dyes (Franciscon et al., 2012).

3.1. Bioremediation of phenolic contaminants and dyes Based on the broad substrate spectrum, tyrosinase has been commonly used to remediate toxic phenolic pollutants in waste water. To detoxify phenolic contaminants, diverse immobilization methods have been developed and thus we, herein, reviewed recent interesting results. For example, Abdollahi et al. (2018) recently developed tyrosinase-immobilized magnetic iron oxide nanoparticles (tyrosinaseMNPs) for detoxifying phenol-containing waste water. They investigated the effect of the catalyst loading, pH, temperature, and initial phenol concentration on the phenol removal efficiency. The tyrosinaseMNPs removed more than 70% of the phenol in synthetic waste water including 2.5 g L-1 of phenol under pH 7.0 and 35 °C. Additionally, the tyrosinase-MNPs retained 100% and 5% of the phenol detoxifying yield after the 3rd and 7th reuse cycle, respectively, resulting in a nanobiocatalyst that could be a potential strategy for phenolic pollutant removal (Abdollahi et al., 2018). Recently diatom silica has emerged as a support material for enzyme immobilization, because not only it is a natural biomaterial that is not toxic to enzymes, its porous structure can provide a large surface area for a higher loading density, but also decrease the mass transfer limitation (Venkatesan et al., 2015). Bayramolgu et al. (2013) utilized diatom biosilica for tyrosinase immobilization via amine functionalization for covalent attachment, thereby achieving a 76.6% immobilization efficiency and a better thermal and storage stability than that of free tyrosinase. Finally, the tyrosinase-biosilica removed 87, 74, and 91% of phenol, p-cresol, and phenyl acetate, respectively (Bayramoglu et al., 2013). Liu et al. (2016) developed a magnetically-separable method for tyrosinase-driven remediation of phenol and bisphenol A in water. Tyrosinase aggregates (Tyr-MNPs-GRO) were prepared by co-immobilization of magnetic nanoparticles (MNPs) and tyrosinase (Tyr) on graphene oxide (GRO). The Tyr-MNPs-GRO efficiently remediated phenol and bisphenol A with a maximum removal efficiency of 98% (0.3 mM of the initial phenol within 39 h) and 74.5% (100 μM of the initial bisphenol A within 2 h), respectively. In addition, the enzyme aggregates maintained over 56% of their initial activity after 5-times reuse for phenol remediation, thereby representing that both easy separation and good reusability enabled the enzyme aggregate to be promising for phenol treatment in waste water (Liu et al., 2016). Xu et al. (2011) designed a practical and inexpensive method for a tyrosinase-driven detoxification of phenolic pollutants in an aqueous phase. Crude tyrosinase solution was cheaply obtained from fresh mushrooms (Xing et al., 2008) and then cross-linked enzyme aggregates (CLEAs) were prepared by precipitation using ammonium sulfate and subsequent cross-linking with glutaraldehyde (Xu et al., 2011). Tyrosinase CLEAs effectively remediated nearly all of the single substrates including phenol (2.5 mM), p-chlorophenol (2.5 mM), p-cresol (2.5 mM), and bisphenol A (21.9 μM) as well as a mixture of substrates that included phenol, p-chlorophenol, and p-cresol. In addition, the tyrosinase CLEAs showed a good reusability, resulting in over 80% of the initial removal rate after 10 times reuse. Interestingly, Xu et al. (2011) verified the detoxifying ability of the tyrosinase CLEAs by growth of Hydra sinensis in phenol-containing synthetic waste water. Given that hydra, a microinvertebrate commonly found in fresh water, not only has a remarkable regenerative capacity but also is highly sensitive to toxic chemicals, it has been widely used as a toxicity test (Beach & Pascoe, 1998). Because hydras show a severe morphological change under harmful environment, the toxicity of phenolic pollutants can be evaluated by observing their morphology. The hydras exhibited a severely damaged morphology after 1 h-exposure to a phenolic mixture, whereas their morphology remained intact in the tyrosinase CLEAs-treated phenolic mixutre, resulting in the successful detoxification of phenolic contaminants. Azo and anthraquinone dyes are widely used synthetic dyes in the textile, pharmaceutical, food, and cosmetic industries and major

3.2. Biosensors for detecting phenolic compounds Constructing biosensors is one of the conventional applications of tyrosinase to monitor and detect phenolic compounds in various samples. In order to improve performance such as the detection limit and sensitivity, diverse materials have been integrated with tyrosinase. Especially, recent progress in nanotechnology has accelerated the fabrication of nanomaterial-based electrodes. Table 1 summarizes the performances of recently reported tyrosinase-based biosensors. Tyrosinase-based biosensors usually analyze phenolic pollutants such as bisphenol A in water (Reza et al., 2015), detect aromatic ingredients in foods and beverages, for example, tyrosol in beer and catechin in tea (Cerrato-Alvarez et al., 2019), and are used in pharmaceutical analysis for diagnosis (Min and Yoo, 2009). In this section, we focused on recently reported atypical analytes that can be detected by tyrosinasebased biosensors. Fang et al. (2016) aimed to detect pest and pathogen infection in crops and thus constructed a bi-enzyme amperometric sensor for detecting methyl salicylate which is the most significant volatile organic compound released from plants during biotic stress (e.g., fungal pathogen infection). In order to improve the sensitivity, salicylate hydroxylase and tyrosinase were co-utilized to build an enzyme cascade reaction: Salicylate hydroxylase reacts with salicylate from methyl salicylate via hydrolysis and generates catechol as an intermediate. Then, catechol is further oxidized by tyrosinase to be converted to 1,2benzoquinone which can be electrochemically reduced to catechol again. Thus, salicylate can be amperometically detected through measuring the reduction current of 1,2-benzoquinone, resulting in a sensitivity, detection limit and quantification limit of 30.6 μA cm−2 μM−1, 13 nM, and 39 nM, respectively, without critical interference from other plant volatile compounds (Fang et al., 2016). Given that tyrosinase is capable of oxidizing diverse aromatic amines and o-aminophenol, Román et al. (2016) recently reported a tyrosinase-based amperometric sensor for detecting and quantifying sulfamethoxazole (SMX) which is the most commonly used drug in the sulfonamide family for preventing bacterial infection. To analyze SMX in situ in water samples, Román et al. (2016) cross-linked tyrosinase to a screen-printed carbon electrode modified with gold nanoparticles. The biosensor exhibited a 22.6 μM detection limit and 20–200 μM linear detection range, which was promising for determination of the SMX levels in various water samples (del Torno-de Román et al., 2016). Bertolino et al. (2011) introduced a competitive reaction into a tyrosinase-based biosensor to indirectly analyze pipemidic acid (PA) which is a synthetic quinolone used as an antibacterial reagent. Because 3

Bioresource Technology 289 (2019) 121730

Bertolino et al. (2011) Guan et al. (2016) Nadifiyine et al. (2013) da Silva et al. (2019)

Detecting benzoic acid in food, beverage, cosmetic, and pharmaceutical Detecting pipemmmidic acid in pharmaceutical samples Detecting atrazine in water Detecting catechin in tea Determining tyramine in fermented food and beverages 0.02–70 0.25–139.1

0.018 0.046 0.03 0.71

10–120

20–300 4–80 0.3–390 5.0–740 10–1000 1–20 0.28–45.1 2.5–50 0.05–50 0.1–0.5 0.01–2.46 0.24 0.57 0.055 0.39 3 0.087 0.066 1.8 0.030 2.4 0.030

Detection of catechol in river and tap water Diagnosis of Parkinson’s disease Sensing catechol in water Detecting bisphenol A in food or drinking package Detecting tyrosol in beer

0.01–50 0.01–50 10–120 0.010–80 20–200 0.013 0.00074 1.66 0.0004 22.6

Detection of dopamine in pharmaceuticals Detection of tyramine in food

Fang et al. (2016) Reza et al. (2015) Apetrei et al. (201) Karim et al. (2014) del Torno-de Román et al. (2016) Lete et al. (2017) Apetrei and Apetrei (2013) Liu et al. (2015) Camargo et al. (2018) Saini et al. (2014) Ibáñez-Redín et al. (2018) Kochana et al. (2015) Cerrato-Alvarez et al. (2019) Wang et al. (2018) Lete et al. (2015) Kochana et al. (2012)

Linear range (μM)

Detecting pest and pathogen in crops Quantifying bisphenol A in drinking water Pharmaceutical analysis Detection of catechol in tea In situ analysis of sulfamethoxazole in water

PA is competitive with the electrochemical reduction of o-benzoquinone which can be produced by tyrosinase-driven catechol oxidation, the peak current of the o-benzoquinone reduction was proportionally decreased when the PA concentration was increased. The biosensor was capable of detecting PA in a range of 0.2–70 μM with a detection limit of 18 nM and thus was successfully applied for analyzing PA in pharmaceutical formulations (Bertolino et al., 2011). Atrazine (2-chrolo-4-ethylamino-6-isopropyl-amino-1,3,5-trizine) is the most widely used herbicide and one of the inhibitors for tyrosinase catalysis. Additionally, atrazine seems to cause a severe health risk even at a very low level (ppb range) and thus either monitoring or detecting atrazine is a significant issue. Based on this inhibitory effect, Guan et al. (2016) constructed a tyrosinase-based atrazine biosensor by in situ entrapping tyrosinase in a tyrosinase-driven L-DOPA polymer on a gold electrode. The biosensor detected atrazine in real water samples from rivers, lakes, and farmland with excellent performance as shown in Table 1 (Guan et al., 2016). Tyramine is a kind of biogenic amine obtained from the decarboxylation of tyrosine and is commonly found in fermented food and beverages. Because tyramine-containing foods might cause severe intoxication when ingested in large amounts, controlling and measuring tyramine are important to food safety. To determine tyramine, enzymatic biosensors have been researched for a long time. Recently, da Silva et al. (2019) constructed a tyrosinase-based amperometric biosensor with a gold nanoparticle doped poly(8-anilino-1-naphthalene sulphonic acid)-modified glassy carbon electrode. The biosensor exhibited outstanding sensitivity for tyramine (19 nA cm−2 μM−1) as well as long-term stability and reproducibility. Additionally, the biosensor had good selectivity for tyramine without any critical interference in the existence of xanthine, hypoxanthine, L-tyrosine, and dopamine. Hence, the biosensor was successfully used to quantify tyramine in dairy food (yogurt and cheese) and fermented beverages (red wine and beer) (da Silva et al., 2019). Given that not only tyrosinase-based amperometric biosensors have been researched to analyze various phenolic derivatives for a long time, but also recent advances in nanotechnology have accelerated to improve the performances of bioelectronics by combining nanomaterials and biomolecules, we expect great progress in tyrosinase-based biosensors for versatile applications in diverse fields.

0.217 μA μM−1 0.019 Pipemmidic acid Atrazine Catechin Tyramine Au-electrode Modified Au electrode Carbon screened electrode Au nanoparticles and polymer modified glassy carbon

3.79 * 10-3

0.34 μA μM−1

Dopamine Tyramine Catechol Catechol L-DOPA Catechol Bisphenol A Tyrosol Catechol Dopamine Benzoic acid Au-disk microelectrode Polypyrrole film TiO2 nanotubes on graphene nanoplatelets Nanodiamond-potatostarch thin film Microplate at 475 nm Functionalized carbon black Modified sol–gel TiO2 matrix Screen-printed Au nanopaticle Graphene oxide modified glassy carbon SWNT-conducting polymer composite Titania-gel modified MWNT

0.539 μA μM−1 3.26

Methyl salicylate Bisphenol A Catechol Catechol Sulfamethoxazole Carbon nanotube Graphene oxide MWNT Screen printed/Au-nanocube Screen printed/Au-nanoparticle

0.107 A M−1

Analyte

83,300 8.15 13.72 μAμM−1

4. L-3,4-dihydroxyphenylalanine (L-DOPA) production

Electrode

Table 1 Performances of tyrosinase-based amperometric biosensors.

Sensitivity (μA cm−2 μM−1)

Limit of detection (μM)

Purpose

Refs.

K. Min, et al.

Parkinson’s disease is a kind of neurological disorder that is caused by a deficiency of the neurotransmitter dopamine in the brain. L-3,4dihydroxyphenylalanine (L-DOPA), which is a precursor of the neurotransmitter dopamine as well as a natural amino acid in humans, has been commonly used as a drug for Parkinson’s disease, because L-DOPA is capable of passing across the blood brain barrier whereas dopamine cannot (Min et al., 2010). Currently, many elderly people suffer from Parkinson’s disease with symptoms of rigidity and tremor, and thus the global market size for L-DOPA is substantial, at about 250 tons per year (Min et al., 2015b). Since Monsanto have commercialized the L-DOPA process by asymmetric hydrogenation for the first time, asymmetric approaches have been widely used for L-DOPA synthesis (Knowles, 2002). However, the process usually has a low conversion rate and poor enantioselectivity, uses a complex reaction procedure, and requires expensive catalysts (e.g., Rb-complex) that function under harsh operational conditions with a low substrate specificity (Sayyed & Sudalai, 2004). Given that biological systems might be promising alternatives for chemically limited reactions, microbial fermentation based on a tyrosine phenol-lyase (Tpl) activity and enzymatic approaches using tyrosinase or p-hydroxyphenolacetate 3-hydroxylase have been researched for biotechnological L-DOPA production (Min et al., 2015b). Tpl converts catechol, pyruvate, and ammonium to LDOPA. Hence, microorganisms with higher Tpl activity have been used 4

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Table 2 Tyrosinase-driven L-DOPA synthesis: Comparison of conversion rate and productivity.

Immobilized

Source

Reactor type

Reducing reagent

Conversion (%)

Agaricus bisporus Agaricus bisporus

Batch (Chitosan beads) Batch (zeolite)

Ascorbic acid Ascorbic acid

44.9

Agaricus bisporus Agaricus bisporus Agaricus bisporus

Batch (nylon 6,6 membrane) Batch (cross-linked enzyme aggregate) Packed bed reactor (Cu-alginate gel entrapment) Batch (chitosan–gelatin composite)

Ascorbic acid Ascorbic acid Ascorbic acid

58 53

Ascorbic acid

Batch (DEAE-Granocel) Continuous (Polyamide membrane) Batch (carbon-felt electrode) Batch (carbon paste electrode)

Ascorbic acid Ascorbic acid Electricity Electricity

Batch (whole-cell biocatalyst) Batch Batch Batch

Ascorbic acid

Aspergillus niger PA2 Agaricus bisporus Agaricus bisporus Agaricus bisporus Agaricus bisporus Free

Aspergillus oryzae Agaricus bisporus Agaricus bisporus Agaricus bisporus

Electricity Electricity

Productivity (mg L−1 h−1)

Refs.

53.97 34 1.70 209 110

Carvalho et al. (2000) Seetharam and Saville (2002) Pialis et al. (1996) Xu et al. (2012) Ates et al. (2007)

56.6

70.8

Agarwal et al. (2016)

30.6 95.9 77.7

113.6 23.66 47.3 15,300

Cieńska et al. (2016) Algieri et al. (2012) Min et al. (2010)) Min et al. (2013)

143.2 49.5 56

366 33.9 97.6 118.3

Ali and Haq (2010) Cieńska et al.(2016) Min et al. (2010) Wu and Zhu (2018)

enzymatic system were analyzed to interpret this remarkable result. The electrical reduction of DOPAquinone to L-DOPA was superior to the catecholase activity oxidizing L-DOPA to DOPAquinone, thereby indicating that the by-product DOPAquinone could not accumulate in the batch system (Min et al., 2013). The electro-enzymatic system with both a prominent conversion rate and the highest productivity might open up the feasibility of commercializing technology for tyrosinasedriven L-DOPA production at an industrial scale. Recently, Wu et al. (2018) introduced the concept of a self-powered system for the electroenzymatic L-DOPA production by combining an enzyme fuel cell (EFC) and an enzymatic electrosynthesis cell (EES). A glucose-based EFC was used as the power source instead of a potentiostat. The EFC and EES were connected by an external resistor that regulated the potential applied at the working electrode for reducing DOPAquinone in the EES compartment. To optimize the self-powered electro-enzymatic system, the effects of the tyrosinase concentration and O2 bubbling were investigated, as a result, the conversion rate and productivity were 56% and 118 mg L−1 h−1, respectively. The selfpowered electroenzymatic system displayed a Coulombic efficiency of 90%. The results indicate that electricity generated from the sugarbased EFC could be used to produce pharmaceuticals. Given that the price of L-tyrosine, glucose, and L-DOPA are about ∼15, 0.3, and 90 $ kg−1, the glucose-powered electro-enzymatic system might be economically feasible. In order to add economic viability to the electroenzymatic L-DOPA production, cost-effective tyrosinase production and immobilization methods for efficient reuse should be developed (Wu and Zhu, 2018).

to produce L-DOPA (Koyanagi et al., 2005), and the Ajinomoto Co. Ltd commercialized a L-DOPA process based on Erwinia herbicola fermentation (Min et al., 2015b). Owing to the outstanding solubility of the substrates in an aqueous phase, microbial fermentation often leads to a higher productivity up to 1.8 g L−1 h−1 of L-DOPA than asymmetric approaches. Nevertheless, microbial fermentation has some drawbacks such as the requirement of a carbon source for cell growth, a long operation time over 10 days including the cell culture period, and a low conversion rate. Accordingly, tyrosinase is emerging as the enzymatic route for L-DOPA production. Tyrosinase catalyzes ortho-hydroxylation of L-tyrosine to L-DOPA by cresolase activity and its catecholase activity sequentially oxidizes LDOPA to the by-product DOPAquinone. For accumulating L-DOPA in a batch reactor, the by-product DOPAquinone should be re-converted to L-DOPA again and thus a reducing reagent is essential: L-ascorbic acid is the most commonly used for reducing DOPAquinone in tyrosinasedriven L-DOPA production system. Table 2 summarizes the performance of tyrosinase-driven L-DOPA production previously reported. Although tyrosinase is widely distributed in nature, fungal tyrosinase has been mainly studied for L-DOPA production using L-ascorbic acid as the reducing reagent. Although diverse materials for immobilization to recycle the biocatalyst and various reactor types have been exploited, the conversion rate and productivity still remain below 60% and 500 mg L−1 h−1, respectively. Thus, tyrosinase-driven L-DOPA production is limited to date until a practical process is developed. In order to overcome the low conversion rate, Min et al. (2010) developed a novel strategy, an electro-enzymatic system, by replacing the reducing reagent with electricity. Instead of ascorbic acid, they introduced a cathode to supply electrons that can directly reduce DOPAquinine to L-DOPA. The electro-enzymatic system with free tyrosinase did not significantly improve the conversion rate and productivity, but the conversion rate was dramatically improved when tyrosinase was immobilized on the cathode, resulting in nearly all of the substrate being converted to L-DOPA with a conversion rate of 95.9% (Min et al., 2010). Although the electro-enzymatic system exhibited an exceptional conversion rate, the productivity was still restricted due to the low solubility of the substrate, which was about 1 mM of L-tyrosine in the aqueous phase. To obtain a highly concentrated substrate, Min et al. (2013) prepared well-dispersed L-tyrosine up to 500 mM by emulsification and then utilized it for the electro-enzymatic L-DOPA production. The viscosity of the highly concentrated well-dispersed Ltyrosine might have hindered mass transfer and thus only a conversion rate of 77.7% was achieved. Despite the viscosity, the productivity was progressively increased dependent on the substrate concentration and finally reached to 15.3 g L-1h−1. The kinetic parameters of the electro-

5. New perspective for lignin refinery Lignin is a phenolic-based natural polymer and its recalcitrant property is often a critical obstacle for obtaining fermentable sugars from biomass. Thus, efficient lignin degradation is significant issue in recent biorefinery processes. Additionally, lignin might be a renewable source of aromatic compounds for the chemical industry for producing value-added polyphenols. Accordingly, we, herein, highlights recently reported new perspectives of tyrosinase related to lignin refineries: promiscuous activity of tyrosinase for cleaving 4-O-5 and Cα-Cβ bonds in dimeric lignin model compounds and value-added polyphenol production from aromatic compounds that can be obtained from delignification. 5.1. Delignification for utilizing a lignocellulosic biomass in a biorefinery Concerns about the depletion of fossil fuels and climate change have 5

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health benefits. Among them, Lee et al. (2016) focused on 7,3′4′-trihydroxyisoflavone (3-ODI),which can be converted from daidzein in soy bean during fermentation, because 3,-ODI is a kind of multifunctional bioactive compounds that has an anti-oxidative effect, skin whitening effect, and cancer chemoprotectant activity. Tyrosinasedriven o-hydroxylation can produce 3-ODI from daidzein, but the catecholase activity catalyzing the sequential oxidation of o-diphenol to quinone usually restricts the production of functional o-diphenol derivatives such as 3-ODI. Hence, they proposed a strategy for protecting odiphenol products by adding borate and L-ascorbic acid: Borate formed a borate-o-diphenol complex at a basic pH and then the complex protected the o-diphenol products from catecholase activity. L-ascorbic acid can directly reduce o-quinones, the by-product from the catecholase activity, to o-diphenol again. To achieve regio-selective o-hydroxylation of daidzein for producing 3-ODI, they performed whole cell biotransformation using E. coli with heterologously expressed tyrosinase from Bacillus megaterium (BmTyr). When using 5 mM daidzein as the substrate in a 400 mL reactor, nearly all of the substrate was converted to 3-ODI over 90 min, resulting in a productivity of 16.3 mg L−1 h−1 DCW-mg−1. Additionally, the proposed strategy was useful to produce orobol and piceatannol from genistein and resveratrol, respectively, with a 95% conversion rate. These results verify that tyrosinase is promising as a monooxygenase for regio-selective o-hydroxylation of diverse monophenolic compounds to produce functional o-diphenol derivatives (Lee et al., 2016). Adding borate and L-ascorbic acid is a promising strategy to produce tyrosinase-driven o-diphenol derivatives, but borate and L-ascorbic acid cause a drastic inactivation of tyrosinase by lowering the environmental pH. Thus, Son et al. (2018) aimed to identify a tyrosinase that is active at acidic pH range. Many bacterial and fungal tyrosinases (e.g. AbTyr and BmTyr) are active at a pH ranging from neutral to basic, whereas the tyrosinase from Burkholderia thailandensis (BtTyr) showed a high activity under an acidic pH ranging from 3 to 6 with an optimum pH of 5 using L-tyrosine as a substrate. The kinetic parameters of AbTyr, BmTyr, tyrosinase from Streptomyces avermitilis (SaTyr), and BtTyr were compared using L-tyrosine and L-DOPA as the substrate at each of their optimum pHs. Compared with the other tyrosinases, BtTyr had a similar range of binding affinities (Km) and a remarkable turnover rate (kcat) for both L-tyrosine and L-DOPA, resulting in at least a 1.5-fold higher catalytic efficiency (kcat/Km) than AbTyr that is the most widely used tyrosinase. Especially, BtTyr showed nearly the same level of activity for both substrates, whereas the other tyrosinases had a much higher activity with L-DOPA as the substrate than with L-tyrosine as the substrate. They additionally validated the crystal structure of BtTyr and revealed that (i) BtTyr is composed of two domains, the N-terminal TYR domain forming the core active center and the C-terminal CAP domain; (ii) BtTyr undergoes pH-dependent dynamic changes in the oligomeric state by forming tetramers at an acidic pH and separating into dimers or monomers as the pH increase; (iii) oligomerization is significant for stabilizing BtTyr at an acidic pH range, and (iv) weakening of the binding between TYR and CAP can enhance the activity. Furthermore, BtTyr-driven production of catechol derivatives was examined: BtTyr successfully converted daidzin, resveratrol, and phloretin to 3′-hydroxydaidzin, piceatannol, and 3-hydroxyphloretin with a conversion rate of 87.3, 55.7, and 40.2%, respectively. Consequently, BtTyr is applicable for producing catechol derivatives at an acidic pH (Son et al., 2018). Lee et al. (2019) recently demonstrated that bacterial tyrosinase is capable of oxidizing polyphenol and then orobol can be quantitatively produced via circular permutation (CP) which covalently connects the protein’s original termini and inserts the reformulated termini elsewhere. CP was conducted on BmTyr in the flexible loop region, resulting in 7 active variants. Among the variants, Cp48, located in the loop which links the extended surface-exposed helix (from Asn10 to Phe 48), was notable for changing the substrate specificity and exhibited an interesting deviation in the activity profile: Cp48 lost nearly all of the

accelerated research interests and efforts toward biorefineries utilizing a lignocellulosic biomass as a sustainable feedstock to produce valueadded fuels and chemicals. In general, a biorefinery system consists of a pretreatment for breaking or loosening the highly recalcitrant lignin, saccharification for obtaining fermentable sugars from the (hemi)cellulosic components, fermentation for producing a target metabolite, and downstream process for separating and purifying of the target. In addition, recent researches have aimed to integrate renewable energy sources with typical biorefinery systems. For example, solar-powered electricity has been combined with a fermentation system using electroactive microorganism that is capable of utilizing electricity as reducing power (Torella et al., 2015). For recalcitrant lignin pretreatment, physico-chemical methods have been commonly used in the actual biorefinery process, even though white- and brown-rot fungi are mainly responsible for decomposing lignin in nature (Knežević et al., 2013). Fungal and bacterial heme-containing peroxidases (e.g, lignin peroxidase [LiP, E.C. 1.11.1.14] (Pham et al., 2016), manganese peroxidase [MnP, E.C. 1.11.1.13] (Hofrichter, 2002), versatile peroxidase [VP, E.C. 1.11.1.16] (Moreira et al., 2007), and dye-decolorizing peroxidase [DyP, E.C. 1.11.1.19] (Ahmad et al., 2011)) are known as significant enzymes for de-lignification in nature. However, their application for pretreatment in the current biorefinery system is still hampered, since heme-containing peroxidases inevitably require hydrogen peroxide, which usually causes inactivation by a suicide mechanism, as electron acceptor and the catalysis is often performed under acidic pH range (pH 3.0–4.5) (Min et al., 2015a). In accordance with Min et al. (2017 a), catalytic promiscuity enables tyrosinase to be a potential candidate for enzymatic pretreatment. Catalytic promiscuity in enzymes is the ability to catalyze distinctly different chemical transformations from their primary function and might contribute to broaden enzymatic applications (Bornscheuer & Kazlauskas, 2004). In addition, a higher substrate specificity, which is an intrinsic feature of enzymes differentiable from chemical catalysts, could be the result of the evolution from the catalytic promiscuities from ancestral enzymes (Nam et al., 2012). Given that lignin is a highly branched phenolic-based natural polymer and tyrosinase has a broad substrate spectrum for diverse phenolics, Min et al. (2017a) explored the catalytic promiscuity of tyrosinase in delignification. They revealed that tyrosinase is capable of oxidizing veratryl alcohol, which is a commonly used substrate for assaying ligninolytic activity, although veratryl alcohol is a non-phenolic compound and not the primary substrate of tyrosinase. Because a high redox potential is required for cleaving the β-O-4 linkage which is widely distributed in lignin, Min et al. (2017b) additionally verified that tyrosinase exhibits a catalytic promiscuity for oxidizing a non-phenolic lignin-related substrate (i.e, veratryl alcohol) with a high redox potential, 1.22 V (vs. Ag/AgCl) via cyclic voltammetry during catalysis. Furthermore, tyrosinase decomposed 4-phenoxyphenol and guaiacyl glycerol-β-guaiacyl ether as dimeric lignin model compounds, thereby representing that the promiscuous activity of tyrosinase is able to cleave 4-O-5 and Cα-Cβ in lignin. Consequently, not only tyrosinase is promising as an enzymebased pretreatment in a biorefinery under neutral pH with molecular oxygen as the electron acceptor but also these results give insight into the in-depth understanding about the evolution of the lignin-degrading enzyme specificity (Min et al., 2017). 5.2. Value-added polyphenol production Although tyrosinase has been mainly exploited for melanin synthesis, L-DOPA production, and detoxification or detection of phenolic compounds in conventional applications, recently tyrosinase-driven polyphenol production has been investigated. Ortho-dihydroxylated phenolic phytochemicals such as hydroxytryrosol from olive oil, esculetin from chicory, and o-hydroxyisoflavones (ODIs) from soy bean paste are functional compounds in food and seem to have potential 6

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cresolase activity for L-tyrosine, but it showed a 3–4 fold increase in the catalytic activity for daidzein, daidzin, and gelatin compared with the wild type BmTyr. Additionally, Cp48 was tested in order to produce orobol by hydroxylation of genistein, resulting in a quantative amount of orobol up to 1.48 g L-1. The results imply that CP might not only open the next door to enhance the activity for bulky substrates (e.g. polyphenols), but also guide the mutational strategy for preparing versatile polyphenols (Lee et al., 2019). Furthermore, Lee et al. (2015) aimed to produce piceatannol, which is a potent anticancer drug, by tyrosinase-driven o-hydroxylation of resveratrol. SaTyr MelC2 was heterologously expressed in E.coli via codon optimization of the helper protein MelC1 which assists in protein folding during translation. Saturated mutagenesis revealed that Y91 in MelC1 is crucial for the expression of active MelC2. The ratio of k1/k2 (i.e., cresolase activity/catecholase activity) can be changed through mutation of the residues either near the entrance of the active site or related to the flexibility of the His residues coordinating the Cu-ions in the active center. Accordingly, Lee et al. (2015) paied attention to I41, which is located at the entrance of the active site of MelC2 above the copper complex and can guide substrate binding, was selected as a significant mutation site. In order to increase the k1/k2 ratio Lee at al. (2015) substituted I41 with aromatic residues. Compared with wild type MelC2, the I41Y mutant exhibited a 7- and 5-fold higher k1/k2 ratio for L-tyrosine and trans-resveratrol, respectively. When incorporating the I41Y mutant with a glucose dehydrogenase-based NADH regeneration system, 290.2 μM of piceatannol was produced from trans-resveratrol, resulting in a production yield of 58.0% (Lee et al., 2015).

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6. Conclusion Herein, we covered the current knowledge about tyrosinase. Recently validated structural information of tyrosinase can lead to understanding its catalytic mechanism as well as improve its properties by enzyme engineering. Additionally, recombinant production of tyrosinase might greatly contribute to open the next door for practical applications. Tyrosinase has been conventionally applicable for the bioremediation of phenolic contaminants, constructing biosensors, and L-DOPA production. Furthermore, recent researches provide new perspectives for tyrosinase, for example, lignin pretreatment in a biorefinery and value-added polyphenol production from lignin-derivatives. We expect further studies will be performed that will address specific questions to achieve these new perspectives. 7. Cited units U: enzyme amount that converts 1 μmole of substrate per 1 min. Da: molecular weight of protein, usually equal to g mole−1. Acknowledgements This research was supported by the New & Renewable Energy Core Technology Program of the Korea Institute of Energy Technology Evaluation and Planning (KETEP) grants from the Ministry of Trade, Industry and Energy (No. 20173010092460) References Abdollahi, K., Yazdani, F., Panahi, R., Mokhtarani, B.J.B., 2018. Biotransformation of phenol in synthetic wastewater using the functionalized magnetic nano-biocatalyst particles carrying tyrosinase. 3 Biotech 8 (10), 419. Agarwal, P., Dubey, S., Singh, M., Singh, R.P., 2016. Aspergillus niger PA2 tyrosinase covalently immobilized on a novel eco-friendly bio-composite of chitosan-gelatin and its evaluation for L-DOPA production. Front. Microbiol. 7 (2088). Ahmad, M., Roberts, J.N., Hardiman, E.M., Singh, R., Eltis, L.D., Bugg, T.D.H., 2011. Identification of DypB from Rhodococcus jostii RHA1 as a lignin peroxidase. Biochemistry 50 (23), 5096–5107. Algieri, C., Donato, L., Bonacci, P., Giorno, L., 2012. Tyrosinase immobilised on

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