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Review

Recent Advances and Challenges in Biomolecule-Based Laccase Mimics for Environmental Applications

by
Zhiliang Liu
1,2,3,
Ling Liu
1,2,3,
Yu Liu
1,2,3,
Yuxuan Wang
1,2,3 and
Linling Yu
1,2,3,*
1
State Key Laboratory of Synthetic Biology, School of Synthetic Biology and Biomanufacturing, Tianjin University, Tianjin 300350, China
2
Frontier Science Center for Synthetic Biology (Ministry of Education), Tianjin University, Tianjin 300350, China
3
Key Laboratory of Systems Bioengineering (Ministry of Education), Tianjin University, Tianjin 300350, China
*
Author to whom correspondence should be addressed.
Catalysts 2025, 15(10), 932; https://doi.org/10.3390/catal15100932
Submission received: 27 August 2025 / Revised: 14 September 2025 / Accepted: 16 September 2025 / Published: 1 October 2025
(This article belongs to the Section Biocatalysis)
Browse Figures
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Abstract

Natural laccase is an environmentally friendly biocatalyst in the degradation of a broad range of toxic pollutants because its catalysis reaction does not require or produce toxic reactants and byproducts. However, its inherent limitations, such as operational sensitivity, poor stability, and difficulty in recovery/reusability, have significantly restricted its practical environmental applications. Consequently, in recent years, researchers have focused on the development of sustainable catalysts to mimic natural laccase. This review focuses on biomolecule-based laccase mimics, which are derived from nucleotides, nucleic acids, amino acids, peptides, and proteins, summarizing their environmental applications. These biomolecule-based laccase mimics not only overcome the limitations of natural laccase by offering advantages such as high stability, ease of recycling, and long-term storage but also exhibit excellent biodegradability, making them green and sustainable catalytic materials. This study aims to present recent progress in biomolecule-based laccase mimics, as well as their challenges, and to offer future directions in laccase-like catalysts for environmental applications.

Graphical Abstract

1. Introduction

Laccase (E.1.10.3.2, diphenol: dioxygen oxidoreductase), which refers to a family of copper-containing polyphenol oxidases, was first extracted from the secretion of the Japanese lacquer tree Rhus vernicifera in 1883 [1]. Since then, it has been found in a wide range of organisms, including plants, fungi, insects, bacteria, archaea, lichens, and sponges [2,3,4]. Due to its high catalytic efficiency, broad substrate specificity (e.g., inorganic cations, monophenols, bisphenols, methoxyphenols, aliphatic amines, anilines, etc.) [5,6,7] and environmentally friendly catalytic properties (unlike other oxidative enzymes that require or generate hydrogen peroxide (H2O2), the substrates are oxidized with molecular oxygen as the final electron acceptor, producing only water as a byproduct) [8], laccase has been established as one of the most promising green alternatives to conventional chemical catalysts [9,10,11]. It has been widely applied in various industries, including papermaking, biomass degradation, textile processing, biosensing, and production [12,13,14,15,16], and especially environmental remediation and pollutant detection [17,18,19], since most phenolic substances and anilines are typical pollutants with high toxicity [20,21,22].
However, the inherent limitations of natural laccase, such as limited long-term storage stability, poor operational robustness, high environmental sensitivity, and poor recyclability/reusability, pose major barriers to its practical applications [23,24,25]. Thus, various enzyme engineering methods have been developed to improve its stability and to ensure reusability [26,27]. Alternatively, the rapid developments and abundant achievements in mimicking natural laccases have provided a wise choice to construct catalysts that not only retain the advantages of natural laccase but also enhance its catalytic performance [28]. Consequently, various laccase-mimicking materials have been designed [29], and they are also called laccase mimics [30].
In detail, laccase mimics, based on simple chemical or biochemical molecules, are designed to mimic the complex biological functions of natural laccases and typically exhibit obvious advantages, including ease of large-scale synthesis, low cost, simple structure, high stability, and excellent recyclability [31,32]. Therefore, laccase mimics hold significant potential for environmental applications [33]. A variety of simple inorganic or organic materials have been used to construct laccase mimics, including metal oxides [34,35], metal sulfides [36], metal nanoparticles [37,38], perovskite materials [39], carbon-based materials [40], and metal organic frameworks (MOFs) [41,42]. Biomolecule-based laccase mimics, which are derived from nucleotides, nucleic acids, amino acids, peptides, and proteins, are more attractive in mimicking laccases, because their bio-sourced characteristics bring out good biodegradability, low toxicity, excellent sustainability, and high similarity in catalytic properties and structures with natural laccases [43,44,45].
Thus, this review focuses on recent advances in biomolecule-based laccase mimics as well as their challenges. Firstly, the catalytic mechanism of laccases was introduced, highlighting the structural basis in constructing laccase mimics. Then, recent progress in laccase mimics based on nucleotides, nucleic acids, amino acids, peptides, and proteins was systematically summarized, with particular emphasis on their environmental applications in pollutant degradation and detection, including environmental monitoring via colorimetric sensing, through representative case studies. Finally, current challenges and potential directions in developing green and sustainable laccase-like catalysts for environmental application were summarized.

2. Catalytic Mechanism of Natural Laccase and the Design Strategy of Laccase Mimics

Laccase is a dimeric or tetrameric glycoprotein [46], and each monomer contains four copper ions to form the catalytic center [47], which serves as the structural basis of its redox activity (Figure 1). Within this catalytic domain, the four copper ions are distributed among three distinct sites to form a Cu(I)–Cu(II) electron transfer system [48]: the type 1 (T1) blue copper center, coordinated by at least one cysteine and two histidine residues; the type 2 (T2) copper center, coordinated by two histidine residues; and the type 3 (T3) copper center, a coupled binuclear site with three histidine ligands per one copper ion. Owing to their close spatial proximity, T2 and T3 together constitute a trinuclear copper cluster [49,50]. During the catalytic cycle, electrons are first transferred from the substrate to the T1 site via the Cu-S (Cys) bond [51], and, thus, the substrate was oxidized with reducing T1 copper from Cu(II) to Cu(I). The electrons are then relayed to the trinuclear T2/T3 cluster through a cysteine–histidine electron transfer pathway via the hydrogen-bond and the π-bond [52], until all four coppers are reduced to Cu(I), rendering laccase fully reduced. Finally, the molecular oxygen (O2) binds the T2/T3 cluster and is reduced to water (H2O) by accepting electrons with oxidizing Cu(I) to Cu(II) and ultimately realizing the catalytic cycle.
Within the copper center structure, the T1 copper site is in direct contact with the substrate; consequently, its reduction potential correlates with the enzyme’s overall reduction potential and modulates catalytic activity [51]. Although the primary coordination geometry of T1 copper is conserved among laccases, significant variations exist in the coordination spheres [52]. Specifically, plant laccases employ methionine as an axial ligand, whereas fungal counterparts feature non-coordinating residues including leucine or phenylalanine [53]. The identity and occupancy of these ligands are established as decisive determinants of reduction potential [51,53]. Laccases featuring methionine at the T1 copper axial position exhibit reduction potentials of 340–490 mV, categorizing them as low-potential variants [53,54]. Medium-potential laccases, characterized by non-coordinating leucine occupying the axial position, display reduction potentials spanning 470–710 mV [54]. Conversely, high-potential laccases possess reduction potentials of 720–780 mV when phenylalanine acts as the axial ligand [54]. The difference in reduction potential between substrate and enzyme governs laccase catalysis for numerous substrates. Notably, high-potential laccases demonstrate higher activity toward anthraquinone dye oxidation relative to medium-/low-potential types. Furthermore, elevating the reduction potential simultaneously accelerates substrate oxidation kinetics and broadens the catalytic scope [55].
In addition, many redox mediators could concomitantly enhance the catalytic efficiency and substrate scope of laccase-catalyzed oxidation, which are generally low-molecular-weight compounds generating radical or cationic intermediates and functioning as electron shuttles to mediate redox communication between the enzyme and sterically hindered or high-molecular-weight substrates [56]. Critically, they enable oxidation of recalcitrant non-phenolic substrates possessing high reduction potentials, thus amplifying catalytic output and substrate diversity [56]. Nevertheless, mediator implementation in field applications faces practical constraints, particularly for environmental remediation processes, and, thus, mediator-free biocatalysis constitutes a strategically significant research focus [57]. For instance, engineered fungal laccases efficiently degrade ethyl green (triphenylmethane class) with 91.64% removal efficiency at 24 h in mediator-free systems [58]. Such mediator-free strategies promise substantial cost reductions and operational simplification for environmental remediation technologies.
Inspired by the architecture of the copper active centers in natural laccase and its Cu(I)–Cu(II) electron transfer system (Figure 1), it is an effective way to design laccase mimics based on the variable-valence metal ions [59], especially copper ions [60], where a similar variable-valence metal electron transfer system realized the catalytic cycle of substrate oxidation by O2. In addition, it is well established that the coordination of biomolecules with metal ions plays crucial roles in genetic metabolism and vital biological activities [61,62]. For instance, the coordination of manganese (Mn) and chlorophyll is a prerequisite for the functioning of the biological photosynthetic system [63], iron porphyrin compounds enable the transport of heme to transport oxygen in the bloodstream [64], and the function of ribozymes (based on RNA) is inseparable from coordination with magnesium ions [65]; further, the catalytic function of natural laccase requires the formation of an active center by the proper coordination of copper ions [66]. Thus, not only are biomolecules easy to coordinate with metal ions to form a variable-valence metal electron transfer system in mimicking laccase from the biomimetic point of view but, also, biomolecule-based catalysts are more in line with green and sustainable requirements with their bio-sourced characteristics from an environmental point of view. In addition, the method of biomolecule coordination with metal ions is also more attractive in terms of operation difficulty, time consumption, conditions and templating [67,68].

3. Nucleotide and Nucleic Acid-Based Laccase Mimics

Nucleotides and nucleic acids serve as excellent ligands for metal ions owing to the presence of nucleobases, phosphate groups, and their associated negative charges, which facilitate metal coordination [69,70,71]. Moreover, they possess excellent biocompatibility and water solubility, rendering them ideal candidates for constructing laccase mimics [72,73,74,75,76,77].

3.1. Nucleotide-Based Laccase Mimics

In 2016, Liang and co-workers [78] used guanosine monophosphate (GMP) to coordinate with copper ions, and a Cu/GMP complex was formed, featuring an amorphous MOF structure and laccase-like activity (Figure 2a), which is one of the earliest examples of biomolecule-based laccase mimics. This Cu/GMP laccase mimic catalyzed a broad range of phenolic pollutant substrates, with comparable catalytic efficiency to natural laccase but at approximately 1/2400 of the cost, and its robust stability under complex environmental conditions was demonstrated [78]. Thereafter, they [79] further immobilized the Cu/GMP complex using magnetic Fe3O4 particles in 2020, which retained similar catalytic properties of the free Cu/GMP but greatly enhanced storage stability, maintaining 100% activity over 13 days, compared to 9 days of the free Cu/GMP. Furthermore, in 2024, Tang et al. [80] substituted Cu2+ with Mn2+ as the active center in coordination with GMP to synthesize a novel laccase mimic, Mn-GMPNS (Figure 2b). This variant showed improved kinetic performance (Michaelis constant of Km = 0.35 mM, catalytic efficiency of kcat/Km = 0.027 (g/L)−1·S−1) for the 2,4-dichlorophenol (2,4-DP), as listed in Table 1, compared to Cu/GMP (Km = 0.59 mM, kcat/Km = 0.023 (g/L)−1·S−1) [80]. In addition, Mn-GMPNS with laccase-like activity has also been employed for the catalytic degradation of some typical dyes, such as malachite green, methyl violet, methyl green and ethyl violet [80].
Similarly, in 2020, Huang et al. [81] developed a laccase mimic based on the coordination between copper ions and adenosine monophosphate (AMP), and it was termed AMP–Cu, featuring a network-like structure (Figure 2c). AMP–Cu exhibited enhanced substrate affinity with a low Km value for 2,4-DP (Table 1), which was only 1/4 that of natural laccase, so it was particularly suitable for detecting trace amounts of phenolic compounds in environmental samples, achieving a limit of detection (LOD) as low as 0.033 μmol·L−1 under complex environmental conditions [81]. In addition, the number of phosphate groups in a nucleotide also affects its coordination with metal ions, thereby influencing its catalytic performance [82], and, thus, Guo and co-workers synthesized a laccase mimic by coordinating nicotinamide adenine dinucleotide hydride (NADH) with copper ions for the colorimetric detection of phosphates (Figure 2d), via Cu-NADH and indigo carmine [83]. The Cu-NADH complex with enhanced electron transfer efficiency and an accelerated Cu2+/Cu+ redox cycle in the copper active center not only resulted in high catalytic activity in air-mediated aryl C-H amination–oxidative coupling reactions between aromatic compounds and 4-phenylurea, achieving high yields (72~91%) [82], but also effectively determined the phosphate content in water, with an LOD as low as 0.37 μM and a linear relationship within a relatively wide concentration range (2–50 μM) [83]. Thus, this Cu-NADH laccase mimic not only held great potential for environmental detection but also broadened the scope of laccase mimics in organic synthesis.

3.2. Nucleic Acid-Based Laccase Mimics

As the superstructure of nucleotides, DNA relies on its phosphate backbone and nucleobases to coordinate with metal ions, behaving similarly to nucleotides. Tran et al. [84] used four single-stranded ssDNA, of which the highest nucleobase content was adenine (A), thymine (T), cytosine (C), and guanine (G), to coordinate with Cu2+ ions for constructing laccase mimics and obtained hybrid nanoflowers (NFs). Notably, the ssDNA sequence with the highest G content exhibited the greatest catalytic activity, denoted as GNF (Figure 3), and the favorable coordination between guanine and copper clusters enhanced the catalytic performance of laccase mimics, yielding a significantly higher catalytic constant (kcat = 7.06 × 1010 min−1, using catechol as a substrate) of GNF compared to free laccase (kcat = 1.57 min−1) and a slightly lower Km (1.84 mM versus 1.88 mM), as listed in Table 1 [84]. Moreover, a paper microfluidic device by integrating the colorimetric detection capabilities of GNF with smartphone-based image processing was further developed, which exhibited excellent selectivity, sensitivity, and stability in detecting phenolic compounds, offering greater convenience and accuracy compared to traditional visual observation of color changes in phenolic pollutant detection [84].
The laccase mimics based on nucleotides/nucleic acids are promising, green and sustainable catalysts owing to their bio-source, low cost, high synthetic yield (for instance, AMP–Cu can be prepared at a 60 mg scale within 30 min) [81], and large specific surface area. However, their structural features are still quite different from those of natural laccase, whose catalytic center microenvironment is based on multi-copper coordination with amino acid residues [85]. Thus, under the same copper content, they struggle to achieve the catalytic activity of natural laccase, which hinders their practical applications.

4. Amino Acid, Peptide, and Protein-Based Laccase Mimics

In natural laccase, the primary binding sites for Cu2+ are distributed on imidazole rings of the histidine residues. Therefore, both histidine and purine (an imidazole derivative) serve as excellent ligands for constructing laccase mimics [86,87]. However, the purine (including A and G) struggles to establish efficient electron transfer pathways and structures that facilitate oxygen absorption (the rate-limiting step) [88]. Consequently, laccase mimics based on amino acids, polypeptides, and proteins, containing amino acid residues, undoubtedly represent a superior choice.

4.1. Amino Acid-Based Laccase Mimics

Amino acid materials, encompassing both natural and unnatural amino acids, possess metal-chelating groups such as amino and carboxyl groups [89]. Some also exhibit self-assembling structures (e.g., benzene rings), making them excellent metal-coordinating materials. Moreover, due to the protein-derived characteristics, low cost, and favorable biodegradability of the amino acids, laccase mimics based on metal-ion coordination and self-assembly of amino acids were demonstrated with enhanced competitiveness [90,91,92].
Firstly, in 2022, Makam et al. [93] used a single natural amino acid phenylalanine (F) to coordinate with divalent copper ions and successfully synthesized the first single-amino-acid-based laccase mimic (F-Cu, Figure 4a). F-Cu was a 2D plate-like crystal biocatalyst, providing a large surface area and numerous active sites with significantly enhanced cost-effectiveness (5400-fold higher than natural laccase), catalytic efficiency (kcat/Km, four orders of magnitude higher, using 2,4-DP as a substrate), and sensitivity (36-fold higher) for the rapid oxidative removal of phenolic pollutants, particularly chlorophenols [93]. Similarly, in 2022, Tang et al. [94] reported a coordination system between cysteine (Cys) and Cu2+ (Cu/CysNPs, Figure 4b), and the enzymatic activity of Cu/CysNPs was maximized at a Cys/Cu stoichiometric ratio of 5:1, exhibiting a higher substrate affinity for 2,4-DP (Km = 0.427 mM) than Cu/GMP (Km = 0.59 mM) and a higher catalytic efficiency (kcat/Km = 2.79 × 10−5 (g/L)−1·S−1 versus kcat/Km = 2.34 × 10−5 (g/L)−1·S−1), as shown in Table 1. Furthermore, Cu/CysNPs efficiently degraded malachite green, achieving over 80% decolorization efficiency after 6 h, highlighting their potential for dye pollutant removal [94].
Although the self-assembly of natural amino acids coordinated with metal ions for constructing laccase mimics offers numerous advantages, the limited number of only 20 natural amino acids restricts the diversity of accessible structures [95]. Tao et al. [96] demonstrated that the unnatural amino acid γ-carboxyglutamic acid (Gla) coordinates metal ions similarly to famous metal-chelating agent EDTA, forming a highly efficient laccase-mimicking material (Gla + Cu(II)) with a stable crystalline structure. This Gla + Cu(II) laccase mimic exhibited maximum initial catalytic velocity and catalytic efficiencies that were 23-fold and about 19-fold higher than those of natural laccase, respectively, while maintaining efficient catalytic performance under extreme conditions for the degradation of the phenolic pollutant. In addition, Liu et al. [97], inspired by Makam et al.’s work [93] and the unnatural amino acid incorporation strategy utilized in artificial metalloenzyme design [98], selected the unnatural amino acid benzophenone-alanine (BpA) [99] to construct a non-cytotoxic laccase mimic (BpA-Cu, Figure 4c). BpA contains a self-assembling structural unit (benzophenone vs. phenyl) and metal-chelating groups (amino and carboxylate), enabling its assembly with copper ions, and the N-H···O=C hydrogen bond pathway and benzophenone–benzophenone aromatic stacking interactions (π-bond pathway) afforded the highly efficient transfer of electrons in the BpA–Cu(I) and BpA–Cu(II) complexes [97]. Thereby, BpA-Cu displayed a 4-fold higher affinity compared to the commercially available high-performance industrialized laccase (Novozym 51003) and a 24% higher catalytic efficiency (using 2,4-DP as the substrate) [86]. Moreover, BpA-Cu exhibited superior low LODs in the colorimetric detection of various phenolic pollutants, including 2,4-DP, 2-aminophenol, catechol, hydroquinone, 2-naphthol, 2-nitrophenol, phenol, and 2,4,6-trichlorophenol [97].
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Figure 4. (a) Schematic illustration of F-Cu formation and catalytic degradation of chlorophenol, reused with permission from Ref. [93]. Copyright (2022), The Authors. (b) Schematic illustration of Cu/CysNPs formation and malachite green decolorization, reused with permission from Ref. [94]. Copyright (2022), The Authors, under exclusive license to Springer Science Business Media, LLC, part of Springer Nature. (c) Schematic illustration of BpA-Cu formation with biocompatibility assessment via MTT assay, reused with permission from Ref. [97]. Copyright (2022), Elsevier. (d) Schematic illustration of Cu-BH formation and sensitive dual-mode sensing strategy for kanamycin detection, reused with permission from Ref. [100]. Copyright (2023), Elsevier. HEPES: 4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid. NH2-BDC: 2-Aminoterephthalic acid. His: Histidine. OPD: o-Phenylenediamine. KAN: Kanamycin sulfate.
Figure 4. (a) Schematic illustration of F-Cu formation and catalytic degradation of chlorophenol, reused with permission from Ref. [93]. Copyright (2022), The Authors. (b) Schematic illustration of Cu/CysNPs formation and malachite green decolorization, reused with permission from Ref. [94]. Copyright (2022), The Authors, under exclusive license to Springer Science Business Media, LLC, part of Springer Nature. (c) Schematic illustration of BpA-Cu formation with biocompatibility assessment via MTT assay, reused with permission from Ref. [97]. Copyright (2022), Elsevier. (d) Schematic illustration of Cu-BH formation and sensitive dual-mode sensing strategy for kanamycin detection, reused with permission from Ref. [100]. Copyright (2023), Elsevier. HEPES: 4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid. NH2-BDC: 2-Aminoterephthalic acid. His: Histidine. OPD: o-Phenylenediamine. KAN: Kanamycin sulfate.
Catalysts 15 00932 g004
Furthermore, Su and co-workers [100] introduced 2-aminoterephthalic acid (NH2-BDC) and histidine (His) as ligands to coordinate with copper ions, and a copper-based dual-ligand laccase mimic structurally resembling MOFs was synthesized (Cu-BH, Figure 4d). This Cu-BH laccase mimic exhibits enhanced fluorescence signals while avoiding environmental interference [100], providing a superior option for detecting phenolic and amine pollutants compared to typical laccase-mimetic-based colorimetric sensors, which rely on single-signal outputs vulnerable to environmental factors [101,102]. Moreover, the sensitive dual-mode sensing strategy for kanamycin with an LOD of 0.033 and 0.26 nM in tap water and milk has been successfully demonstrated on Cu-BH, with visualization facilitated by smartphone-based RGB (a color model used in digital devices and light-based media to create a gamut of colors from a small set of primary colors of red, green, and blue light) analysis [100]. Building on the above work, they [103] further synthesized the MnO2/Cu-BDC-His laccase mimic in situ via KMnO4-mediated oxidation, which effectively degraded dyes and, in real time, simultaneously identified the mixed tetracycline antibiotics in a range of 5–200 µM via a wavelength-based colorimetric array sensor, thus providing a promising approach for environmental monitoring in aquatic and soil systems.
Laccase mimics based on a single amino acid exhibit significant advantages regarding stability, cost-effectiveness, and recyclability [104]. Yet, due to the simple structure of amino acids, it is hard to fully replicate the complex active center and electron transfer pathways composed of multiple key amino acids in natural laccase [105]. Amino acid-based laccase mimics still face challenges in achieving comparable substrate affinities, despite exhibiting higher catalytic activity than those of natural laccase (such as F-Cu and Cu/CysNPs) [93,94]. Thus, co-assembly of different amino acids with variable-valence metal ions would be a promising way to strategize high-performance laccase-like catalysts.

4.2. Peptide-Based Laccase Mimics

Peptides generally contain diverse amino acids, offering a higher possibility in full replication of the complex active center and electron transfer pathways in natural laccase than single amino acids. Moreover, in addition to constructing copper active centers, mimicking the cysteine–histidine (Cys-His) electron transfer pathway in natural laccase is crucial [106,107]. Hence, identifying suitable peptide ligands that facilitate electron transfer from the metal center to the ligand, thereby enhancing laccase-like catalytic activity, has become a prominent research focus.
Wang et al. [108], in 2019, chose the Cys-His dipeptide to synthesize the laccase mimic via its coordination with copper ions (CH-Cu, Figure 5a), and this CH-Cu laccase mimic exhibited a broad substrate spectrum, with the catalytic efficiency approximately three orders of magnitude greater than natural laccase in degrading environmental pollutants such as chlorophenols and bisphenols. Beyond CH-Cu, Wang et al. further explored the coordination of various dipeptides with copper ions [109]. Notably, the CA-Cu (Figure 5a), formed via coordination of Cys-Asp with copper ions, exhibited the highest laccase-like activity (32.8% relative to natural laccase), followed by CH-Cu (~29%), under equivalent copper concentrations [109]. Moreover, the presence of chloride ions enhanced CA-Cu activity and conferred stability under heavy metal ion-rich conditions, and, hence, CA-Cu held considerable potential for applications in environmental remediation processes involving elevated chlorine and heavy metal ion concentrations [109].
Glutathione (GSH), a principal thiol-containing biomolecule in living organisms, serves as an effective metal chelator [110,111]. Hence, Li et al. [112] coordinated GSH with copper ions to fabricate a laccase mimic, GSH-Cu (Figure 5b), and the valence state of copper ions in this laccase mimic was modulated via the sulfhydryl group of GSH, thereby exhibiting properties analogous to natural laccase. Based on GSH-Cu, a portable, cost-effective, and user-friendly detection platform integrating test paper and smartphone technology was developed and successfully applied for on-site thiram detection in food and environmental samples [112]. Recently, another endogenous peptide, carnosine, was self-assembled with manganese ions to form a novel laccase mimic, Mn-Car, with a unique structure, which can drive the efficient generation of two types of free radicals: superoxide radicals (O2·−) and semiquinone radicals (SQ·−) [113]. Therefore, based on this Mn-Car, a novel colorimetric detection method with high sensitivity and selectivity for kanamycin antibiotics in water samples was developed, with an LOD as low as 0.102 μM [113].
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Figure 5. (a) Schematic illustration of CH-Cu and CA-Cu formation, bisphenol degradation, and stability under high Cl ions and heavy metal environments, reused with permission from Ref. [108]. Copyright (2019), Elsevier and Ref. [109]. Copyright (2021), Royal Society of Chemistry. (b) Schematic illustration of GSH-Cu formation with smartphone-integrated test strip platform for thiram detection, reused with permission from Ref. [112]. Copyright (2022), Elsevier. (c) Schematic illustration of EP-Cu formation and phenols degradation, reused with permission from Ref. [114]. Copyright (2024), Elsevier. (d) Schematic illustration of FF/ICA-Cu formation and its sensitivity for environmental change, reused with permission from Ref. [115]. Copyright (2024), Elsevier. DMF: Dimethylformamide. GSH: Glutathione. EP: Peptides obtained from activated sludge. FF: Diphenylalanine peptide. ICA: 4-imidazolecarboxaldehyde.
Figure 5. (a) Schematic illustration of CH-Cu and CA-Cu formation, bisphenol degradation, and stability under high Cl ions and heavy metal environments, reused with permission from Ref. [108]. Copyright (2019), Elsevier and Ref. [109]. Copyright (2021), Royal Society of Chemistry. (b) Schematic illustration of GSH-Cu formation with smartphone-integrated test strip platform for thiram detection, reused with permission from Ref. [112]. Copyright (2022), Elsevier. (c) Schematic illustration of EP-Cu formation and phenols degradation, reused with permission from Ref. [114]. Copyright (2024), Elsevier. (d) Schematic illustration of FF/ICA-Cu formation and its sensitivity for environmental change, reused with permission from Ref. [115]. Copyright (2024), Elsevier. DMF: Dimethylformamide. GSH: Glutathione. EP: Peptides obtained from activated sludge. FF: Diphenylalanine peptide. ICA: 4-imidazolecarboxaldehyde.
Catalysts 15 00932 g005
Furthermore, building upon the previously reported copper-based two-ligand laccase mimic Cu-BH [100], enhanced catalytic performance has been observed in peptide-based two-ligand laccase mimics [114,115]. Extracellular polymeric substances (EPSs) derived from activated sludge [116,117,118] can be enzymatically digested to yield a histidine-containing polypeptide (denoted as EP), and it could serve as an effective ligand coordinating with copper ions for synthesizing a laccase mimic with regularly porous spherical structures (Figure 5c) [114]. The specific porous structures of EP-Cu endowed it with higher substrate affinity for 2,4-DP (Km = 0.094 mM) compared to GSH-Cu (Km = 6.37 mM) and natural laccase (Km = 0.16 mM) [114], as summarized in Table 1, showing great promise for applications in phenolic degradation and biosensing. Similarly, Dong et al. [115] fabricated a laccase mimic, FF/ICA-Cu, via supramolecular assembly of the diphenylalanine peptide (FF), 4-imidazolecarboxaldehyde (ICA), and copper ions, forming a structure analogous to the active center of natural laccase (Figure 5d). Compared to the laccase mimic GSH-Cu (Km = 6.37 mM) [112], FF/ICA-Cu exhibited higher substrate affinity for 2,4-DP (Km = 0.188 mM, Table 1) [115], though this value remains lower than that of EP-Cu [114]. Additionally, the colorimetric detection of phenolic epinephrine by FF/ICA-Cu offered high sensitivity and specificity, presenting a convenient and precise approach for epinephrine detection in the environment [115].
From the above examples, it is clear that peptide-based laccase mimics generally exhibit higher catalytic activity than those based on amino acids. This is because peptides with more complex structures can more comprehensively mimic the structural features crucial for the optimal catalytic function of natural laccase and replicate catalytic centers and functional groups essential in the laccase’s microenvironment through more diverse combinations, thereby facilitating superior mimicry. However, comparing with the industrially producible amino acid monomers, peptide ligands exhibiting desired properties tend to be more expensive, thus hindering their widespread application.

4.3. Protein-Based Laccase Mimics

Among the biomolecules discussed, proteins exhibit the highest structural similarity to natural laccase, making protein-based laccase mimics particularly suitable for replicating structural features such as catalytic centers and microenvironments to achieve optimal laccase-like catalytic activity. Thus, utilizing inexpensive and abundant proteins to construct laccase mimics represents an effective approach.
Bovine serum albumin (BSA) is a typical inexpensive and abundant protein, and it can reversibly bind metal ions as a ligand, thereby inducing novel biological activities [119]. Rashtbary et al. [120] synthesized a laccase mimic in 2020 by coordinating BSA with copper ions (Figure 6a), and its laccase-like activity was evaluated using a colorimetric guaiacol oxidation assay, revealing a Km vale of 0.159 mM (Table 1). In addition, it demonstrated efficient and highly selective decolorization of malachite green, yielding less toxic degradation products [120]. Based on this, in 2022, Huang et al. [121] synthesized a structurally more stable BSA-Cu laccase mimic assisted by the ionic liquid tetrabutylammonium hydroxide (TBAOH), and the application of TBAOH enhanced BSA-Cu’s effectiveness in catechol degradation and increased its sensitivity for epinephrine detection compared to natural laccase. Building on these developments, in 2023, Wang et al. [122] prepared laccase mimic BSA-Cu3(PO4)2 with laccase-like activity via one-step co-precipitation in PBS buffer, outperforming natural laccase in stability. Notably, its laccase-like activity could be enhanced by thiocholine, an acetylcholinesterase (AChE) hydrolysis product of acetylthiocholine, facilitating a colorimetric strategy for AChE activity determination and AChE inhibitor testing [122]. Hence, the BSA-Cu3(PO4)2-based system also enabled the detection of carbaryl, a carbamate pesticide, achieving an ultralow detection limit of 0.1 μg/L [122], broadening the application of laccase mimics in environmental monitoring.
In addition, converting natural enzymes into laccase mimics is also a feasible strategy. Carla et al. [123] prepared the laccase mimic GTL-Mn by mixing Geobacillus thermocatenulatus lipase (GTL) with Mn salts in an aqueous phase at 50 °C (Figure 6b), in which Mn ions primarily coordinated with the carboxyl groups of aspartic acid residues within the enzyme scaffold and thereby facilitated the cross-linking between protein molecules. This coordination induced conformational changes that altered the enzyme’s function, enabling it to oxidize a broad spectrum of substrates, such as L-DOPA and phloridzin [123]; thus, the application of laccase mimics in environmental monitoring was further broadened. In addition, its catalytic efficiency is 300-fold higher than that of Yungi laccase, and its stability at 40 °C is twice that of Novozym 51003 laccase [123], proving the potential of biometric catalysts in environmental applications.
Protein-based laccase mimics generally exhibit excellent catalytic activity; however, the identification of suitable protein ligands remains a major challenge, especially for inexpensive and abundant ones. To date, most studies have focused predominantly on BSA, with limited exploration of alternative protein scaffolds. Although advanced techniques such as directed evolution and protein engineering can be employed to generate suitable ligands, the associated technical complexity and high cost significantly hinder their broader application in practical settings.

5. Hybrid Biomolecule-Based Laccase Mimics

DNA and amino acids represent versatile and abundant biomolecular resources. DNA can serve as an effective scaffold for biocatalysis [124], while amino acids function as promising structural units for DNA functionalization [125]. The hybridization of these two biomolecules could offer significantly enhanced structural and catalytic versatility to DNA-based systems.
In a pioneering study, Yum et al. [126] developed a series of His-DNA hybrid molecules by covalently incorporating histidine residues into DNA strands via D-threonyl linkers, followed by coordination with copper ions to form a series of Cu-His-DNA laccase mimics (Figure 7). Comparative analyses indicated that metal ion coordination, amino acid residues, and DNA structural conformation collectively influence catalytic performance, in which Cu2+ was essential for inducing laccase-like activity through metal–amino acid coordination and the variations in DNA structure impacted both Km and kcat values [126]. Kinetic assays revealed that the optimal Cu-His-DNA exhibited catalytic activity superior to that of natural laccase [126], and as a biodegradable bio-hybrid catalyst, Cu-His-DNA represented a promising alternative to natural laccase for applications in environmental remediation.
Table 1. Kinetic parameters of laccase mimics in the catalytic reaction of 2,4-DP and 4-AP.
Table 1. Kinetic parameters of laccase mimics in the catalytic reaction of 2,4-DP and 4-AP.
Laccase MimicsBiomolecule[E0]
(g·L−1)		Vmax
(×10−5 mM·S−1)		Km
(mM)		kcat/Km
(×10−5 (g·L−1)−1·S−1)		Reference
Cu/GMPNucleotide0.11.380.592.34 a[78]
Mn-GMPNSNucleotide0.10.930.352.66 a[80]
AMP-CuNucleotide0.12.170.0924.1 a[81]
Cu-NADHNucleotide1.00.0740.2070.357 a[83]
GNFNucleic acid0.19.001.8448.9 a[84]
F-CuAmino acid1.98 × 10−56.000.1916,000[93]
Cu/CysNPsAmino acid1.01.190.4272.79 a[94]
Gla + Cu(II)Amino acid0.15.080.12423 a[96]
BpA-CuAmino acid0.12.600.07372[97]
Cu-BHAmino acid1.00.130.091.44 a[100]
CH-CuPeptide0.112.20.4229.1 a[108]
CA-CuPeptide0.113.00.12108 a[109]
GSH-CuPeptide--0.0386.37--[112]
Mn-carPeptide--21.6640.723--[113]
EP-CuPeptide0.1100.960.0941074 a[114]
FF/ICA-CuPeptide--0.130.188--[115]
BSA-Cu bprotein--0.04 mM/min0.15916.73 mM−1·min−1[120]
GTL-Mnprotein--------[123]
Cu-His-DNAHybrid-biomolecule--0.4760.190.16 mM−1·min−1[126]
a kcat/Km value was calculated according to mass concentration provided in the reference. b Kinetic parameters of BSA-Cu were studied using guaiacol as a substrate.
The construction of laccase mimics using hybrid biomolecules integrates the advantages of multiple biomolecular components, facilitating laccase-like activities with superior performance while maintaining excellent biodegradability and biocompatibility. This approach represents a significant developmental direction in the field of laccase-mimics. However, current research on the construction of laccase mimics via hybrid biomolecules remains limited, and both the hybridization methods and strategies require further exploration and optimization.

6. Conclusions

Laccase mimics exhibit advantages such as low cost, high stability, and recyclability, making them promising alternatives to natural laccase in the field of environmental pollution control. This review highlights that biomolecule-based laccase mimics possess excellent laccase-like catalytic activity and substrate affinity. Among them, laccase mimics constructed from nucleotides, nucleic acids, and amino acids offer superior cost-effectiveness and scalability, while those based on peptides and proteins are more capable of mimicking the structural features of natural laccase to achieve enhanced catalytic efficiency and substrate specificity.
It is evident from these studies that the choice of biological ligand material plays a pivotal role in the rational design of laccase mimics. Since no single type of biomolecule can fully replicate the active center, electron transfer pathway, and microenvironment of natural enzymes, hybrid strategies that combine multiple biomolecular ligands offer a promising direction. Such combinations can integrate advantages, including self-assembling structures (e.g., benzene rings), cysteine–histidine electron pathways, and metal coordination microenvironments, thereby enabling the construction of laccase mimics that rival or even surpass the performance of natural laccase. Furthermore, the intrinsic structural complexity of natural enzymes poses a major challenge for complete mimicry through conventional approaches alone. Future efforts may leverage artificial intelligence in molecular design to optimize structural models [127], focusing on increasing the redox potential of laccase mimics, researching mediator-free biocatalytic systems, and guide the rational development of next-generation laccase mimics with enhanced degradation capabilities for environmental pollutants. In parallel, more sensitive, rapid, user-friendly, and specific biosensors can be designed to support more efficient environmental monitoring and management.

Author Contributions

Conceptualization, L.Y.; investigation and literature review, Z.L., L.L. and L.Y.; rational organization of reviewed data, Z.L., Y.L. and Y.W.; software, Z.L.; supervision: L.Y.; resources, L.Y.; visualization, Z.L. and Y.W.; writing—original draft preparation, Z.L. and L.L.; writing—review and editing, Y.L. and L.Y.; funding acquisition, L.Y.; project administration, L.Y. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (No. 22378306).

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflicts of interest.

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Figure 1. Scheme of the structure and catalytic mechanism of laccase (PDB ID: 1GSK). Two red arrows refer to electron transfer pathways; T1, T2, T3 balls refer to three types of copper ions of the laccase copper center.
Figure 1. Scheme of the structure and catalytic mechanism of laccase (PDB ID: 1GSK). Two red arrows refer to electron transfer pathways; T1, T2, T3 balls refer to three types of copper ions of the laccase copper center.
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Catalysts 15 00932 g002
Figure 2. (a) Schematic illustration of Cu/GMP formation and phenols conversion, reused with permission from Ref. [78]. Copyright (2017), American Chemical Society. (b) Schematic illustration of Mn–GMPNS formation and dye decolorization, reused with permission from Ref. [80]. Copyright (2024), American Chemical Society. (c) Schematic illustration of AMP-Cu formation with detection and removal of phenols in environment, reused with permission from Ref. [81]. Copyright (2020), The Chemical Industry and Engineering Society of China, and Chemical Industry Press. (d) Schematic illustration of Cu-NADH formation and colorimetric assay for phosphate, reused with permission from Ref. [82]. Copyright (2024), Elsevier, and Ref. [83]. Copyright (2022), Springer Nature. 4-AP: 4-Aminoantipyrine.
Figure 2. (a) Schematic illustration of Cu/GMP formation and phenols conversion, reused with permission from Ref. [78]. Copyright (2017), American Chemical Society. (b) Schematic illustration of Mn–GMPNS formation and dye decolorization, reused with permission from Ref. [80]. Copyright (2024), American Chemical Society. (c) Schematic illustration of AMP-Cu formation with detection and removal of phenols in environment, reused with permission from Ref. [81]. Copyright (2020), The Chemical Industry and Engineering Society of China, and Chemical Industry Press. (d) Schematic illustration of Cu-NADH formation and colorimetric assay for phosphate, reused with permission from Ref. [82]. Copyright (2024), Elsevier, and Ref. [83]. Copyright (2022), Springer Nature. 4-AP: 4-Aminoantipyrine.
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Catalysts 15 00932 g003
Figure 3. Schematic illustration of GNF and paper microfluidic device for colorimetric detection of phenolic compounds, reused with permission from Ref. [84]. Copyright (2021), Elsevier. PBS: Phosphate-Buffered Saline Buffer. GNF: Hybrid nanoflowers composed of guanine-rich ssDNA and copper phosphate.
Figure 3. Schematic illustration of GNF and paper microfluidic device for colorimetric detection of phenolic compounds, reused with permission from Ref. [84]. Copyright (2021), Elsevier. PBS: Phosphate-Buffered Saline Buffer. GNF: Hybrid nanoflowers composed of guanine-rich ssDNA and copper phosphate.
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Catalysts 15 00932 g006
Figure 6. (a) Schematic illustration of BSA-Cu formation with laccase-like activity assay using guaiacol and malachite green decolorization, reused with permission from Ref. [120]. Copyright (2020), Elsevier. (b) Schematic illustration of GTL-Mn formation for L-DOPA oxidation and phlorizin oxidative polymerization, reused with permission from Ref. [123]. Copyright (2024), The Authors. BSA: Bovine serum albumin (PDB code: 1YQS). GTL: Geobacillus thermocatenulatus lipase (PDB code: 2W22).
Figure 6. (a) Schematic illustration of BSA-Cu formation with laccase-like activity assay using guaiacol and malachite green decolorization, reused with permission from Ref. [120]. Copyright (2020), Elsevier. (b) Schematic illustration of GTL-Mn formation for L-DOPA oxidation and phlorizin oxidative polymerization, reused with permission from Ref. [123]. Copyright (2024), The Authors. BSA: Bovine serum albumin (PDB code: 1YQS). GTL: Geobacillus thermocatenulatus lipase (PDB code: 2W22).
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Figure 7. Schematic illustration of Cu-His-DNA formation and laccase-like activity assay process, reused with permission from Ref. [126]. Copyright (2023), Royal Society of Chemistry.
Figure 7. Schematic illustration of Cu-His-DNA formation and laccase-like activity assay process, reused with permission from Ref. [126]. Copyright (2023), Royal Society of Chemistry.
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Liu, Z.; Liu, L.; Liu, Y.; Wang, Y.; Yu, L. Recent Advances and Challenges in Biomolecule-Based Laccase Mimics for Environmental Applications. Catalysts 2025, 15, 932. https://doi.org/10.3390/catal15100932

AMA Style

Liu Z, Liu L, Liu Y, Wang Y, Yu L. Recent Advances and Challenges in Biomolecule-Based Laccase Mimics for Environmental Applications. Catalysts. 2025; 15(10):932. https://doi.org/10.3390/catal15100932

Chicago/Turabian Style

Liu, Zhiliang, Ling Liu, Yu Liu, Yuxuan Wang, and Linling Yu. 2025. "Recent Advances and Challenges in Biomolecule-Based Laccase Mimics for Environmental Applications" Catalysts 15, no. 10: 932. https://doi.org/10.3390/catal15100932

APA Style

Liu, Z., Liu, L., Liu, Y., Wang, Y., & Yu, L. (2025). Recent Advances and Challenges in Biomolecule-Based Laccase Mimics for Environmental Applications. Catalysts, 15(10), 932. https://doi.org/10.3390/catal15100932

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