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Natural, Designed and Engineered Metalloenzymes: Structure, Catalytic Mechanisms and Applications
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Natural, Designed and Engineered Metalloenzymes: Structure, Catalytic Mechanisms and Applications

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 27448

Special Issue Editors

Prof. Dr. Angela Lombardi

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Guest Editor
Department of Chemical Sciences, Universita degli Studi di Napoli Federico II, Naples, Italy
Interests: synthetic metalloproteins; heme- and non-heme- iron containing protein mimics; protein design; de novo design; peptide and protein chemistry; metalloenzyme functional characterization; spectroscopic and structural characterization; coordination chemistry and bioinorganic chemistry; structure/function relationships of metalloproteins and metalloenzymes; application of metalloenzymes and their mimics in biosensing, catalysis, diagnostics; drug design; design of constrained peptides
Prof. Flavia Nastri

E-Mail Website
Guest Editor
Department of Chemical Sciences, University of Naples “Federico II,” Complesso Universitario Monte S. Angelo, via Cintia, 80126 Napoli, Italy
Interests: materials science; metalloenzyme; catalysts
Dr. Linda Leone

E-Mail Website
Guest Editor
Department of Chemical Sciences, Università degli Studi di Napoli Federico IIdisabled, Naples, Italy
Interests: bioinorganic chemistry; catalysis; metalloproteins; coordination chemistry; protein design; hemeproteins; redox chemistry; peptide synthesis

Special Issue Information

Dear Colleagues,

This Special Issue aims to gather the most recent research in the field of natural, designed and engineered metalloenzymes and their applications.

Natural metalloenzymes represent a huge source of inspiration for chemists, owing to the incredible variety of challenging transformations they perform in living systems. Understanding the molecular basis for the extraordinary efficiency and selectivity of biocatalysts is a fascinating research field that has stimulated detailed structural and mechanistic studies. Further, the desire to exploit the outstanding properties of native enzymes to practical applications has boosted the development of artificial metalloenzymes, which were conceived to expand their reaction scope even toward new-to-nature activities while improving their robustness. Various strategies have been applied in this field with this aim in mind, involving either the engineering of native protein scaffolds or the design of completely artificial proteins from scratch. The applications of these systems span different areas of chemistry and biotechnology, ranging from biocatalysis for sustainable chemistry and bioremediation to energy production and the construction of bio-based nanomaterials.

We warmly welcome contributions concerning all the aspects of this field, including structural characterization, computational studies, mechanistic investigations and the growing variety of applications that natural and artificial metalloenzymes may find.

Prof. Dr. Angela Lombardi
Prof. Flavia Nastri
Dr. Linda Leone
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • metalloenzymes
  • catalysis
  • biocatalysis
  • protein design and engineering
  • abiotic catalysis
  • bio-based nanomaterials
  • biotechnology
  • reaction mechanism

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Published Papers (10 papers)

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Editorial

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3 pages, 183 KiB  
Editorial
Natural, Designed and Engineered Metalloenzymes: Structure, Catalytic Mechanisms and Applications
by Linda Leone, Flavia Nastri and Angela Lombardi
Int. J. Mol. Sci. 2023, 24(18), 14255; https://doi.org/10.3390/ijms241814255 - 19 Sep 2023
Cited by 2 | Viewed by 1027
Abstract
Bioinorganic chemists have become engaged in the challenge of elucidating the molecular mechanisms that govern how protein scaffolds modulate the properties of metal cofactors [...] Full article
(This article belongs to the Special Issue Natural, Designed and Engineered Metalloenzymes: Structure, Catalytic Mechanisms and Applications)

Research

Jump to: Editorial, Review

12 pages, 6070 KiB  
Article
A De Novo Designed Trimeric Metalloprotein as a Nip Model of the Acetyl-CoA Synthase
by Dhanashree Selvan and Saumen Chakraborty
Int. J. Mol. Sci. 2023, 24(12), 10317; https://doi.org/10.3390/ijms241210317 - 19 Jun 2023
Cited by 2 | Viewed by 1412
Abstract
We present a Nip site model of acetyl coenzyme-A synthase (ACS) within a de novo-designed trimer peptide that self-assembles to produce a homoleptic Ni(Cys)3 binding motif. Spectroscopic and kinetic studies of ligand binding demonstrate that Ni binding stabilizes the peptide assembly [...] Read more.
We present a Nip site model of acetyl coenzyme-A synthase (ACS) within a de novo-designed trimer peptide that self-assembles to produce a homoleptic Ni(Cys)3 binding motif. Spectroscopic and kinetic studies of ligand binding demonstrate that Ni binding stabilizes the peptide assembly and produces a terminal NiI-CO complex. When the CO-bound state is reacted with a methyl donor, a new species is quickly produced with new spectral features. While the metal-bound CO is albeit unactivated, the presence of the methyl donor produces an activated metal-CO complex. Selective outer sphere steric modifications demonstrate that the physical properties of the ligand-bound states are altered differently depending on the location of the steric modification above or below the Ni site. Full article
(This article belongs to the Special Issue Natural, Designed and Engineered Metalloenzymes: Structure, Catalytic Mechanisms and Applications)
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17 pages, 3683 KiB  
Article
Selective Oxidation of Halophenols Catalyzed by an Artificial Miniaturized Peroxidase
by Daniele D’Alonzo, Maria De Fenza, Vincenzo Pavone, Angela Lombardi and Flavia Nastri
Int. J. Mol. Sci. 2023, 24(9), 8058; https://doi.org/10.3390/ijms24098058 - 29 Apr 2023
Cited by 10 | Viewed by 1753
Abstract
The development of artificial enzymes for application in sustainable technologies, such as the transformation of environmental pollutants or biomass, is one of the most challenging goals in metalloenzyme design. In this work, we describe the oxidation of mono-, di-, tri- and penta-halogenated phenols [...] Read more.
The development of artificial enzymes for application in sustainable technologies, such as the transformation of environmental pollutants or biomass, is one of the most challenging goals in metalloenzyme design. In this work, we describe the oxidation of mono-, di-, tri- and penta-halogenated phenols catalyzed by the artificial metalloenzyme Fe-MC6*a. It promoted the dehalogenation of 4-fluorophenol into the corresponding 1,4-benzoquinone, while under the same experimental conditions, 4-chloro, 4-bromo and 4-iodophenol were selectively converted into higher molecular weight compounds. Analysis of the 4-chlorophenol oxidation products clarified that oligomers based on C-O bonds were exclusively formed in this case. All results show that Fe-MC6*a holds intriguing enzymatic properties, as it catalyzes halophenol oxidation with substrate-dependent chemoselectivity. Full article
(This article belongs to the Special Issue Natural, Designed and Engineered Metalloenzymes: Structure, Catalytic Mechanisms and Applications)
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15 pages, 3462 KiB  
Article
Photocatalytic Hydrogen Production and Carbon Dioxide Reduction Catalyzed by an Artificial Cobalt Hemoprotein
by Guillermo A. Oliveira Udry, Laura Tiessler-Sala, Eva Pugliese, Agathe Urvoas, Zakaria Halime, Jean-Didier Maréchal, Jean-Pierre Mahy and Rémy Ricoux
Int. J. Mol. Sci. 2022, 23(23), 14640; https://doi.org/10.3390/ijms232314640 - 24 Nov 2022
Cited by 7 | Viewed by 2715
Abstract
The covalent insertion of a cobalt heme into the cavity of an artificial protein named alpha Rep (αRep) leads to an artificial cobalt hemoprotein that is active as a catalyst not only for the photo-induced production of H2, but also for [...] Read more.
The covalent insertion of a cobalt heme into the cavity of an artificial protein named alpha Rep (αRep) leads to an artificial cobalt hemoprotein that is active as a catalyst not only for the photo-induced production of H2, but also for the reduction of CO2 in a neutral aqueous solution. This new artificial metalloenzyme has been purified and characterized by Matrix Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry (MALDI-TOF MS), circular dichroism, and UltraViolet–Visible spectroscopy. Using theoretical experiments, the structure of this biohybrid and the positioning of the residues near the metal complex were examined, which made it possible to complete the coordination of the cobalt ion by an axial glutamine Gln283 ligand. While the Co(III)–porphyrin catalyst alone showed weak catalytic activity for both reactions, 10 times more H2 and four times more CO2 were produced when the Co(III)–porphyrin complex was buried in the hydrophobic cavity of the protein. This study thus provides a solid basis for further improvement of these biohybrids using well-designed modifications of the second and outer coordination sphere by site-directed mutagenesis of the host protein. Full article
(This article belongs to the Special Issue Natural, Designed and Engineered Metalloenzymes: Structure, Catalytic Mechanisms and Applications)
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12 pages, 7013 KiB  
Article
Reactivity of Myoglobin Reconstituted with Cobalt Corrole toward Hydrogen Peroxide
by Koji Oohora, Hirotaka Tomoda and Takashi Hayashi
Int. J. Mol. Sci. 2022, 23(9), 4829; https://doi.org/10.3390/ijms23094829 - 27 Apr 2022
Cited by 4 | Viewed by 2373
Abstract
The protein matrix of natural metalloenzymes regulates the reactivity of metal complexes to establish unique catalysts. We describe the incorporation of a cobalt complex of corrole (CoCor), a trianionic porphyrinoid metal ligand, into an apo-form of myoglobin to provide a reconstituted protein (rMb(CoCor)). [...] Read more.
The protein matrix of natural metalloenzymes regulates the reactivity of metal complexes to establish unique catalysts. We describe the incorporation of a cobalt complex of corrole (CoCor), a trianionic porphyrinoid metal ligand, into an apo-form of myoglobin to provide a reconstituted protein (rMb(CoCor)). This protein was characterized by UV-vis, EPR, and mass spectroscopic measurements. The reaction of rMb(CoCor) with hydrogen peroxide promotes an irreversible oxidation of the CoCor cofactor, whereas the same reaction in the presence of a phenol derivative yields the cation radical form of CoCor. Detailed kinetic investigations indicate the formation of a transient hydroperoxo complex of rMb(CoCor) which promotes the oxidation of the phenol derivatives. This mechanism is significantly different for native heme-dependent peroxidases, which generate a metal-oxo species as an active intermediate in a reaction with hydrogen peroxide. The present findings of unique reactivity will contribute to further design of artificial metalloenzymes. Full article
(This article belongs to the Special Issue Natural, Designed and Engineered Metalloenzymes: Structure, Catalytic Mechanisms and Applications)
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18 pages, 3079 KiB  
Article
Functional Conversion of Acetyl-Coenzyme a Synthase to a Nickel Superoxide Dismutase via Rational Design of Coordination Microenvironment for the Nid-Site
by Yaozhu Wei, Yajun Zhou, Hong Yuan, Yi Liu, Ying-Wu Lin, Jihu Su and Xiangshi Tan
Int. J. Mol. Sci. 2022, 23(5), 2652; https://doi.org/10.3390/ijms23052652 - 28 Feb 2022
Cited by 2 | Viewed by 1745
Abstract
The Nid site coordination microenvironment of a truncated acetyl-coenzyme A synthase has been designed systematically for functional conversion to a Ni-SOD-like enzyme. To this end, the first strategy is to introduce an axial histidine ligand, using mutations F598H, S594H and S594H-GP individually. [...] Read more.
The Nid site coordination microenvironment of a truncated acetyl-coenzyme A synthase has been designed systematically for functional conversion to a Ni-SOD-like enzyme. To this end, the first strategy is to introduce an axial histidine ligand, using mutations F598H, S594H and S594H-GP individually. The resulting three mutants obtained Ni-SOD-like activity successfully, although the catalytic activity was about 10-fold lower than in native Ni-SOD. The second strategy is to mimic the H-bond network in the second sphere coordination microenvironment of the native Ni-SOD. Two mutations based on F598H (EFG-F598H and YGP-F598H) were designed. The successful EFG-F598H exhibited ~3-fold Ni-SOD-like activity of F598H. These designed Ni-SOD-like metalloproteins were characterized by UV/Vis, EPR and Cyclic voltammetry while F598H was also characterized by X-ray protein crystallography. The pH titrations were performed to reveal the source of the two protons required for forming H2O2 in the SOD catalytic reaction. Based on all of the results, a proposed catalytic mechanism for the Ni-SOD-like metalloproteins is presented. Full article
(This article belongs to the Special Issue Natural, Designed and Engineered Metalloenzymes: Structure, Catalytic Mechanisms and Applications)
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19 pages, 3774 KiB  
Article
In Silico and Experimental ADAM17 Kinetic Modeling as Basis for Future Screening System for Modulators
by Marian Bienstein, Dmitriy Minond, Ulrich Schwaneberg, Mehdi D. Davari and Daniela Yildiz
Int. J. Mol. Sci. 2022, 23(3), 1368; https://doi.org/10.3390/ijms23031368 - 25 Jan 2022
Cited by 6 | Viewed by 3623
Abstract
Understanding the mechanisms of modulators’ action on enzymes is crucial for optimizing and designing pharmaceutical substances. The acute inflammatory response, in particular, is regulated mainly by a disintegrin and metalloproteinase (ADAM) 17. ADAM17 processes several disease mediators such as TNFα and APP, releasing [...] Read more.
Understanding the mechanisms of modulators’ action on enzymes is crucial for optimizing and designing pharmaceutical substances. The acute inflammatory response, in particular, is regulated mainly by a disintegrin and metalloproteinase (ADAM) 17. ADAM17 processes several disease mediators such as TNFα and APP, releasing their soluble ectodomains (shedding). A malfunction of this process leads to a disturbed inflammatory response. Chemical protease inhibitors such as TAPI-1 were used in the past to inhibit ADAM17 proteolytic activity. However, due to ADAM17′s broad expression and activity profile, the development of active-site-directed ADAM17 inhibitor was discontinued. New ‘exosite’ (secondary substrate binding site) inhibitors with substrate selectivity raised the hope of a substrate-selective modulation as a promising approach for inflammatory disease therapy. This work aimed to develop a high-throughput screen for potential ADAM17 modulators as therapeutic drugs. By combining experimental and in silico methods (structural modeling and docking), we modeled the kinetics of ADAM17 inhibitor. The results explain ADAM17 inhibition mechanisms and give a methodology for studying selective inhibition towards the design of pharmaceutical substances with higher selectivity. Full article
(This article belongs to the Special Issue Natural, Designed and Engineered Metalloenzymes: Structure, Catalytic Mechanisms and Applications)
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Graphical abstract

15 pages, 3419 KiB  
Article
Design and Engineering of an Efficient Peroxidase Using Myoglobin for Dye Decolorization and Lignin Bioconversion
by Wen-Jie Guo, Jia-Kun Xu, Sheng-Tao Wu, Shu-Qin Gao, Ge-Bo Wen, Xiangshi Tan and Ying-Wu Lin
Int. J. Mol. Sci. 2022, 23(1), 413; https://doi.org/10.3390/ijms23010413 - 30 Dec 2021
Cited by 13 | Viewed by 3256
Abstract
The treatment of environmental pollutants such as synthetic dyes and lignin has received much attention, especially for biotechnological treatments using both native and artificial metalloenzymes. In this study, we designed and engineered an efficient peroxidase using the O2 carrier myoglobin (Mb) as [...] Read more.
The treatment of environmental pollutants such as synthetic dyes and lignin has received much attention, especially for biotechnological treatments using both native and artificial metalloenzymes. In this study, we designed and engineered an efficient peroxidase using the O2 carrier myoglobin (Mb) as a protein scaffold by four mutations (F43Y/T67R/P88W/F138W), which combines the key structural features of natural peroxidases such as the presence of a conserved His-Arg pair and Tyr/Trp residues close to the heme active center. Kinetic studies revealed that the quadruple mutant exhibits considerably enhanced peroxidase activity, with the catalytic efficiency (kcat/Km) comparable to that of the most efficient natural enzyme, horseradish peroxidase (HRP). Moreover, the designed enzyme can effectively decolorize a variety of synthetic organic dyes and catalyze the bioconversion of lignin, such as Kraft lignin and a model compound, guaiacylglycerol-β-guaiacyl ether (GGE). As analyzed by HPLC and ESI-MS, we identified several bioconversion products of GGE, as produced via bond cleavage followed by dimerization or trimerization, which illustrates the mechanism for lignin bioconversion. This study indicates that the designed enzyme could be exploited for the decolorization of textile wastewater contaminated with various dyes, as well as for the bioconversion of lignin to produce more value-added products. Full article
(This article belongs to the Special Issue Natural, Designed and Engineered Metalloenzymes: Structure, Catalytic Mechanisms and Applications)
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Review

Jump to: Editorial, Research

41 pages, 6422 KiB  
Review
Enzymatic and Bioinspired Systems for Hydrogen Production
by Linda Leone, Gianmattia Sgueglia, Salvatore La Gatta, Marco Chino, Flavia Nastri and Angela Lombardi
Int. J. Mol. Sci. 2023, 24(10), 8605; https://doi.org/10.3390/ijms24108605 - 11 May 2023
Cited by 20 | Viewed by 3762
Abstract
The extraordinary potential of hydrogen as a clean and sustainable fuel has sparked the interest of the scientific community to find environmentally friendly methods for its production. Biological catalysts are the most attractive solution, as they usually operate under mild conditions and do [...] Read more.
The extraordinary potential of hydrogen as a clean and sustainable fuel has sparked the interest of the scientific community to find environmentally friendly methods for its production. Biological catalysts are the most attractive solution, as they usually operate under mild conditions and do not produce carbon-containing byproducts. Hydrogenases promote reversible proton reduction to hydrogen in a variety of anoxic bacteria and algae, displaying unparallel catalytic performances. Attempts to use these sophisticated enzymes in scalable hydrogen production have been hampered by limitations associated with their production and stability. Inspired by nature, significant efforts have been made in the development of artificial systems able to promote the hydrogen evolution reaction, via either electrochemical or light-driven catalysis. Starting from small-molecule coordination compounds, peptide- and protein-based architectures have been constructed around the catalytic center with the aim of reproducing hydrogenase function into robust, efficient, and cost-effective catalysts. In this review, we first provide an overview of the structural and functional properties of hydrogenases, along with their integration in devices for hydrogen and energy production. Then, we describe the most recent advances in the development of homogeneous hydrogen evolution catalysts envisioned to mimic hydrogenases. Full article
(This article belongs to the Special Issue Natural, Designed and Engineered Metalloenzymes: Structure, Catalytic Mechanisms and Applications)
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45 pages, 5597 KiB  
Review
Recent Theoretical Insights into the Oxidative Degradation of Biopolymers and Plastics by Metalloenzymes
by Anna Rovaletti, Luca De Gioia, Piercarlo Fantucci, Claudio Greco, Jacopo Vertemara, Giuseppe Zampella, Federica Arrigoni and Luca Bertini
Int. J. Mol. Sci. 2023, 24(7), 6368; https://doi.org/10.3390/ijms24076368 - 28 Mar 2023
Cited by 11 | Viewed by 4252
Abstract
Molecular modeling techniques have become indispensable in many fields of molecular sciences in which the details related to mechanisms and reactivity need to be studied at an atomistic level. This review article provides a collection of computational modeling works on a topic of [...] Read more.
Molecular modeling techniques have become indispensable in many fields of molecular sciences in which the details related to mechanisms and reactivity need to be studied at an atomistic level. This review article provides a collection of computational modeling works on a topic of enormous interest and urgent relevance: the properties of metalloenzymes involved in the degradation and valorization of natural biopolymers and synthetic plastics on the basis of both circular biofuel production and bioremediation strategies. In particular, we will focus on lytic polysaccharide monooxygenase, laccases, and various heme peroxidases involved in the processing of polysaccharides, lignins, rubbers, and some synthetic polymers. Special attention will be dedicated to the interaction between these enzymes and their substrate studied at different levels of theory, starting from classical molecular docking and molecular dynamics techniques up to techniques based on quantum chemistry. Full article
(This article belongs to the Special Issue Natural, Designed and Engineered Metalloenzymes: Structure, Catalytic Mechanisms and Applications)
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