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Designed Evolution of Artificial Metalloenzymes Based on Streptavidin or Carbonic Anhydrase as Protein Scaffold

English title Designed Evolution of Artificial Metalloenzymes Based on Streptavidin or Carbonic Anhydrase as Protein Scaffold
Applicant Ward Thomas R.
Number 126366
Funding scheme Project funding
Research institution Institut für Anorganische Chemie Universität Basel
Institution of higher education University of Basel - BS
Main discipline Inorganic Chemistry
Start/End 01.10.2009 - 30.09.2012
Approved amount 667'652.00
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All Disciplines (2)

Discipline
Inorganic Chemistry
Organic Chemistry

Keywords (14)

Carbonic Anhydrase; Artificial metalloenzyme; Lewis acid catalysis; Oxidation; Biotin Streptavidin; Tyrosine allylation; hydrolase; catalysis; biomimetic chemistry; sustainable chemistry; enzyme; homogeneous catalyst; chirality; second coordination sphere

Lay Summary (English)

Lead
Lay summary
"Catalysis is the concept which best captures the Spirit of Chemistry: the Miracle of consumption and regeneration."In a catalytic cycle, a molecule, the catalyst, intimately participates to the reaction by accelerating the chemical transformation but is not consumed. Such catalysts have enormous societal impact, significantly decreasing the energy (and thus cost) required to produce various products, ranging from the delicate process of digestion, to fertilizers to sustain life on earth.Natural enzymes have evolved over millions of years to orchestrate the ballet of Life at a minimal energetic cost. A human being only requires 2000 Watts to sustain his daily activities. For this, we rely on 30'000 different proteins, most of which acting as enzymes.To address the requirements for the production of various chemicals, ranging from paints, pharmaceuticals, fertilisers, foods etc., different types of catalysts are used: enzymes, homogeneous- and heterogeneous catalysts. All three types offer advantages and disadvantages.With the aim of exploiting their most attractive and complementary features, it is proposed to merge homogeneous and enzymatic catalysis to yield artificial metalloenzymes. As we have demonstrated in the past, incorporation of an active metal moiety within a protein environment affords hybrid catalysts with very promising properties, including high activities and selectivities, reminiscent of both homogeneous and enzymatic catalysts.Within this project, it is proposed to extend the concept of metalloenzymes towards i) other protein hosts and ii) more challenging oxidation reactions. For this purpose, we pursue a highly interdisciplinary and synergistic approach, including synthesis, molecular biology, enzymology, molecular modelling, X-ray crystallography etc. Oxidation reactions are central to addressing the grand energy challenge. Indeed, the selective catalyzed oxidation of i) abundant methane to methanol or ii) water to dioxygen would represent a big step towards solving both the energy crisis and the global warming.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Design of a functional nitric oxide reductase within a myoglobin scaffold
Kohler V., Ward T. R. (2017), Design of a functional nitric oxide reductase within a myoglobin scaffold, in Chembiochem : a European journal of chemical biology, 11, 1049-1051.
Arylsulfonamides as inhibitors for carbonic anhydrase: prediction & validation
Schmid Maurus, Nogueira Elisa S., Monnard Fabien W., Ward Thomas R., Meuwly Markus (2012), Arylsulfonamides as inhibitors for carbonic anhydrase: prediction & validation, in Chem. Sci, 3, 690-700.
Biotinylated Rh(III) Complexes in Engineered Streptavidin for Accelerated Asymmetric C-H Activation
Hyster Todd K., Knoerr Livia, Ward Thomas R., Rovis Tomislav (2012), Biotinylated Rh(III) Complexes in Engineered Streptavidin for Accelerated Asymmetric C-H Activation, in Science, 338, 500-503.
Chemically Programmed Supramolecular Assembly of Hemoprotein and Streptavidin with Alternating Alignment
Oohora Koji, Burazerovic Sabina, Onoda Akira, Wilson Yvonne M., Ward Thomas R., Hayashi Takashi (2012), Chemically Programmed Supramolecular Assembly of Hemoprotein and Streptavidin with Alternating Alignment, in Angew. Chem. Int. Ed., 51, 3818-3821.
Identification of two-histidines one-carboxylate binding motifs in proteins amenable to facial coordination to metals
Amrein Beat, Schmid Maurus, Collet Guillaume, Cuniasse Philippe, Gilardoni Francois, Seebeck Florian P., Ward Thomas R. (2012), Identification of two-histidines one-carboxylate binding motifs in proteins amenable to facial coordination to metals, in Metallomics, 4, 379-88.
Redox-Active Ligands in Catalysis
Praneeth Vijayendran K. K., Ringenberg Mark R., Ward Thomas R. (2012), Redox-Active Ligands in Catalysis, in Angewandte Chem. Int. Ed., 51, 10228-10234.
Artificial metalloenzymes based on the biotin-avidin technology: enantioselective catalysis and beyond
Ward T. R. (2011), Artificial metalloenzymes based on the biotin-avidin technology: enantioselective catalysis and beyond, in Accounts of chemical research, 44, 47-57.
Artificial Metalloenzymes Based on the Biotin-Avidin Technology: Enantioselective Catalysis and Beyond
Ward Thomas R. (2011), Artificial Metalloenzymes Based on the Biotin-Avidin Technology: Enantioselective Catalysis and Beyond, in Acc. Chem. Res., 44, 47-57.
Artificial metalloenzymes for olefin metathesis based on the biotin-(strept)avidin technology
Lo C., Ringenberg M. R., Gnandt D., Wilson Y., Ward T. R. (2011), Artificial metalloenzymes for olefin metathesis based on the biotin-(strept)avidin technology, in Chemical communications, 47(29), 8238-8240.
Artificial transfer hydrogenases for the enantioselective reduction of cyclic imines
Durrenberger M., Heinisch T., Wilson Y. M., Rossel T., Nogueira E., Knorr L., Mutschler A., Kersten K., Zimbron M. J., Pierron J., Schirmer T., Ward T. R. (2011), Artificial transfer hydrogenases for the enantioselective reduction of cyclic imines, in Angewandte Chemie, 50, 3026-3031.
Burkavidin: a novel secreted biotin-binding protein from the human pathogen Burkholderia pseudomallei
Sardo A., Wohlschlager T., Lo C., Zoller H., Ward T. R., Creus M. (2011), Burkavidin: a novel secreted biotin-binding protein from the human pathogen Burkholderia pseudomallei, in Protein expression and purification, 77(2), 131-139.
Design and evolution of artificial metalloenzymes: Biomimetic aspects
Creus Marc, Ward Thomas R. (2011), Design and evolution of artificial metalloenzymes: Biomimetic aspects, in Progress Inorg. Chem., 57, 203-253.
Human Carbonic Anhydrase II as a host for piano-stool complexes bearing a sulfonamide anchor
Monnard F. W., Heinisch T., Nogueira E. S., Schirmer T., Ward T. R. (2011), Human Carbonic Anhydrase II as a host for piano-stool complexes bearing a sulfonamide anchor, in Chemical communications, 47(29), 8238-8240.
Merging the best of two worlds: artificial metalloenzymes for enantioselective catalysis
Ringenberg M. R., Ward T. R. (2011), Merging the best of two worlds: artificial metalloenzymes for enantioselective catalysis, in Chemical communications, 47(30), 8470-8476.
Artificial metalloenzymes: enantioselective catalysis and beyond
Ward Thomas R. (2010), Artificial metalloenzymes: enantioselective catalysis and beyond, in Chimia, 64, 850-852.
Bioorganic and bioinorganic chemistry
Constable E. C., Housecroft C. E., Creus M., Gademann K., Giese B., Ward T. R., Woggon W. D., Chougnet A. (2010), Bioorganic and bioinorganic chemistry, in Chimia, 64(12), 846-854.
Chemo-genetic optimization of DNA recognition by metallodrugs using a presenter-protein strategy
Zimbron J. M., Sardo A., Heinisch T., Wohlschlager T., Gradinaru J., Massa C., Schirmer T., Creus M., Ward T. R. (2010), Chemo-genetic optimization of DNA recognition by metallodrugs using a presenter-protein strategy, in Chemistry, 16(43), 12883-12889.
Design of a Functional Nitric Oxide Reductase within a Myoglobin Scaffold
Koehler Valentin, Ward Thomas R. (2010), Design of a Functional Nitric Oxide Reductase within a Myoglobin Scaffold, in ChemBioChem, 11, 1049-1051.
Design strategies for the creation of artificial metalloenzymes
Heinisch T., Ward T. R. (2010), Design strategies for the creation of artificial metalloenzymes, in Current opinion in chemical biology, 14(2), 184-199.
Flexibility of a biotinylated ligand in artificial metalloenzymes based on streptavidin--an insight from molecular dynamics simulations with classical and ab initio force fields
Panek J. J., Ward T. R., Jezierska-Mazzarello A., Novic M. (2010), Flexibility of a biotinylated ligand in artificial metalloenzymes based on streptavidin--an insight from molecular dynamics simulations with classical and ab initio force fields, in Journal of computer-aided molecular design, 24(9), 719-732.
Improving the Enantioselectivity of Artificial Transfer Hydrogenases Based on the Biotin-Streptavidin Technology by Combinations of Point Mutations
Pordea A., Creus M., Letondor C., Ivanova A., Ward Th. (2010), Improving the Enantioselectivity of Artificial Transfer Hydrogenases Based on the Biotin-Streptavidin Technology by Combinations of Point Mutations, in Inorg. Chim. Acta, 363, 601-604.
Protein-based hybrid catalysts--design and evolution
Kohler V., Wilson Y. M., Lo C., Sardo A., Ward T. R. (2010), Protein-based hybrid catalysts--design and evolution, in Current opinion in biotechnology, 21(6), 744-752.
Proteins as host for enantioselective catalysis: artificial metalloenzymes based on the biotin-streptavidin technology
Mao Jincheng, Ward Thomas R. (2010), Proteins as host for enantioselective catalysis: artificial metalloenzymes based on the biotin-streptavidin technology, in West Sussex, 361-376.
Artificial metalloenzymes for enantioselective catalysis based on the biotin-avidin technology
Steinreiber Johannes, Ward Thomas R. (2009), Artificial metalloenzymes for enantioselective catalysis based on the biotin-avidin technology, in Top. Organomet. Chem, 25, 93-112.
Artificial Metalloenzymes: Combining the Best Features of Homogeneous and Enzymatic Catalysis
Pordea A., Ward Th. (2009), Artificial Metalloenzymes: Combining the Best Features of Homogeneous and Enzymatic Catalysis, in Synlett, 20, 3225-3236.
Artificial metalloenzymes: combining the best features of homogeneous and enzymatic catalysis
Pordea Anca, Ward Thomas R. (2009), Artificial metalloenzymes: combining the best features of homogeneous and enzymatic catalysis, in Synlett, 3225-3236.
Effects of tryptophan residue fluorination on streptavidin stability and biotin-streptavidin interactions via molecular dynamics simulations
Panek Jaroslaw J., Ward Thomas R., Jezierska Aneta, Novic Marjana (2009), Effects of tryptophan residue fluorination on streptavidin stability and biotin-streptavidin interactions via molecular dynamics simulations, in J. Mol. Model, 15, 257-66.
Flexibility of a biotinylated ligand in artificial metalloenzymes based on streptavidin-an insight from molecular dynamics simulations with classical and ab initio force fields
Panek Jaroslaw J., Ward Thomas R., Jezierska-Mazzarello Aneta, Novic Marjana (2009), Flexibility of a biotinylated ligand in artificial metalloenzymes based on streptavidin-an insight from molecular dynamics simulations with classical and ab initio force fields, in J.Mol.Model, 719-732.
Incorporation of Biotinylated Manganese Salen Complexes into Streptavidin New Artificial Metalloenzymes for Enantioselective Sulfoxidation
Pordea A., Mathis D., Ward Th. (2009), Incorporation of Biotinylated Manganese Salen Complexes into Streptavidin New Artificial Metalloenzymes for Enantioselective Sulfoxidation, in J. Organomet. Chem., 694, 930-936.
Site-Dependent Excited-State Dynamics of a Fluorescent Probe Bound to Avidin and Streptavidin
Fuerstenberg Alexandre, Kel Oksana, Gradinaru Julieta, Ward Thomas R., Emery Daniel, Bollot Guillaume, Mareda Jiri, Vauthey Eric (2009), Site-Dependent Excited-State Dynamics of a Fluorescent Probe Bound to Avidin and Streptavidin, in ChemPhysChem, 10, 1517-1532.
An artificial metalloenzyme for olefin metathesis
Mayer C., Gillingham D. G., Ward T. R., Hilvert D., An artificial metalloenzyme for olefin metathesis, in Chemical communications.
OsO(4) Streptavidin: A Tunable Hybrid Catalyst for the Enantioselective cis-Dihydroxylation of Olefins
Kohler V., Mao J., Heinisch T., Pordea A., Sardo A., Wilson Y. M., Knorr L., Creus M., Prost J. C., Schirmer T., Ward T. R., OsO(4) Streptavidin: A Tunable Hybrid Catalyst for the Enantioselective cis-Dihydroxylation of Olefins, in Angewandte Chemie, 50(advance ar).

Collaboration

Group / person Country
Types of collaboration
Biozentrum, University of Basel (Prof. T. Schirmer, X-ray crystallography) Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel

Scientific events



Self-organised

Title Date Place
31 Regiosymposium 11.09.2011 Sornetan, Switzerland

Awards

Title Year
2010 SCS Fall meeting poster prize 2010

Associated projects

Number Title Start Funding scheme
113348 Broadening the scope of artificial metalloenzymes based on the biotinavidin technology 01.10.2006 Project funding
144354 Directed Evolution of Artificial Metalloenzymes : Towards Chemical Biology Applications 01.10.2012 Project funding
139133 Structure, dynamics and interactions of paramagnetic centers characterised by Electrn Paramagnetic Resonance 01.12.2011 R'EQUIP

Abstract

With the aim of complementing enzymes and homogeneous catalysts, artificial metalloenzymes have has attracted increasing attention in recent years. Artificial metalloenzymes result from the anchoring of a catalytically active organometallic moiety within a macromolecular host (protein or DNA) thus affording versatile catalysts for a variety of enantioselective transformations. In the past six years, the Ward group has been exploiting the biotin-avidin technology to produce artificial metalloenzymes for enantioselective hydrogenation, transfer-hydrogenation, allylic alkylation and sulfoxidation. Relying on a chemogenetic optimization scheme, enantioselectivities exceeding 90 % were achieved. This optimization strategy relies on the systematic variation of both the ligand moiety as well as the spacer between the biotin anchor and the metal center (chemical optimization); combined with targeted mutations on the protein scaffold. A recent X-ray structure of an artificial transfer hydrogenase has revealed several leads for the design of improved artificial metalloenzymes, and forms the basis of the present proposal.Within the project outlined herein, it is proposed to evaluate and compare the potential of human carbonic anhydrase (HCA II) as a host for the incorporation of organometallic moieties bearing an aryl-sulfonamide anchor (which typically display nM affinities for HCA II). Throughout the project, the potential of HCA II will be compared to the potential of streptavidin (using biotinylated organometallic catalysts) as host for the same catalytic transformation. Thanks to QM-MM modelling, we propose to further refine the design of artificial metalloenzymes by introducing point mutations which will allow to i) additionally fix the metal moiety via an amino-acid side chain and ii) activate and orient the substrate. In a biomimetic spirit, it is proposed to focus primarily on bis-imine ligands (as mimick for bis-histidine coordination) bearing either a sulfonamide or a biotin anchor. These ligands will be complemented by an aminoacid residue provided by the host protein (Glu, Asp, His, Cys etc) to mimick the “facial triad” widely represented among a variety of naturally occuring enzymes. Orienting and activating the substrate will be achieved by introduction of a suitable residue on the protein scaffold.The catalytic potential of the resulting artificial metalloenzymes will be evaluated for both Lewis-acid catalysis as well as more challenging oxidation reactions. Reactions include: hydrolysis of esters and amides, epoxide ring opening by water, Diels-Alder and conjugate additions, oxidation of racemic alcohols, epoxidation and C-H activation. With the aim of extending the field of applications toward chemical biology, it is proposed to evaluate the potential of artificial metalloenzymes for the site-specific recognition of DNA (hydrolysis) and of proteins (allylation of tyrosine residues).
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