Artificial Metalloproteins for Binding and Stabilization of a Semiquinone Radical

Ségaud, Nathalie; Drienovská, Ivana; Chen, Juan; Browne, Wesley R.; Roelfes, Gérard

doi:10.1021/acs.inorgchem.7b02073

Cited by 15 publications

(20 citation statements)

References 43 publications

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“…In an interesting recent development, the Roelfes group described the binding and stabilization of semiquinone radicals (Figure8e) by artificial metalloproteins containing a number of first row metals in the LmrR_M89Bpy-Ala template. [38] Although catalytic functionh as not been demonstrated, this study may provide af irst step towards harnessing the chemistry of unstabler adicals, with potentialf uture applications in catalysis.…”

Section: Artificial Metalloenzymes Containing Metal-chelating Amino Amentioning

confidence: 95%

“…Although the catalytic efficiencies of the artificial metalloenzymes created in the LmrR template remain modest, these studies demonstrate that the installation of metal chelating amino acids into proteins can lead to the creation of metalloprotein catalysts for non‐biological, enantioselective transformations. In an interesting recent development, the Roelfes group described the binding and stabilization of semiquinone radicals (Figure e) by artificial metalloproteins containing a number of first row metals in the LmrR_M89Bpy‐Ala template . Although catalytic function has not been demonstrated, this study may provide a first step towards harnessing the chemistry of unstable radicals, with potential future applications in catalysis.…”

Section: Artificial Metalloenzymes Containing Metal‐chelating Amino Amentioning

confidence: 99%

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Engineered Metalloenzymes with Non‐Canonical Coordination Environments

Hayashi

Hilvert

Green

2018

Chemistry A European J

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Nature employs a limited number of genetically encoded, metal-coordinating residues to create metalloenzymes with diverse structures and functions. Engineered components of the cellular translation machinery can now be exploited to encode non-canonical ligands with user-defined electronic and structural properties. This ability to install "chemically programmed" ligands into proteins can provide powerful chemical probes of metalloenzyme mechanism and presents excellent opportunities to create metalloprotein catalysts with augmented properties and novel activities. In this Concept article, we provide an overview of several recent studies describing the creation of engineered metalloenzymes with interesting catalytic properties, and reveal how characterization of these systems has advanced our understanding of nature's bioinorganic mechanisms. We also highlight how powerful laboratory evolution protocols can be readily adapted to allow optimization of metalloenzymes with non-canonical ligands. This approach combines beneficial features of small molecule and protein catalysis by allowing the installation of a greater variety of local metal coordination environments into evolvable protein scaffolds, and holds great promise for the future creation of powerful metalloprotein catalysts for a host of synthetically valuable transformations.

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Section: Artificial Metalloenzymes Containing Metal-chelating Amino Amentioning

confidence: 95%

Section: Artificial Metalloenzymes Containing Metal‐chelating Amino Amentioning

confidence: 99%

Engineered Metalloenzymes with Non‐Canonical Coordination Environments

Hayashi

Hilvert

Green

2018

Chemistry A European J

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“…It was shown that other divalent first-row transition-metal ions, such asNi(II), Co(II), and Zn(II), are also efficiently bound to BpyA. 36 The corresponding iron protein could also be created, albeit this required the introduction of additional carboxylate moieties in the vicinity of the metal-BpyA site, most likely to act as additional ligands to the iron center.…”

Section: Artificial Metalloenzymes With Covalently Attached Metal Cofmentioning

confidence: 99%

Section: Artificial Metalloenzymes With Covalently Attached Metal Cofmentioning

confidence: 99%

LmrR: A Privileged Scaffold for Artificial Metalloenzymes

2019

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ConspectusThe biotechnological revolution has made it possible to create enzymes for many reactions by directed evolution. However, because of the immense number of possibilities, the availability of enzymes that possess a basal level of the desired catalytic activity is a prerequisite for success. For new-to-nature reactions, artificial metalloenzymes (ARMs), which are rationally designed hybrids of proteins and catalytically active transition-metal complexes, can be such a starting point.This Account details our efforts toward the creation of ARMs for the catalysis of new-to-nature reactions. Key to our approach is the notion that the binding of substrates, that is, effective molarity, is a key component to achieving large accelerations in catalysis. For this reason, our designs are based on the multidrug resistance regulator LmrR, a dimeric transcription factor with a large, hydrophobic binding pocket at its dimer interface. In this pocket, there are two tryptophan moieties, which are important for promiscuous binding of planar hydrophobic conjugated compounds by π-stacking. The catalytic machinery is introduced either by the covalent linkage of a catalytically active metal complex or via the ligand or supramolecular assembly, taking advantage of the two central tryptophan moieties for noncovalent binding of transition-metal complexes.Designs based on the chemical modification of LmrR were successful in catalysis, but this approach proved too laborious to be practical. Therefore, expanded genetic code methodologies were used to introduce metal binding unnatural amino acids during LmrR biosynthesis in vivo. These ARMs have been successfully applied in Cu(II) catalyzed Friedel–Crafts alkylation of indoles. The extension to MDRs from the TetR family resulted in ARMs capable of providing the opposite enantiomer of the Friedel–Crafts product. We have employed a computationally assisted redesign of these ARMs to create a more active and selective artificial hydratase, introducing a glutamate as a general base at a judicious position so it can activate and direct the incoming water nucleophile.A supramolecularly assembled ARM from LmrR and copper(II)–phenanthroline was successful in Friedel–Crafts alkylation reactions, giving rise to up to 94% ee. Also, hemin was bound, resulting in an artificial heme enzyme for enantioselective cyclopropanation reactions. The importance of structural dynamics of LmrR was suggested by computational studies, which showed that the pore can open up to allow access of substrates to the catalytic iron center, which, according to the crystal structure, is deeply buried inside the protein.Finally, the assembly approaches were combined to introduce both a catalytic and a regulatory domain, resulting in an ARM that was specifically activated in the presence of Fe(II) salts but not Zn(II) salts.Our work demonstrates that LmrR is a privileged scaffold for ARM design: It allows for multiple assembly methods and even combinations of these, it can be applied in a variety of different catalytic reac...

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“…Metal complexes found in naturally evolved proteins play an important role in the stabilization of the 3D structure and function of proteins. Inspired by these metal complexes, metals and ligands that are not used in naturally evolved proteins have been incorporated into protein and peptide scaffolds to utilize the potency of the formed metal complexes and/or regulate the structure of the scaffolds . For example, Lee et al demonstrated that a copper‐bipyridine complex formed in a DNA binding protein could oxidatively cleave DNA .…”

Section: Introductionmentioning

confidence: 99%

Phosphorogenic and spontaneous formation of tris(bipyridine)ruthenium in peptide scaffolds

Karimiavargani

Tada

Minagawa

et al. 2019

Journal of Peptide Science

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Redox‐active ruthenium complexes have been widely used in various fields; however, the harsh conditions required for their synthesis are not always conducive to their subsequent use in biological applications. In this study, we demonstrate the spontaneous formation of a derivative of tris(bipyridine)ruthenium at 37°C through the coordination of three bipyridyl ligands incorporated into a peptide to a ruthenium ion. Specifically, we synthesized six bipyridyl‐functionalized peptides with randomly chosen sequences. The six peptides bound to ruthenium ions and exhibited similar spectroscopic and electrochemical features to tris(bipyridine)ruthenium, indicating the formation of ruthenium complexes as we anticipated. The photo‐excited triplet state of the ruthenium complex formed in the peptides exhibited an approximately 1.6‐fold longer lifetime than that of tris(bipyridine)ruthenium. We also found that the photo‐excited state of the ruthenium complexes was able to transfer an electron to methyl viologen, indicating that the ruthenium complexes formed in the peptides had the same ability to transfer charge as tris(bipyridine)ruthenium. We believe that this strategy of producing ruthenium complexes in peptides under mild conditions will pave the way for developing new metallopeptides and metalloproteins containing functional metal‐complexes.

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Artificial Metalloproteins for Binding and Stabilization of a Semiquinone Radical

Cited by 15 publications

References 43 publications

Engineered Metalloenzymes with Non‐Canonical Coordination Environments

Engineered Metalloenzymes with Non‐Canonical Coordination Environments

LmrR: A Privileged Scaffold for Artificial Metalloenzymes

Phosphorogenic and spontaneous formation of tris(bipyridine)ruthenium in peptide scaffolds

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