Cavazza, C.; Ménage, S.

Angew. Chem. Int. Ed. 2013, 52, 3922-3925, 10.1002/anie.201209021

The substrate for an artificial iron monooxygenase was selected by using docking calculations. The high catalytic efficiency of the reported enzyme for sulfide oxidation was directly correlated to the predicted substrate binding mode in the protein cavity, thus illustrating the synergetic effect of the substrate binding site, protein scaffold, and catalytic site.

Apfel, U.-P.; Happe, T.; Kurisu, G.

Chem. Sci. 2016, 7, 959-968, 10.1039/C5SC03397G

Crystal structures of semisynthetic [FeFe]-hydrogenases with variations in the [2Fe] cluster show little structural differences despite strong effects on activity.

Liu, X.; Wang, J.; Wu, Y.; Zhong, F.

J. Am. Chem. Soc. 2021, 143, 617-622, 10.1021/jacs.0c10882

Devising artificial photoenzymes for abiological bond-forming reactions is of high synthetic value but also a tremendous challenge. Disclosed herein is the first photobiocatalytic cross-coupling of aryl halides enabled by a designer artificial dehalogenase, which features a genetically encoded benzophenone chromophore and site-specifically modified synthetic NiII(bpy) cofactor with tunable proximity to streamline the dual catalysis. Transient absorption studies suggest the likelihood of energy transfer activation in the elementary organometallic event. This design strategy is viable to significantly expand the catalytic repertoire of artificial photoenzymes for useful organic transformations.

Ménage, S.

J. Mol. Catal. A: Chem. 2016, 416, 20-28, 10.1016/j.molcata.2016.02.015

A new artificial oxidase has been developed for selective transformation of thioanisole. The catalytic activity of an iron inorganic complex, FeLibu, embedded in a transport protein NikA has been investigated in aqueous media. High efficiency (up to 1367 t), frequency 459 TON min−1 and selectivity (up to 69%) make this easy to use catalytic system an asset for a sustainable chemistry.

Apfel, U.-P.; Happe, T.

Dalton Trans. 2017, 46, 16947-16958, 10.1039/C7DT03785F

Combination of biological and chemical methods allow for creation of [FeFe]-hydrogenases with an artificial synthetic cofactor.

Cavazza, C.; Ménage, S.

J. Am. Chem. Soc. 2017, 139, 17994-18002, 10.1021/jacs.7b09343

Designing systems that merge the advantages of heterogeneous catalysis, enzymology, and molecular catalysis represents the next major goal for sustainable chemistry. Cross-linked enzyme crystals display most of these essential assets (well-designed mesoporous support, protein selectivity, and molecular recognition of substrates). Nevertheless, a lack of reaction diversity, particularly in the field of oxidation, remains a constraint for their increased use in the field. Here, thanks to the design of cross-linked artificial nonheme iron oxygenase crystals, we filled this gap by developing biobased heterogeneous catalysts capable of oxidizing carbon–carbon double bonds. First, reductive O2 activation induces selective oxidative cleavage, revealing the indestructible character of the solid catalyst (at least 30 000 turnover numbers without any loss of activity). Second, the use of 2-electron oxidants allows selective and high-efficiency hydroxychlorination with thousands of turnover numbers. This new technology by far outperforms catalysis using the inorganic complexes alone, or even the artificial enzymes in solution. The combination of easy catalyst synthesis, the improvement of “omic” technologies, and automation of protein crystallization makes this strategy a real opportunity for the future of (bio)catalysis.

Ménage, S.

Artificial Metalloenzymes and MetalloDNAzymes in Catalysis: From Design to Applications 2018, 199-224, 10.1002/9783527804085.ch7

Artificial metalloenzymes broadens the scope of possibilities for catalysis at the crossroad of biocatalysis and metal‐based catalysis. The content of this chapter illustrates this outline in the field of oxidation, thanks to remarkable achievements for epoxidation and sulfoxidation in particular. Selectivity, especially enantioselectivity, is benchmarked based on six design strategies (ranging from protein engineering to de novo design), revealing that artificial systems may compete natural ones.

Ménage, S.

Isr. J. Chem. 2015, 55, 61-75, 10.1002/ijch.201400110

The principle of enzyme mimics has been raised to its pinnacle by the design of hybrids made from inorganic complexes embedded into biomolecules. The present review focuses on the design of artificial metalloenzymes for oxidation reactions by oxygen transfer reactions, with a special focus on proteins anchoring inorganic complexes or metal ions via supramolecular interactions. Such reactions are of great interest for the organic synthesis of building blocks. In the first part, following an overview of the different design of artificial enzymes, the review presents contributions to the rational design of efficient hybrid biocatalysts via supramolecular host/guest approaches, based on the nature of the inorganic complex and the nature of the protein, with special attention to the substrate binding. In the second part, the original purpose of artificial metalloenzymes has been twisted to enable the observation of transient intermediates, to decipher metal‐based oxidation mechanisms. The host protein crystals have been used as crystalline molecular‐scale vessels, within which inorganic catalytic reactions have been followed, thanks to X‐ray crystallography. These hybrids should be an alternative to enzymes for sustainable chemistry.

Happe, T.

Nat. Chem. Biol. 2013, 9, 607-609, 10.1038/Nchembio.1311

Hydrogenases catalyze the formation of hydrogen. The cofactor ('H-cluster') of [FeFe]-hydrogenases consists of a [4Fe-4S] cluster bridged to a unique [2Fe] subcluster whose biosynthesis in vivo requires hydrogenase-specific maturases. Here we show that a chemical mimic of the [2Fe] subcluster can reconstitute apo-hydrogenase to full activity, independent of helper proteins. The assembled H-cluster is virtually indistinguishable from the native cofactor. This procedure will be a powerful tool for developing new artificial H2-producing catalysts.

Happe, T.; Hemschemeier, A.

Nat. Rev. Chem. 2018, 2, 231-243, 10.1038/s41570-018-0029-3

Metal cofactors considerably widen the catalytic space of naturally occurring enzymes whose specific and enantioselective catalytic activity constitutes a blueprint for economically relevant chemical syntheses. To optimize natural enzymes and uncover novel reactivity, we need a detailed understanding of cofactor–protein interactions, which can be challenging to obtain in the case of enzymes with sophisticated cofactors. As a case study, we summarize recent research on the [FeFe]-hydrogenases, which interconvert protons, electrons and dihydrogen at a unique iron-based active site. We can now chemically synthesize the complex cofactor and incorporate it into an apo-protein to afford functional enzymes. By varying both the cofactor and the polypeptide components, we have obtained detailed knowledge on what is required for a metal cluster to process H2. In parallel, the design of artificial proteins and catalytically active nucleic acids are advancing rapidly. In this Perspective, we introduce these fields and outline how chemists and biologists can use this knowledge to develop novel tailored semisynthetic catalysts.

Cavazza, C.; Ménage, S.

ChemBioChem 2009, 10, 545-552, 10.1002/cbic.200800595

Magic Mn–salen metallozyme: The design of an original, artificial, inorganic, complex‐protein adduct, has led to a better understanding of the synergistic effects of both partners. The exclusive formation of sulfoxides by the hybrid biocatalyst, as opposed to sulfone in the case of the free inorganic complex, highlights the modulating role of the inorganic‐complex‐binding site in the protein.