Rational design provides an attractive strategy to tune and control the reactivity of bioinspired catalysts. Although there has been considerable progress in the design of heme oxidase mimetics with active-site environments of ever-growing complexity and catalytic efficiency, their stability during turnover is still an open challenge. Herein, we show that the simple incorporation of two 2-aminoisobutyric acids into an artificial peptide-based peroxidase results in a new catalyst (Fe -MC6*a) with higher resistance against oxidative damage and higher catalytic efficiency. The turnover number of this catalyst is twice as high as that of its predecessor. These results point out the protective role exerted by the peptide matrix and pave the way to the synthesis of robust bioinspired catalysts.

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Metalloproteins utilize O as an oxidant, and they often achieve a 4-electron reduction without H O or oxygen radical release. Several proteins have been designed to catalyze one or two-electron oxidative chemistry, but the de novo design of a protein that catalyzes the net 4-electron reduction of O has not been reported yet. We report the construction of a diiron-binding four-helix bundle, made up of two different covalently linked α monomers, through click chemistry. Surprisingly, the prototype protein, DF-C1, showed a large divergence in its reactivity from earlier DFs (DF: due ferri, two iron). DFs release the quinone imine and free H O in the oxidation of 4-aminophenol in the presence of O , whereas Fe -DF-C1 sequesters the quinone imine into the active site, and catalyzes inside the scaffold an oxidative coupling between oxidized and reduced 4-aminophenol. The asymmetry of the scaffold allowed a fine-engineering of the substrate binding pocket, that ensures selectivity.

Manganese-porphyrins are important tools in catalysis, due to their capability to promote a wide variety of synthetically valuable transformations. Despite their great reactivity, the difficulties to control the reaction selectivity and to protect the catalyst from self-degradation hamper their practical application. Compared to small-molecule porphyrin complexes, metalloenzymes display remarkable features, because the reactivity of the metal center is finely modulated by a complex interplay of interactions within the protein matrix. In the effort to combine the catalytic potential of manganese porphyrins with the unique properties of biological catalysts, artificial metalloenzymes have been reported, mainly by incorporation of manganese-porphyrins into native protein scaffolds. Here we describe the spectroscopic and catalytic properties of Mn-Mimochrome VI*a (Mn-MC6*a), a mini-protein with a manganese deuteroporphyrin active site within a scaffold of two synthetic peptides covalently bound to the porphyrin. Mn-MC6*a is an efficient catalyst endowed with peroxygenase activity. The UV-vis absorption spectrum of Mn-MC6*a resembles that of Mn-reconstituted horseradish peroxidase (Mn-HRP), both in the resting and high-valent oxidized states. Remarkably, Mn-MC6*a shows a higher reactivity compared to Mn-HRP, because higher yields and chemoselectivity were observed in thioether oxidation. Experimental evidences also provided indications on the nature of the high-valent reactive intermediate and on the sulfoxidation mechanism.

Inspired by natural heme-proteins, scientists have attempted for decades to design efficient and selective metalloporphyrin-based oxidation catalysts. Starting from the pioneering work on small molecule mimics in the late 1970s, we have assisted to a tremendous progress in designing cages of different nature and complexity, able to accommodate metalloporphyrins. With the intent of tuning and controlling their reactivity, more and more sophisticated and diverse environments are continuously exploited. In this review, we will survey the current state of art in oxidation catalysis using iron- and manganese-porphyrins housed within designed or engineered protein cages. We will also examine the innovative metal-organic framework (MOF) systems, exploited to achieving an enzyme-like environment around the metalloporphyrin cofactor.