Metalloenzyme mimics

S. D. Dong, R. Breslow, Bifunctional cyclodextrin metalloenzyme mimics. Tetrahedron Lett., 1998, 39, 9343-9346. 

NON-SYMMETRIC DINUCLEATING LIGANDS FOR OXIDATION CATALYSTS TEMPLATES FOR REALISTIC DINUCLEAR METALLOENZYME MIMICS... 

Metallomicellar-catalyzed reactions, inclnding hydrolysis, oxidorednction, and C—C bond formation, might characterize these snpramolecular objects as metalloenzyme mimics that use hydrophobic microenvironment and active centers in constrained domains. In this direction, formal approaches using Michaelis-Menten methods known for enzyme chemistry were applied to kinetics characterization of micellar catalysis. In addition, recent achievements of advanced organometallic reactions such as Heck, Suzuki, and Sonogashira couplings as well as olefin metathesis, directly in water and at room temperature, make the use of surfactants particularly promising to lower the environmental impact, which has become a requirement for the chemical industry in the past years. ... 

The system illustrated by (272) forms the basis of a model for the zinc-containing metalloenzyme, carbonic anhydrase (Tabushi Kuroda, 1984). It contains Zn(n) bound to imidazole groups at the end of a hydrophobic pocket, as well as basic (amine) groups which are favourably placed to interact with a substrate carbon dioxide molecule. These are both features for the natural enzyme whose function is to catalyze the reversible hydration of carbon dioxide. The synthetic system is able to mimic the action of the enzyme (although side reactions also occur). Nevertheless, the formation of bicarbonate is still many orders of magnitude slower than occurs for the enzyme. 

One purpose of our work is to mimic the chiral environment of the enzymes. Therefore, we thought it a reasonable goal to supply chiral models for the active sites of metalloenzymes. This was achieved before by Alsfasser et al. 113) or Vahrenkamp et al. 114) via amino acids that have been incorporated into the ligand systems. Modification of Tp ligands by chiral pyrazoles derived from the chiral pool is another way to chiral W,W,iV tripod ligands and has been achieved before by W. B. Tolman and coworkers (115). Thus, first we focused on the synthesis of a racemic mixture of a chiral NJtl,0 scorpionate... 

Researchers studying the metalloenzyme hydrogenase would like to design small compounds that mimic this enzyme s ability to reversibly reduce protons to H2 and H2 to 2H+, using an active center that contains iron and nickel. Cobalamins (vitamin and its derivatives) contain an easily activated Co-C bond that has a number of biological functions, one of which is as a methyl transferase, 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR). This enzyme converts homocysteine (an amino acid that has one more CH2 group in its alkyl side chain than cysteine see Figure 2.2) to methionine as methylcobalamin is converted to cobalamin. 

The Tpx ligands can mimic the coordination environment created by three imidazolyl groups from histidine residues, which is frequently found in the active sites of metalloenzymes. Higher valent bis(ix-oxo) species, [(Tpx)M( i-0)2M(Tpx)] via 0-0 cleavage of [(Tpx)M( x-r 2 r 2-02)M(Tpx)] intermediates, but also peroxo, hydroperoxo, and alkylperoxo species, active species undergoing oxidative C-C cleavage reaction, stable hydrocarbyl complexes, and dinuclear xenophilic complexes, [(Tpx)M-M L71], are all relevant to chemical and biological processes, most of which are associated with transition metal catalytic species. 

The study of model complexes as metalloenzyme mimetics has a long tradition in bioinorganic chemistry (see Chem. Rev. 2004, 104, issue 2 for a complete revision). Several Ni-Fe-based complexes have been prepared, with structural features similar to those found in the FeNi active site.98 Nevertheless, none of them has been tested in its ability to coordinate or decompose H2. Present research is mainly centered in mimicking the thiolate ligands in the Fe-Ni coordination. It has to be mentioned that Fe-only hydrogenase mimics able to electrocatalyze proton reduction have been recently reported.99... 

To mimic nature is a demanding but appealing task. Many metalloenzymes are difficult to isolate and purify, and thus to obtain in sufficient quantities to employ in a commercially... 

The active site in CAII has been modelled using a tris(pyrazolyl)hydroborato ligand (28.22) to mimic the three histidine residues that bind Zn in the metalloenzyme. Because Zn is a metal ion, it tolerates a range of coordination geometries. However, tris(pyrazolyl)hydro-borato ligands are tripodal (see Section 19.7) and can force tetrahedral coordination in a complex of type [Zn(28.22)X]. The hydroxo complex 28.23 is one of a series... 

Although metal ions have large catalytic effects, such effects are limited to substrates which can bind metal ions. Thus, it was expected that the combination of catalytic ability of a metal ion and the binding ability of a cyclodextrin would produce an excellent catalyst which mimics a metalloenzyme. 

We reasoned that one could mimic Nature by incorporating cofactors and metal ions to broaden the scope of accessible reactions catalyzed by protein scaffolds. Different approaches for the generation of artificial metalloenzymes have recently been reviewed [2-16]. Herein, we present the developments in the field of artificial metalloenzymes for enantioselective catalysis based on the biotin-avidin technology. The discussion includes a short introduction on the biotin-avidin technology followed by several examples of chemogenetic optimization of the performance of artificial metalloenzymes based on this technology. 

---