Cyclodextrin-based enzyme mimics

Artificial enzymes with metal ions can also hydrolyze phosphate esters (alkaline phosphatase is such a natural zinc enzyme). We examined the hydrolysis of p-nitro-phenyfdiphenylphosphate (29) by zinc complex 30, and also saw that in a micelle the related complex 31 was an even more effective catalyst [118]. Again the most likely mechanism is the bifunctional Zn-OH acting as both a Lewis acid and a hydroxide nucleophile, as in many zinc enzymes. By attaching the zinc complex 30 to one or two cyclodextrins, we saw even better catalysis with these full enzyme mimics [119]. A catalyst based on 25 - in which a bound La3+ cooperates with H202, not water - accelerates the cleavage of bis-p-nitrophenyl phosphate by over 108-fold relative to uncatalyzed hydrolysis [120]. This is an enormous acceleration. 

Material Conversion - Natural and Artificial Enzymes Enzymes perform highly selective and highly efficient molecular conversion based on sophisticated three-dimensional arrangements of amino acids. Artificial enzyme mimics can be constructed using cyclodextrins and Hpid bilayer membranes. 

Cyclodextrins have proven to be the most popular enzyme mimics, catalyzing various reactions. Cyclodextrin-based neoglycoenzymes with improved efficiency have also been designed and synthesized. Cyclodextrin-modified enzymes have potential application as biosensors as well as in the formulation of effective and biodegradable drug delivery systems for enzyme replacement therapy [84]. 

D.-Q. Yuan, S. D. Dong, R. Breslow, Cyclodextrin-based class I aldolase enzyme mimics to catalyse crossed aldol condensations, Tetrahedron Lett., 1998, 39, 7673-7676. 

The contribution from Iwao Tabushi (Kyoto) was based on his work with chemically-modified cyclodextrins as enzyme models. The asymmetrically bifunctionalised cyclodextrins (3a,3b) were synthesised in order to mimic the aminotransferase activity of Vitamin B5. The A-B regio-isomer (3a) was used to effect the transformation of keto-acids into L-amino acids with 96% ee. The elegance of the system was demonstrated by the fact that the B-A regioisomer (3b) performs the same reaction on keto-acids to give the corresponding D-amino acids acids with identical enantiomeric excesses. 

Using modified P-cyclodextrine 23, Bender et al. report a ji-cyclodextrine based artificial enzyme mimic with a catalytic triad that has catalyzed hydrolysis rates of 10 -10 faster for norbomyl cinnamate ester [21], They show that 1 mol of 23 could be used in the hydrolysis of more than 10 mol of substrate, which proves a multiple turnover of the catalyst. The proposed mechanism is shown in Fig. 7.1. This mechanism was evaluated and questioned by Zimmerman [22],... 

Ribonuclease A is a member of a group of enzymes that cleave RNA using general acid-base catalysis without a metal ion in the enzyme. In ribonuclease A, such catalysis is performed by two imidazoles of histidine units, one as the free base (Im) and the other, protonated, as the acid (ImH+). To mimic this in an artificial enzyme, we prepared (3-cyclodextrin bis-imidazoles 41 [124]. The first one was a mixture of the... 

We created a mimic of the cleavage of the cyclic phosphate by this enzyme by attaching two imidazole groups to a cyclodextrin molecule in well-defined positions (18). In water, the cyclodextrin bound a cyclic phosphate substrate—not, however, one derived from RNA—and performed the cleavage of the cyclic phosphate by using the two imidazoles as the enzyme does. That is, one functioned as a base, which delivered water... 

So far, cyclodextrin (CD 4) derivatives have been the most successful artificial enzymes based on small synthetic host molecules. Since CD derivatives form inclusion complexes with various hydrophobic molecules, they have been utilized as binding pockets." " Examples are illustrated by 5 and 6. The CD derivative indicated in 5 is a mimic of ribonuclease in which the two histidyl imidazoles of the active site are believed to act as a general acid and a general base catalyst. The CD dimer indicated in acts as an artificial metalloesterase manifesting selectivity toward esters with two hydrophobic groups. 

Classically, the bell-shaped dependence of rate of the enzymic reaction on pH has been attributed to general acid and base catalysis by the two histidine residues in the active site, His-12 and His-119 (66). Support for this explanation based on the kinetic properties of a model system was first provided by an observation by Breslow and co-workers that 8-cyclodextrin functionalized with two imidazole groups will catalyze the 1,2-cyclic phosphate of 4-rert-butylcatechol (67). The dependence of hydrolysis rate on pH mimics that of RNase A, and this behavior demonstrates that the presence of two imidazole functional groups on a nonionizable framework is the simplest kinetic mimic of the enzyme. 

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