Enzymes organic approach

Biological catalysts — enzymes — are usually proteins. The development of new protein syntheses is nowadays dominated by genetic protein engineering (see section 4.1.2.6). Bio-organic approaches towards novel catalytically active structures and replicating systems try to manage without biopolymers. 

As with adults, the primary organ responsible for drug metabolism in children is the liver. Although the cytochrome P450 system is fully developed at birth, it functions more slowly than in adults. Phase I oxidation reactions and demethylation enzyme systems are significantly reduced at birth. However, the reductive enzyme systems approach adult levels and the methylation pathways are enhanced at birth. This often contributes to the production of different metabolites in newborns from those in adults. For example, newborns metabolize approximately 30% of theophylline to caffeine rather than to uric acid derivatives, as occurs in adults. While most phase I enzymes have reached adult levels by 6 months of age, alcohol dehydrogenase activity appears around 2 months of age and approaches adult levels only by age 5 years. 

The increase in cell production due to UF is shown in Figure 3.103.76 Clostridium histolyticum is cultivated in batch and continuous fermentors. In the batch system, the organism approaches a stationary phase at about the twelfth hour due to toxic metabolite production. In the continuous fermentor, fresh substrate is fed continuously and the toxic products are continuously removed enabling growth to continue well past the fortieth hour. Likewise, the enzyme production from this fermentor is enhanced (see Figure... 

Enzyme Organic Cosubstrates Approach the Reaction Center From One Direction Only" Through a Special Structural Feature, Inorganic Cosubstrates (FI20, / , PPt) Approach the Catalytic Center From a Direction Oopposate to That Required (or Organic Acceptors ... 

PMi3-Sub dissolved in [EMIM] [(CF3S02)2N] for the transesterification of N-acetyl-L-phenylalanine ethyl ester with 1-butanol further revealed an increase in the reaction rate (306 nmol min (mg enzyme)" ) in comparison to performing the reaction in the organic solvent toluene (93 nmol min (mg enzyme)" ). This approach offers the potential to obtain high enzymatic activity in pure ionic liquids without immobilization of enzyme or addition of water [77]. 

There are three basic approaches to enzyme (replacement) therapy, involving the direct administration of the enzyme, organ or tissue transplantation, and extracorporeal administration. The latter involves the use of extracorporeal shunts in which the insolubilized enzymes are encapsulated in inert microcapsules (Chang, 1977a) and this could have application to disorders where the substrate is readily diffusible and available in the circulation, although not so applicable to the acutely ill neonate. Organ and tissue... 

Interestingly, at very low concentrations of micellised Qi(DS)2, the rate of the reaction of 5.1a with 5.2 was observed to be zero-order in 5.1 a and only depending on the concentration of Cu(DS)2 and 5.2. This is akin to the turn-over and saturation kinetics exhibited by enzymes. The acceleration relative to the reaction in organic media in the absence of catalyst, also approaches enzyme-like magnitudes compared to the process in acetonitrile (Chapter 2), Cu(DS)2 micelles accelerate the Diels-Alder reaction between 5.1a and 5.2 by a factor of 1.8710 . This extremely high catalytic efficiency shows how a combination of a beneficial aqueous solvent effect, Lewis-acid catalysis and micellar catalysis can lead to tremendous accelerations. 

The primary disadvantage of the conjugate addition approach is the necessity of performing two chiral operations (resolution or asymmetric synthesis) ia order to obtain exclusively the stereochemicaHy desired end product. However, the advent of enzymatic resolutions and stereoselective reduciag agents has resulted ia new methods to efficiently produce chiral enones and CO-chain synthons, respectively (see Enzymes, industrial Enzymes in ORGANIC synthesis). Eor example, treatment of the racemic hydroxy enone (70) with commercially available porciae pancreatic Hpase (PPL) ia vinyl acetate gave a separable mixture of (5)-hydroxyenone (71) and (R)-acetate (72) with enantiomeric excess (ee) of 90% or better (204). 

Siace the late 1980s, there has been considerable activity ia the development of fermentative approaches for the preparation of the amide from the nitrile. Organisms such as A.chromohacter (35), A.grohactenum (36), Streptomjces (37), Phodococcus (38,39), and Comebacterium (40) have been described. Purified enzymes ia either free (41) or immobilized form (42,43) have also been used ia this appHcation. 

An even more elegant approach for the production of D-phydroxyphenylglydne on an industrial scale uses foe bacterium. Agrobacterium radiobacter (Figure A8.8). The organism is able to produce both D-hydantoinase and a second enzyme, N-carbamoyl-D-amino acid aminohydrolase, which catalyse the hydrolysis of N-carbamoyl-D-amino add. 

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