Enzyme-catalyzed therapeutic activation

NB2001 (23), a prodrug of triclosan, has been developed based on the enzyme-catalyzed therapeutic activation (ECTA) concept. Evidence supporting ring opening of the cephalosporin moiety by penicillin-binding proteins and/ or (3-lactamases to release triclosan at the bacterium site, as well as sub-pg/mL MIC on [3-lactamase-positive strains, demonstrates the potential of this approach [42]. 

In another study, the carrier protein was replaced by an enzyme compatible solid-phase resin (PEGA), and enzyme-catalyzed cyclization was used to probe substrate specificity. This study demonstrated also that oxo-esters are tolerated as substrates for TE domains, and then-preparation in library format served as an excellent tool for substrate specificity studies, as well as for preparation of cyclized peptides. Figure 13.11 shows how the TycA TE showed selectivity for only residues 1 and 9 (colored in red), and changes at all other residues were tolerated [42]. Hydrogen bonding interactions are shown in green. Several compounds made from this series were shown to demonstrate improved therapeutic indices (with respect to hemolysis) while retaining antimicrobial activity. 

Enzyme Reaction catalyzed Therapeutic application Method for detection of activity Definition of activity unit ... 

Deficiency of thiopurine S-methyl transferase (TPMT) is another phenotype that exhibits inter-ethnic differences in frequency. TPMT is an enzyme that catalyzes methylation of therapeutic agents used in the treatment of acute lymphoblastic leukemia, rheumatoid arthritis, and autoimmune/inflammatory diseases, as well as in organ transplantation. Patients who have TPMT deficiency experience less efficient methylation and are at greater risk of fatal toxicity when treated with standard doses of fhiopurines. TPMT phenotype is defined by erythrocyte 6-mercapto-purine methylation. African American populations exhibit a 20% lower erythrocyte TPMT than Caucasian Americans, and persons of Chinese descent tend to exhibit greater activity than either of these other American subpopulations. 

This is known as Michaelis-Menten or saturation kinetics. The processes that involve specific interactions between chemicals and proteins such as plasma protein binding, active excretion from the kidney or liver via transporters, and metabolism catalyzed by enzymes can be saturated. This is because there are a specific number of binding sites that can be fully occupied at higher doses. In some cases, cofactors are required, and their concentration may be limiting (see chap. 7 for salicylate, paracetamol toxicity). These all lead to an increase in the free concentration of the chemical. Some drugs, such as phenytoin, exhibit saturation of metabolism and therefore nonlinear kinetics at therapeutic doses. Alcohol metabolism is also saturated at even normal levels of intake. Under these circumstances, the rate of... 

Cholesterol can either be obtained in the diet or synthesized in the liver. High levels of cholesterol and its metabolites decrease the amount and inhibit the activity of HMG CoA reductase, the enzyme that catalyzes the committed step in cholesterol biosynthesis. This enzyme can also be inhibited therapeutically... 

In the case of biocatalysis, enzymes [3] and catalytic antibodies [4] have attracted most attention. Since enzymes are inherently the more active catalysts, they have been used most often. Indeed, many industrial processes for the enantioselective production of certain chiral intermediates are based on the application of enzymes, as in the lipase-catalyzed kinetic resolution of an epoxy-ester used in the production of the anti-hypertensive therapeutic Diltiazem [5]. Recently, it has been noted that there seems to be a trend in industry to use enzymes more often than in the past... 

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