Semisynthetic model enzymes

Studies on the Mechanism of Action and Stereochemical Behavior of Semisynthetic Model Enzymes... 

Representatives of another important class of plant-derived semisynthetic compounds are the camptothecin (27) derivatives, irinotecan (28) and topotecan (29). Camptothecin (27) was originally discovered as an antileukemic agent in a mouse model when isolated from Camptotheca acuminata Decne. Compounds (28) and (29) are both employed in cancer chemotherapy. These substances are important mechanistically because of their activity against the enzyme, topoisomerase I. These compounds were designed to address efficacy and toxicity concerns with the parent compound, camptothecin, and its sodium salt. ... 

In our initial research on semisynthetic enzymes, we examined briefly the modification of the serine proteinase a-chymotrypsin, perhaps the best understood of the proteolytic enzymes. A logical choice as a residue for alkylation in the active site of a-chymotrypsin is His-57. However, an examination of a three-dimensional model (Lab Quip) of chymotrypsin in which coenzyme analogs were covalently attached to His-57 suggested strongly that such modifications would block completely the enzyme s active site region and that the probability of new reactions being catalyzed by the modified enzyme would be low. Another possible site of modification of chymotrypsin that could be considered was Met-192. This residue, located on the periphery of the... 

Several groups have shown that SHP-2 and SHP-1 are C-terminally phosphory-lated on two tyrosine residues but the function of these phosphorylation events is controversial. One model is that these phosphorylation events may recruit SH2 domain containing adaptor proteins such as Grb2. Another model is that they may modulate the activity of the enzymes. To address these problems, EPL was employed to incorporate the phosphonate analogs Pmp or F2Pmp at the sites of modification. Semisynthetic proteins containing one or two phosphonates at the physiologic sites were prepared [24, 27, 28]. 

Recently Keyes (80-82) described an interesting approach to the synthesis of semisynthetic enzymes. A protein was partially denaturated and then brought in contact with an inhibitor of an enzyme to be modelled. 

Semisynthetic enzymes will have to be prepared and compared for their activity and need to be spectroscopically characterized. The requirements for models in a biological environment are high with respect to stability and solubility another challenge for the bioinorganic chemist. 

Figure 8.18 Semisynthetic production of [FeFe]-H2ase from the insertion of an active site model complex into the apo-hydrogenase enzyme.

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