Mutation Polarity

Enzyme preparations from liver or microbial sources were reported to show rather high substrate specificity [76] for the natural phosphorylated acceptor d-(18) but, at much reduced reaction rates, offer a rather broad substrate tolerance for polar, short-chain aldehydes [77-79]. Simple aliphatic or aromatic aldehydes are not converted. Therefore, the aldolase from Escherichia coli has been mutated for improved acceptance of nonphosphorylated and enantiomeric substrates toward facilitated enzymatic syntheses ofboth d- and t-sugars [80,81]. High stereoselectivity of the wild-type enzyme has been utilized in the preparation of compounds (23) / (24) and in a two-step enzymatic synthesis of (22), the N-terminal amino acid portion of nikkomycin antibiotics (Figure 10.12) [82]. 

Even though the free energy difference is a path independent quantity, it is observed that certain sampling difficulties arise when a polar solute is transferred to a non polar solute accompanied by a large change in molecular volume. Under this circumstance, if one attempts mutation of both the partial charges and the non bonded parameters simultaneously, the solute-solvent energy increases enormously as a consequence of very close... 

The less polar methyl ester 2 as prodrug showed better results in vivo and inhibits both farnesylation of the Ras protein and growth of Ras-transformed cells, whilst proliferation of Raf- or Mos-transformed cells was not influenced. Growth of human pancreatic adenocarcinoma cells with mutated K-Ras, c-Myc and p53 genes was inhibited by application of 2. If the compound is administered over a period of 5 days to mice with implanted Ras-dependent tumors, tumor growth can be reduced by up to 66% compared to untreated mice, whereas application of the antitumor antibiotic doxorubicin only resulted in 33% reduction under the same conditions. It is particularly noteworthy that treatment with the /1-turn mimetic - in contrast to treatment with doxorubicin - was without any visible side effects, such as weight loss. 

Jordan, E., Saedler, H., and Starlinger, P. (1967). Strong polar mutations in the transferase gene of the galactose operon in E. coli. Molec. Gen. Genet. 100 296-306. 

The functional importance of the rigidity of the SCF has been further tested with a Cull mutant, whose NTD and CTD were engineered to be linked by a flexible linker sequence (Figure 7.9) [85]. This mutant was made in two steps. First, the hydrophobic packing interface between the NTD and the CTD was disrupted by mutating two residues on the NTD and three on the CTD to polar amino acids. Second, the two domains were connected with 12- or 18-residue polar linkers. The... 

Polarity The phenomenon where a mutation in one gene exerts cis effects on downstream genes. Usually polar mutations lower expression of the downstream genes. 

---