Now here's a nice paper that ties together facts from two of the previous posts. A Japanese group has investigated the role of aromatic amino acids for stabilizing cationic intermediates in the enzyme sites of squalene synthases, which bring about one of the most beautiful and classic reaction cascades in biology. The enzymatic cascades investigated included especially the squalene-hopene cascade, although the squalene-lanosterol-cholesterol pathway is probably better known to Homo sapiens.
By substituting Phe and Tyr in the active sites by O-methyl Tyr, Trp, and most importantly, mono, di and tri fluoro Phenylalanines, these workers found that there is a clear correlation between rates of cyclization and cation-pi interaction energies. The Trp and O-methyl Tyr cases introduced an unwanted variable- sterics, which disorganized the active site at higher temperature. That's why the use of the fluoro Phe s, to preserve VdW similarity. Fluoro benzene has a lower cation-pi stabilization energy than benzene, and it naturally becomes even lower with more fluorine substitution. In this case, more fluorination led to decreased activity. I am sure there are other factors are play, but from their analysis, the cation-pi energy definitely seems to be an important determinant. The pioneer of cation-pi interactions for structural biology is of course Dennis Dougherty.
Ref: J. Am. Chem. Soc.; 2006; ASAP Web Release Date: 20-Sep-2006; (Article) DOI: 10.1021/ja063358p
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