Transition State Analysis of Model and Enzymatic Prenylation Reactions

Lenevich, S.; Xu, J.; Hosokawa, A.; Cramer, C. J.; Distefano, M. D.
J. Am. Chem. Soc. 2007, 129, 5796.

To obtain a transition state (TS) structure for an enzyme catalyzed prenylation reaction, S_N1 and S_N2 model substitution reactions with dimethylallyl chloride were first studied. ¹³C kinetic isotope effects (KIEs) for the model reactions were measured by a natural abundance NMR method and used to validate the computational methods that would be used in the subsequent determination of the enzymatic TS structure. Using a primary ¹³C KIE and a secondary ²H KIE measured via mass spectrometry, a TS structure for the enzyme catalyzed reaction was computed; a density functional level of electronic structure theory using the mPW1N functional in combination with the 6-31+G(d) basis set was employed for those calculations. That structure has a C-O bond length of 1.69 ang and a C-S bond length of 3.70 ang. While the former bond length is similar to that for a nonenzymatic S_N2 reaction, the latter is considerably (0.90 ang) longer, indicating that the enzyme effects catalysis via an "exploded" TS structure.

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