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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, SN1 and SN2 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 SN2 reaction, the latter is considerably (0.90 ang) longer, indicating that the enzyme effects catalysis via an "exploded" TS structure.

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