Dimethylallyltryptophan synthase. An enzyme-catalyzed electrophilic aromatic substitution

• Published in: Journal of the American Chemical Society Vol. 114; no. 19; pp. 7354 - 7360
• Main Authors: Gebler, John C, Woodside, Andrew B, Poulter, C. Dale
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 01.09.1992; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Multidisciplinary; Physical Sciences; Science & Technology; PRENYL TRANSFER-REACTION; PATHWAY; STEPWISE MECHANISM; AMINO-ACIDS; BIOSYNTHESIS; COUPLING REACTION; FARNESYLPYROPHOSPHATE SYNTHETASE
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja00045a004

Dimethylallyltryptophan (DMAT) synthase catalyzes the alkylation of L-tryptophan at C(4) by dimethylallyl diphosphate (DMAPP) in the first pathway-specific step in the biosynthesis of ergot alkaloids. The mechanism of the reaction was studied with analogs of both substrates. Five 7-substituted derivatives of N-acetyltryptophan (2, Z = OCH3, CH3, F, CF3, and NO2) were synthesized. The L enantiomers of the free amino acids were obtained by selective hydrolysis of the racemate using aminoacylase from Aspergillus. In addition, the E and Z fluoromethyl and difluoromethyl analogs of DMAPP (1, Y = CH3, CH2F, CHF2) were prepared. Rates of the enzyme-catalyzed reactions were measured for the dimethylallyl derivatives with L-tryptophan and for the L-tryptophan derivatives with DMAPP. In addition, the relative reactivities of the methanesulfonate derivatives of the DMAPP analogs were determined for solvolysis in aqueous acetone. A Hammett plot for the tryptophan analogs gave a good linear correlation with rho = -2.0. In addition, a Hammett plot of the logarithms of the relative rates of solvolysis and enzyme-catalyzed alkylation gave a positive linear correlation. These results indicate that the prenyl-transfer reaction catalyzed by DMAT synthase is an electrophilic aromatic substitution and is mechanistically similar to the electrophilic alkylation catalyzed by farnesyl diphosphate synthase.