Research Project
6442844
DESCRIPTION (provided by applicant): Neuroactive tryptamine derivatives can be prepared by a new coupled-enzyme process developed in Phase 1 by combining tryptophan-synthetic and -decarboxylating enzymes. This comprises the first reported single-pot aminoethylation process. The tryptamine products can thereby be conveniently produced from readily-available indole precursors. Expression systems which provide higher enzyme yields will be utilized in order to permit scaleup to preparative reaction systems. The gene encoding Camptothectin accuminata tryptophan decarboxylase 1 (TDC 1) will be redesigned to optimize expression in E. coli. Stepwise binding of tryptophan synthase subunits and mutation of specific sites on the enzyme surface in order to improve enzyme activity following immobilization. Directed evolution will be explored in an effort to broaden the substrate ranges of two enzymes. New substrates will be tested he process will be utilized in the preparation of the migraine drugs rizatriptan, and sumatriptan, as well as melatonin and a series of melatonin receptor active compounds. PROPOSED COMMERCIAL APPLICATION: The coupled aminoethylation process will be used to make intermediates for neuropharmaceuticals, including both currently-approved and developmental neuroactive drugs.
