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Abstract

Grant Number:	5R44MH062244-03
PI Name:	KILGORE, JAMES L.
PI Email:	jkilgore@biocatalytics.com
PI Title:
Project Title:	Coupled Enzyme Process for Tryptamine Synthesis

Abstract: 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.

Thesaurus Terms:
chemical synthesis, enzyme mechanism, enzyme substrate, immobilized enzyme, indole, method development, tryptamine
aromatic L aminoacid decarboxylase, enzyme activity, melatonin, sumatriptan, tryptophan synthase
Escherichia coli, directed evolution, thin layer chromatography

Institution:	BIOCATALYTICS, INC.
	129 N HILL AVE, STE 103
	PASADENA, CA 911051955
Fiscal Year:	2003
Department:
Project Start:	01-JUL-2000
Project End:	31-JAN-2004
ICD:	NATIONAL INSTITUTE OF MENTAL HEALTH
IRG:	ZRG1

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