Coupled Enzyme Process for Tryptamine Synthesis

描述(申请人提供)：神经活性色胺衍生物可 由第一阶段开发的新的偶联酶工艺制备，通过 色氨酸-合成酶和脱羧酶。这包括第一个 报道了一锅法氨乙基化工艺。色胺产品可以 从而方便地从容易获得的吲哚前体中制备。 提供较高酶产量的表达系统将按顺序使用 以允许放大到制备反应系统。编码基因 喜树碱色氨酸脱羧酶1(TDC 1)将重新设计 优化在大肠杆菌中的表达。色氨酸合成酶的逐步结合 酶表面特定位点的亚基和突变 提高固定化后的酶活性。定向进化将是 在努力扩大两种酶的底物范围方面进行了探索。新的 将测试底物将在制备过程中使用的过程 偏头痛药物利扎曲坦、舒马曲坦以及褪黑素等一系列药物 褪黑素受体活性化合物。 建议的商业应用： 偶合的氨基乙基化过程将用于生产 神经药物，包括目前批准的和正在开发的 神经活性药物。

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.