BIOSYNTHESIS OF TAXOL AND RELATED COMPOUNDS

紫杉醇，一种从短叶红豆杉和其它植物中分离的二萜衍生物， 红豆杉属植物，是一种重要的新型抗癌药物。 已经 FDA批准用于治疗卵巢癌， 对抗乳腺癌、肺癌和其他癌症。 泰索帝，一种半合成类似物， 也正在进行临床评估，到目前为止，效果非常好。 这些临床上的成功提出了确保足够的 这些药物的商业供应。 结构的复杂性 对于这些药物的经济上可行的全合成来说不是好兆头， 即使在即将取代新的树皮提取， 从更丰富的紫杉烷，10-脱乙酰基巴卡亭-III，作为 紫杉醇的商业来源，这些和未来一代的供应 基于紫杉烷的药物将依赖于至少 功能化的紫杉烷环系统。 这是该项目的长期目标，阐明，在化学， 酶的，最终，基因水平，生物合成途径， 紫杉醇和相关的紫杉烷在紫杉植物中组装。 我们建议 (1)建立了紫杉烷环系的形成模式， 推测的前体，香叶基香叶基焦磷酸，（2）绘制 从初始烃前体到完全烃前体的反应 紫杉醇的功能化紫杉烷部分，（3）获得对 苯丙氨酸转化为苯异丝氨酸和苯甲酸 紫杉醇部分和（4）确认模型和连接的阶段， C-13侧链连接到环系统上，并分离催化 这个过程 作为这些研究的工具，我们还将开发和 将红豆杉细胞培养物优化至紫杉烷生产水平， 生物合成实验 预计所产生的信息将有助于提供 努力开发替代生物技术的知识基础 这些重要的新的抗肿瘤药物的商业生产方法 毒品

Taxol, a diterpene derivative isolated from Taxus brevifolia and other Taxus species, is an important new anti-cancer agent. It has been approved by the FDA for treatment of ovarian cancer and also shows promise against breast, lung and other cancers. Taxotere, a semisynthetic analog, is also undergoing clinical evaluation with, so far, excellent results. These clinical successes have raised the problem of securing adequate commercial supplies of these drugs. The complexity of the structures does not bode well for an economically viable total synthesis of these drugs, and even after the imminent replacement of new bark extraction by semisynthesis from a more abundant taxane, 10-deacetylbaccatin-III, as the commercial source of taxol, the supply of these and future generation taxane-based drugs will depend on biosynthesis of at least the functionalized taxane ring system for years to come. It is the long-term goal of this project to elucidate, at the chemical, enzymatic and eventually, genetic level, the biosynthetic pathway by which taxol and related taxanes are assembled in the yew plant. We propose to (1) establish the mode of formation of the taxane ring system from its presumed precursor, geranylgeranyl pyrophosphate, (2) map the sequence of reactions leading from the initial hydrocarbon precursor to the fully functionalized taxane moiety of taxol, (3) gain mechanistic insight into the transformation of phenylalanine into the phenylisoserine and benzoate moieties of taxol and (4) confirm the model and stage of attachment of the C-13 side chain to the ring system and isolate the enzyme(s) catalyzing this process. As a tool for these studies we will also develop and optimize Taxus cell cultures to levels of taxane production useful for biosynthetic experiments. It is anticipated that the information generated will help provide the knowledge base for efforts to develop alternative biotechnological processes for the commercial production of these important new antitumor drugs.