BIOSYNTHESIS OF TAXOL AND RELATED COMPOUNDS

紫杉醇及相关化合物的生物合成

• 批准号: 2106989
• 负责人: HEINZ G FLOSS
• 金额: $ 20.47万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-08-05 至 1999-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2106989
• 关键词: Conifera; biosynthesis; paclitaxel; plant extracts; plant physiology; tissue /cell culture

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.

紫杉醇，一种从短叶红豆杉和其他植物中分离出来的二萜衍生物 红豆杉属植物，是一种重要的新型抗癌剂。 它一直 经 FDA 批准用于治疗卵巢癌，也显示出希望 对抗乳腺癌、肺癌和其他癌症。 泰索帝，一种半合成类似物， 还正在进行临床评估，到目前为止，结果良好。 这些临床成功提出了确保足够的 这些药物的商业供应。 结构的复杂性确实 对于经济上可行的这些药物的全合成来说不是好兆头， 甚至在即将更换新的树皮提取物之后 由更丰富的紫杉烷 10-脱乙酰浆果赤霉素-III 半合成 紫杉醇的商业来源、这些以及下一代的供应 基于紫杉烷的药物将取决于至少以下物质的生物合成 未来几年的功能化紫杉烷环系统。 该项目的长期目标是在化学领域阐明， 酶促以及最终的基因水平，生物合成途径 紫杉醇和相关紫杉烷类化合物在红豆杉植物中组装。 我们建议 (1)从紫杉烷环系的形成模式出发 推测的前体，香叶基香叶基焦磷酸，（2）绘制以下序列 从最初的碳氢化合物前体到完全的反应 紫杉醇的功能化紫杉烷部分，（3）获得机制洞察 苯丙氨酸转化为苯异丝氨酸和苯甲酸盐 紫杉醇的部分和（4）确认模型和附着阶段 C-13 侧链连接到环系统并分离催化酶 这个过程。 作为这些研究的工具，我们还将开发和 优化红豆杉细胞培养物以达到有用的紫杉烷生产水平 生物合成实验。 预计生成的信息将有助于提供 努力开发替代生物技术的知识库 这些重要的新型抗肿瘤药物的商业化生产工艺 药物。