Insights into the biosynthesis of isoprenoid precursors and their potential in semisynthetic strategies

深入了解类异戊二烯前体的生物合成及其在半合成策略中的潜力

• 批准号: 195109706
• 负责人: Professor Dr. Michael Groll
• 金额: --
• 依托单位: Department of Chemistry
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2011
• 资助国家: 德国
• 起止时间: 2010-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/195109706?language=en
• 关键词: Insights; into; biosynthesis; isoprenoid; precursors

Isoprenoids (terpenes) are the largest group of known natural products (at least 35,000) [1]. Whereas animals biosynthesize isoprenoids via the mevalonate pathway, it is now established that many pathogenic bacteria and the apicomplexan subgroup of pathogenic protozoa use the more recently discovered nonmevalonate pathway for that purpose. The enzymes of the non-mevalonate pathway are essential in these pathogens. They are promising targets for the development of novel antiinfective drugs which should be exempt from target-related toxicity, due to the absence of the pathway in the human host. The final steps of the non-mevalonate pathway affording the universal isoprenoid precursors IPP and DMAPP are catalyzed by two iron-sulfur proteins specified by the ispG and ispH genes. Recently, we have determined the crystal structures of IspG and IspH protein. This work will serve as basis for the further elucidation of the reaction mechanisms of these proteins, using X-ray crystallography, enzyme kinetics, NMR and as well as sitedirected mutagenesis. These methods will also be applied to study the mode of action of IspG and IspH inhibitors.

类异戊二烯（萜烯）是已知天然产物中最大的一类（至少35，000种）[1]。尽管动物通过甲羟戊酸途径生物合成类异戊二烯，但现在已经确定许多病原性细菌和病原性原生动物的顶复门亚群使用最近发现的非甲羟戊酸途径用于该目的。非甲羟戊酸途径的酶在这些病原体中是必不可少的。它们是开发新型抗感染药物的有希望的靶点，由于在人类宿主中不存在该途径，这些药物应免于靶点相关毒性。提供通用类异戊二烯前体IPP和DMAPP的非甲羟戊酸途径的最后步骤由ispG和ispH基因指定的两种铁硫蛋白催化。最近，我们已经确定了IspG和IspH蛋白的晶体结构。这项工作将作为基础，进一步阐明这些蛋白质的反应机制，使用X射线晶体学，酶动力学，NMR和以及定点诱变。这些方法也将用于研究IspG和IspH抑制剂的作用模式。