Biosynthesis of the selective Gq protein inhibitor FR900359 in Chromobacterium vaccinii as basis for compound supply and structural modifications

牛痘色杆菌中选择性 Gq 蛋白抑制剂 FR900359 的生物合成作为化合物供应和结构修饰的基础

• 批准号: 290827466
• 负责人: Dr. Max Crüsemann
• 金额: --
• 依托单位: Institut für Pharmazeutische Biologie
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/290827466?language=en
• 关键词: Biosynthesis; selective; Gq; protein; inhibitor

The depsipeptide FR900359 (FR) is a selective inhibitor of Galphaq proteins and thus extremely useful as a pharmacological tool. This natural product is present in the higher plant Ardisia crenata, which is known to harbor symbiotic bacteria of the genus Burkholderia. To date, we sequenced the genes for a putative nonribosomal peptide synthetase from the endophytic Burkholderia. Within the project the biosynthesis of FR will be elucidated on the genetic and biochemical level. This shall serve as a basis for the heterologous expression and genetic engineering of FR derivatives. The sequence of the biosynthetic gene cluster for FR production will also be employed for mining publicly available bacterial genomes for bacterial strains, being able to produce FR or related compounds. Structural variants of FR will also be obtained by direct semi-synthetic modification of FR, and additionally by addressing the isolation of minor depsipeptide-metabolites from A. crenata. Further depsipeptides shall be obtained from other Ardisia species known to have bacterial symbionts. All FR derivatives will be assessed in comparison to FR for their bioactivity and will give a deep insight into structure-activity relationships.

缩肽FR 900359（FR）是Galphaq蛋白的选择性抑制剂，因此作为药理学工具非常有用。这种天然产物存在于高等植物Ardisia crenata中，已知其含有伯克霍尔德氏菌属的共生细菌。到目前为止，我们测序了一个假定的非核糖体肽合成酶的基因从内生伯克霍尔德氏菌。在该项目中，FR的生物合成将在遗传和生物化学水平上阐明。这将作为FR衍生物的异源表达和基因工程的基础。用于FR生产的生物合成基因簇的序列也将用于挖掘能够生产FR或相关化合物的细菌菌株的公开可用的细菌基因组。FR的结构变体也将通过FR的直接半合成修饰获得，另外还将通过从A中分离次要缩酚酸肽代谢物获得。钝齿。其他缩肽应从已知具有细菌共生体的其他紫金牛属物种获得。所有FR衍生物将进行评估，比较FR的生物活性，并将深入了解结构-活性关系。