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

FR900359 （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赤心蒿中，已知含有伯克氏菌属的共生细菌。迄今为止，我们对一种假定的来自内生伯克氏菌的非核糖体肽合成酶的基因进行了测序。在项目中，FR的生物合成将在遗传和生化水平上得到阐明。这将为FR衍生物的异源表达和基因工程奠定基础。生产FR的生物合成基因簇的序列也将用于挖掘公开可用的细菌基因组，以寻找能够生产FR或相关化合物的细菌菌株。FR的结构变异也将通过直接半合成修饰获得，此外，还将通过从A. creatata中分离少量的抑郁肽代谢物来获得。进一步的沉积肽应从已知的具有细菌共生体的其他紫荆属物种中获得。所有FR衍生物将与FR进行生物活性比较评估，并将深入了解结构-活性关系。

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.