Heterologous Expression, Biosynthetic Studies, and Ecological Function of the Selective Gq-Signaling Inhibitor FR900359.
Max CruesemannRaphael ReherIsabella SchamariAlexander O BrachmannTsubasa OhbayashiMarkus KuschakDavide MalfaciniAlexander SeidingerMarta Pinto-CarbóRené RicharzTatjana ReuterStefan KehrausAsis HallabMisty AttwoodHelgi B SchiöthPeter MergaertYoshitomo KikuchiTill F SchäberleEvi KostenisDaniela WenzelChrista E MüllerJörn PielAurélien CarlierLeo EberlGabriele M KönigPublished in: Angewandte Chemie (International ed. in English) (2017)
The cyclic depsipeptide FR900359 (FR), isolated from the tropical plant Ardisia crenata, is a strong and selective inhibitor of Gq proteins, making it an indispensable pharmacological tool to study Gq-related processes, as well as a promising drug candidate. Gq inhibition is a novel mode of action for defense chemicals and crucial for the ecological function of FR, as shown by in vivo experiments in mice, its affinity to insect Gq proteins, and insect toxicity studies. The uncultured endosymbiont of A. crenata was sequenced, revealing the FR nonribosomal peptide synthetase (frs) gene cluster. We here provide a detailed model of FR biosynthesis, supported by in vitro enzymatic and bioinformatic studies, and the novel analogue AC-1, which demonstrates the flexibility of the FR starter condensation domains. Finally, expression of the frs genes in E. coli led to heterologous FR production in a cultivable, bacterial host for the first time.
Keyphrases
- poor prognosis
- climate change
- escherichia coli
- case control
- binding protein
- dna methylation
- hydrogen peroxide
- gene expression
- type diabetes
- nitric oxide
- risk assessment
- zika virus
- oxidative stress
- metabolic syndrome
- human health
- electronic health record
- high fat diet induced
- insulin resistance
- aedes aegypti
- copy number
- genome wide identification
- transcription factor
- capillary electrophoresis