A chemical probe unravels the reactive proteome of health-associated catechols

ABSTRACT: Catechol-containing natural products are common constituents of foods, drinks, and drugs. Natural products carrying this motif are often associated with beneficial biological effects such as anticancer activity and neuroprotection. However, the molecular mode of action behind these properties is poorly understood. Here, we apply a mass spectrometry-based competitive chemical proteomics approach to elucidate the target scope of catechol-containing bioactive molecules from diverse foods and drugs. Inspired by the protein reactivity of catecholamine neurotransmitters, we designed and synthesised a broadly reactive minimalist catechol chemical probe based on dopamine. Initial labelling experiments in live human cells demonstrated broad protein binding by the probe, which was largely outcompeted by its parent compound dopamine. Next, we investigated the competition profile of a selection of biologically relevant catechol-containing compounds. With this approach, we characterised the protein reactivity and the target scope of dopamine and ten catechols. Strikingly, proteins associated with the endoplasmic reticulum (ER) were among the main targets. ER stress assays in the presence of reactive catechols revealed an activation of the IRE1-branch of the unfolded protein response (UPR), whereas unreactive catechols had no effect. As the UPR is an intriguing oncology target, this provides a possible explanation of the health-promoting effects attributed to many catechol natural products.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell

SUBMITTER: Angela Weigert Muñoz  

LAB HEAD: Stephan A. Sieber

PROVIDER: PXD043348 | Pride | 2023-10-24

REPOSITORIES: Pride