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NEWS Chemists from Umeå University, together with researchers in Hamburg have created a direct method for capture and identification of bacterial toxin target substrates. Their results have been published in the scientific journal Nature Chemistry.
Bacterial infections are the basis of numerous human diseases. In the course of their developmental history, many of these pathogens have developed strategies to manipulate the infected host cell for their own benefit. For this purpose, they release bacterial enzymes that can modify key human factors in order to specifically influence their function. A profound molecular understanding of these manipulative processes is important in order to investigate and possibly even treat the resulting diseases.
A major problem in the investigation of bacterial infections is often the identification of the respective manipulated key factors in humans, since the few cellular targets in myriads of similar structures must be specifically detected. Methods that enable such identification of manipulated pathways in the human cell can therefore potentially accelerate the gain of knowledge for the underlying processes in bacterial diseases.
Together with research partner Professor Aymelt Itzen from the Institute of Biochemistry and Signal transduction at the University Clinic Hamburg Eppendorf, Germany, Professor Christian Hedberg and his colleagues at the Department of Chemistry at Umeå universitet have developed a new method that may in future potentially facilitate the systematic identification of targets for a particular family of bacterial enzymes.
The family of FIC proteins is particularly common in bacteria and in many cases probably causes the modification of host proteins with an adenosine monophosphate group. This process is also known as AMPylation.
Despite the knowledge of this FIC family and its discovery in bacteria, the protein targets in humans cannot be easily predicted, nor identified by classical methods, like proteomics.
“We have therefore developed a chemical method to directly capture the target proteins covalently with the bacterial FIC enzymes, and subsequently identify which host cell proteins that reacted”, says Christian Hedberg.
For this purpose, the chemistry of the adenosine triphosphates and their precursor forms was chemically modified in such a way that they can form a permanent complex between the FIC enzyme and the human target protein.
“With the established approach we hope to be able to address FIC enzymes of relevant human pathogens in the near future and identify their targets in human cells. This could lay the molecular foundations for a better understanding of bacterial diseases in the long term”.
A key to the success of this project was the combination of organic chemistry, biochemistry, structural biology and mass spectrometry, which in this form was only conceivable with our cooperation partners from the University Clinic Hamburg. The project has received generous funding from Knut and Alice Wallenberg Foundation, which has enabled carrying out a high risk project during long time.
Burak Gulen et al: Identification of targets of AMPylating Fic enzymes by co-substrate-mediated covalent capture. Nature Chemistry volume 12, pages732–739(2020).