An inositol pyrophosphate second messenger arises in plants and mammals: functions and interactomes of 4/6-PP-InsP5

• Applicant: Professor Dr. Henning Jessen
• Subject Area: Biological and Biomimetic Chemistry
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 560443421

Inositol pyrophosphates are an important group of second messengers regulating a diverse array of biological activities. The number of phosphates attached to the 6 carbon atoms of the myo-inositol core structure is typically larger than 7 for most known inositol pyrophosphates. The structures can exist as meso compounds (e.g. 5-PP-InsP5, an inositol pyrophosphate with 7 phosphates, where the diphosphate group is positioned at carbon number 5), or as chiral representatives, such as 1-PP-InsP5 or its enantiomer 3-PP-InsP5. Intriguingly, the kinases and phosphatases present in biology are isomer specific. For a long time, it has been believed that in mammalian and plant systems, only 1-PP-InsP5, 5-PP-InsP5, and 1,5-PP2-InsP4 exist and that 5-PP-InsP5 is the main signalling molecule. As a consequence, large efforts have been put forward to derive the functions of 5-PP-InsP5 in biology, with significant success. We have recently shown however, that in many instances, it is actually not 5-PP-InsP5 that is the main isomer, but in fact either 4-PP-InsP5 and/or 6-PP-InsP5, two enantiomers with respect to one another. The above discussed points raise several important questions regarding the new inositol pyrophosphate isomer 4/6-PP-InsP5 that will be addressed in this proposal. Critical points addressed in this proposal are: 1) Synthesis of new pull-down probes (photoaffinity and affigel) for the new PP-InsP5 isomers. 2) Delineation of interactomes in plants and mammalian cells 3) Validation of binding partners of 4/6-PP-InsP5 and structural evaluation 4) Delineation of the absolute stereochemistry of the natural isomer. These goals will be enabled by a combination of synthetic organic chemistry, analytical chemistry, and biochemistry. The data obtained in this project will provide new research avenues in inositol pyrophosphate research. The tools designed and obtained in the project as well as data collected will be made accessible to the community through reagent and data sharing. Overall, this research will widen our understanding of a newly discovered second messenger that has been overlooked for 30 years.

• DFG Programme: Research Grants