The IP3 3-kinase is capable of binding and phosphorylating various analogs of its substrate, IP3, thus demonstrating new biosynthetic capabilities. This discovery opens new perspectives in the field of drug design.

Inositol 1,4,5-trisphosphate (IP3) is a second messenger that binds to specific IP3 receptors (IP3R) on the endoplasmic reticulum, triggering the release of intracellular Ca2+. The Ca2+ signals cease when IP3 is metabolized, primarily by the enzyme IP3 3-kinase (IP3K), which belongs to the family of inositol polyphosphate kinases (IPKs). This enzyme is highly specific, converting exclusively IP3 into Inositol 1,3,4,5-tetrakisphosphate (IP4). The catalytic activity of IP3K is crucial for processes such as memory, the immune system, and tumor progression, making it an attractive target for cancer research.

At the Institute of Physical Chemistry Blas Cabrera, we have led a study on IP3K in collaboration with Prof. Barry V.L. Potter from the University of Oxford and Dr. Charles A. Brearley from the University of East Anglia. This study broadens our understanding of the biosynthetic capabilities of IP3K beyond its natural substrate, IP3, despite its notable specificity within its enzyme family. To achieve this, we have leveraged the potential of techniques such as X-ray crystallography, chemical synthesis and fluorescence anisotropy, among others.

Our results show that IP3K displays a plasticity that confers tolerance to IP3-derived ligands with modifications, mainly at positions 1 and 3 of the inositol ring. Moreover, IP3K exhibits activity against unexpected ligands, particularly those based on carbohydrates, and those modifying the reactive position 3, changing the secondary hydroxyl (CH-OH) to primary hydroxyl (CH-CH2-OH). These discoveries allow us to better understand the entire family of IPKs involved in the synthesis of IPs with multiple biological functions. Furthermore, they pave the way for the design of selective ligands against proteins that bind IP3, opening new perspectives for the development of targeted therapies in various biological contexts, including cancer research.

M. A. Márquez-Moñino, R. Ortega-García, H. Whitfield, A. M. Riley, L. Infantes, S.W. Garrett, M. L. Shipton, C.A. Brearley, B.V.L. Potter & B. González. “Substrate Promiscuity of inositol 1,4,5-trisphosphate kinase driven by structurally-modified ligands and active site plasticity” Nat. Commun., 2024, 15:1502
doi: 10.1038/s41467-024-45917-5