Scientists from the IQFR and the University of Oxford reveal how a family of proteins, essential for inositide and phosphate metabolism in eukaryotes, act on three types of key compounds.

This work gives the clues to understand the promiscuity of DDP1, an enzyme belonging to the NUDIX family that accommodates and act on three different types of substrates,  pyrophosphoinositols (PP-InsPs), diadenosine polyphosphates (ApnA) and inorganic polyphosphates (polyPs), all essential for living beings. This work, published in the Journal of Science Advances, explains how DDP1 recognizes these substrates by clamping their phosphate groups. In addition, the work reveals how their pyrophosphate groups are hydrolyzed in a specific area, near a motif called NUDIX. This recognition involves a complementarity of many positive and negative charges from the protein and its substrates.

But, why is DDP1 important? Phosphorus, so necessary for life, is one of the most abundant minerals in our body and, together with calcium, one of the components of our bones. In the cell, phosphate is part of paramount molecules as DNA, RNA, lipids and some proteins, and is key as a store and supply of cellular energy (ATP). Consequently, the cell must be able to capture, use, store and regulate this element in order to function correctly. DDP1 participates in this regulation and constitutes the link between the metabolism of inositol polyphosphates and inorganic polyphosphates in the yeast Saccharomyces cerevisiae, which represents a hot topic in this field. Moreover, knowing in detail how DDP1 works in fungi and yeast pave the way to understand its mechanism of action in eukaryotic organisms.

This study, accomplished by Protein Crystallography, can help in the development of new antifungal drugs targeted to phosphate regulation, enabling the cure of opportunistic infections caused by fungi.

Publicación: M. Á. Márquez-Moñino, R. Ortega-García, M. L. Shipton, E. Franco-Echevarría, A. M. Riley, J. Sanz-Aparicio, B. V. L. Potter, B. González. Multiple substrate recognition by yeast diadenosine and diphosphoinositol polyphosphate phosphohydrolase through phosphate clamping. Science Advances 7, eabf6744 (2021)

https://advances.sciencemag.org/content/7/17/eabf6744/tab-pdf