Research projects

Our goal of treating phosphomannomutase 2 (PMM2) deficiency is closer thanks to our development of a platform for experimental identification of pharmacochaperone-curable disease-causing PMM2 mutations (Segovia-Falquina. Hum Mutat 2022). The determination of CAD structure for better diagnosis/understanding of CAD deficiency is also nearer as we achieved CAD homooligomer stabilization by bioengineering (introduction of interchain disulfide bridges) (Del Caño-Ochoa. Molecules 2023). A breakthrough towards better molecular understanding/diagnosis/therapy of NAGS deficiency is our determination (thanks to cryoelectron microscopy) of the first structure of a complete eukaryotic NAGS enzyme. Using compared biology approaches, we have tackled the unsolved question of the specific function of PLPHP (protein causing vitamin B6-dependent epilepsy) (Tremiño. Life (Basel) 2022). To help differentiate disease-causing and benign missense mutations in P5CS deficiency diagnosis, we have introduced recombinantly produced purified non-human P5CSs to surmount assay difficulties with the pure human enzyme. We have also reaped tangential fruits. Our CPS1 deficiency work has enabled our participation in the identification of a small-molecule inhibitor of CPS1 with anti-lung-cancer potential (Makris. Cancer Commun 2023). Our molecular dynamics skills developed for this project have enabled us to advance the molecular understanding of the rare neurodisease due to Gemin5 mutations (Francisco-Velilla. Life Sci Alliance. 2022; & Comput Struct Biotechnol J.2022). Using our project tools, we have described and characterized a novel inborn error of metabolism (phosphopantothenoylcysteine decarboxylase deficiency (Bravo-Alonso. J Inherit Metab Dis.2022). Finally, we should mention our organization in Valencia (16-20/10/2022) of the “International conference on ureagenesis defects and allied conditions 2022. Novel models and treatment options” (https://www.ureagenesis2022.es/). This meeting, closely related to this project, brought 75 generally outstanding delegates (including the Nobel Laureate Sir John Walker) from 16 countries and three continents. It was partially supported by the FRA and will produce an issue of the Journal of Inherited Metabolic Diseases.