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Characterization of macromolecular targets as a key to understanding, diagnosis and design of therapies in rare diseases

20th national competition for scientific and technical research

Rare diseases

Senior Researcher : Vicente Rubio Zamora

Research Centre or Institution : Instituto de Biomedicina de Valencia. CSIC.


This project focuses on six inborn errors of metabolism and their targets. A key milestone has been our determination of the structure of human phosphomannomutase 2 (PMM2) bound to its activator glucose-1,6-bisphosphate, thus inferring pathogenic mechanisms and susceptibility to pharmacochaperones for the mutations described in its deficiency (Briso-Montano et al. al. JIMD 2021), the efficacy of which we can now test experimentally (submitted article). Another important milestone, in this case for Δ1-pyrroline-5-carboxylate synthase (P5CS) deficiency, has been our determination of the complex structure of P5CS, by cryoelectron microscopy (cryo-EM), explaining the paradox that, according to the mutation, the deficit has dominant or recessive inheritance. In carbamyl-phosphate synthetase 1 (CPS1) deficiency, the study of the effects of its clinical mutations has revealed the (stabilizing) function of the last two domains of CPS1 for wwhose function was still unknown, with clear implications for the prediction of pathogenicity of CPS1 mutations.  

We have also advanced the understanding of vitamin B6-dependent epilepsy by determining the structure of the human PLP homeostasis protein (PLPHP), characterizing the effects of its mutations found in epileptic patients; as well as the understanding of the deficiency of NAG synthase (NAGS) by stabilizing the recombinant human enzyme and using it to establish the effects of its mutations described in this deficiency. With regard to the highly complex trifunctional enzyme CAD and its deficiencies, we have modeled CAD (Del Caño-Ochoa et al. Protein Sci.2021;30:1995) and launched structural validation of the model by EM of CAD carrying stabilizing mutations. Tangential achievements: discovery of potential anti-TB agents acting on bacterial G5K (homologous to the G5K domain of P5CS) (Panciera et al. Eur J Med Chem. 2022); and investigation of CPS1 and NAGS as potential antibody targets in auto-injurious diseases (Boilard et al. Arthritis Rheumatol. 2022).


Scientific Production
Magazine Articles 5
Communications at national conferences -
Communications at international conferences 2


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