[SCAN] Inborn errors of metabolism: structural-functional studies to understand rare genetic disorders

Title: Inborn errors of metabolism: structural-functional studies to understand rare genetic disorders

Speaker: João Vicente, Structural Genomics Group - Macromolecular Crystallography Unit

Abstract:  Inborn errors of metabolism (IEM) are rare genetic inherited disorders caused by mutations in genes encoding enzymes or transporters, resulting in accumulation of substrates and/or depletion of products. IEM exhibit quite diverse clinical spectra, early neuronal and motor impairment being common traits. Few drugs have reached the market for these diseases, and treatment options are mostly based on dietary restrictions, which often fail to revert developmental delays, and are burdensome for patients and their families. Knowledge on the molecular bases of IEM is paramount to devise effective alternative therapeutic strategies. Most mutations in IEM are missense mutations that generate protein variants with functional and structural impairments at multiple levels: catalytic activity, allosteric regulation, folding, oligomerization, aggregation. Therefore, working with the recombinant protein variants has allowed understanding the molecular details underlying their pathogenicity, and enabled the discovery of chemical compounds with pharmacological potential to restore protein structure and function (pharmacological chaperones). Herein, I will describe our studies in collaboration with the Metabolism and Genetics Group at the Faculty of Pharmacy, University of Lisbon, on how we have used protein biochemistry and biophysics to: i) understand the molecular bases of pathogenicity in clinically relevant protein variants identified in pyruvate dehydrogenase complex deficiency patients; and ii) screen a small library of compounds to act as pharmacological chaperones for phenylalanine hydroxylase, for the treatment of phenylketonuria.
 

ITQB NOVA Virtual Auditorium 

https://zoom.us/j/93139069443