Structural and functional impact of clinically relevant E1α variants causing pyruvate dehydrogenase complex deficiency

Hana Pavlu-Pereira, Diana Lousa, Catarina S. Tomé, Cristina Florindo, Maria João Silva, Isabel Tavares de Almeida, Paula Leandro, Isabel Rivera, João B. Vicente

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)


Pyruvate dehydrogenase complex (PDC) catalyzes the oxidative decarboxylation of pyruvate to acetyl-coenzyme A, hinging glycolysis and the tricarboxylic acid cycle. PDC deficiency, an inborn error of metabolism, has a broad phenotypic spectrum. Symptoms range from fatal lactic acidosis or progressive neuromuscular impairment in the neonatal period, to chronic neurodegeneration. Most disease-causing mutations in PDC deficiency affect the PDHA1 gene, encoding the α subunit of the PDC-E1 component. Detailed biophysical analysis of pathogenic protein variants is a challenging approach to support the design of therapies based on improving and correcting protein structure and function. Herein, we report the characterization of clinically relevant PDC-E1α variants identified in Portuguese PDC deficient patients. These variants bear amino acid substitutions in different structural regions of PDC-E1α. The structural and functional analyses of recombinant heterotetrameric (αα’ββ’) PDC-E1 variants, combined with molecular dynamics (MD) simulations, show a limited impact of the amino acid changes on the conformational stability, apart from the increased propensity for aggregation of the p.R253G variant as compared to wild-type PDC-E1. However, all variants presented a functional impairment in terms of lower residual PDC-E1 enzymatic activity and ≈3–100 × lower affinity for the thiamine pyrophosphate (TPP) cofactor, in comparison with wild-type PDC-E1. MD simulations neatly showed generally decreased stability (increased flexibility) of all variants with respect to the WT heterotetramer, particularly in the TPP binding region. These results are discussed in light of disease severity of the patients bearing such mutations and highlight the difficulty of developing chaperone-based therapies for PDC deficiency.

Original languageEnglish
Pages (from-to)78-88
Number of pages11
Publication statusPublished - Apr 2021


  • Cofactor affinity
  • Inborn errors of metabolism
  • Missense mutations
  • Protein aggregation
  • Protein misfolding
  • Pyruvate dehydrogenase complex deficiency


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