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

Solvent accessibility of E1α and E1β residues with known missense mutations causing pyruvate dehydrogenase complex (PDC) deficiency: Impact on PDC‐E1 structure and function

“…3,4,23 For example, based on in vitro testing in cultured fibroblasts and by evaluating clinical impact of thiamine supplementation in patients, pathogenic PDHA1 variants, such as E1α Glu46Ala (α-helix 1), Cys72Phe (α-helix 2), Phe176-Leu (α-helix 8), Arg224Gly (β-sheet 9), Arg349His (β-sheet 13), and Arg349Cys (β-sheet 13), impact E1α regions that are either not directly participating in TPP binding or have low affinity for TPP, and are considered thiamine-responsive although it has not been definitely proven. 3,4,23 In contrast, the E1α Arg90Trp variant (located between β-sheet 5 and α-helix 3), where Arg90 directly binds TPP and is catalytically crucial, is unresponsive to thiamine, at least in vitro in cultured fibroblasts. 3 Solvent accessible surface area (SASA) of wild-type amino acid residues in proteins allows for the identification of solvent accessible vs inaccessible residues providing insight into the relationship between the solvent accessibility of residues undergoing variation and pathogenicity of missense variants as well as the impact of the change on stability, folding, and function of proteins.…”

“…12,22 However, recent investigations into the structure and function impact of specific missense mutations (predominant type) in PDHA1 provide insight into the severity of the clinical phenotype and choice of therapeutics based on location of the disease-causing missense variant (DMV) within the 3D E1 model. 3,4,23 For example, based on in vitro testing in cultured fibroblasts and by evaluating clinical impact of thiamine supplementation in patients, pathogenic PDHA1 variants, such as E1α Glu46Ala (α-helix 1), Cys72Phe (α-helix 2), Phe176-Leu (α-helix 8), Arg224Gly (β-sheet 9), Arg349His (β-sheet 13), and Arg349Cys (β-sheet 13), impact E1α regions that are either not directly participating in TPP binding or have low affinity for TPP, and are considered thiamine-responsive although it has not been definitely proven. 3,4,23 In contrast, the E1α Arg90Trp variant (located between β-sheet 5 and α-helix 3), where Arg90 directly binds TPP and is catalytically crucial, is unresponsive to thiamine, at least in vitro in cultured fibroblasts.…”

“…The prevailing understanding is that genotype‐phenotype correlations between different PDHA1 spontaneous mutations (also the case with other primary PDC gene mutations) are quite limited and not reliably prognostic 12,22 . However, recent investigations into the structure and function impact of specific missense mutations (predominant type) in PDHA1 provide insight into the severity of the clinical phenotype and choice of therapeutics based on location of the disease‐causing missense variant (DMV) within the 3D E1 model 3,4,23 . For example, based on in vitro testing in cultured fibroblasts and by evaluating clinical impact of thiamine supplementation in patients, pathogenic PDHA1 variants, such as E1α Glu46Ala (α‐helix 1), Cys72Phe (α‐helix 2), Phe176Leu (α‐helix 8), Arg224Gly (β‐sheet 9), Arg349His (β‐sheet 13), and Arg349Cys (β‐sheet 13), impact E1α regions that are either not directly participating in TPP binding or have low affinity for TPP, and are considered thiamine‐responsive although it has not been definitely proven 3,4,23 .…”

Insulin reduces pyroptosis-induced inflammation by PDHA1 dephosphorylation-mediated NLRP3 activation during myocardial ischemia-reperfusion injury

“…It is well known that phosphorylation and deficiency of PDHA1 inhibit pyruvate dehydrogenase complex (PDHc) activity limiting mitochondrial glucose oxidation and leading to lactic acid fermentation. [11][12][13] Therefore, regulation of lactic acid fermentation by PDHA1 may be a new strategy for the treatment of NLRP3 inflammasome activation.…”

Conditional Knockout of Pdha1 in Mouse Hippocampus Impairs Cognitive Function: The Possible Involvement of Lactate

“…Pyruvate dehydrogenase E1 component subunit alpha (PDHA1) is a critical subunit of PDC. The clinical symptoms of PDC deficiency range from fatal lactic acidosis or progressive neuromuscular injury to chronic neurodegeneration ( Robinson, 2006 ; Imbard et al, 2011 ; Patel et al, 2012 ; Pavlu-Pereira et al, 2021 ). These symptoms suggest that the nervous system is susceptible to perturbations in PDC activity due to its dependence on carbohydrate metabolism ( Gray et al, 2014 ).…”