Structural and Functional Analyses of the Human PDH Complex Suggest a “Division-of-Labor” Mechanism by Local E1 and E3 Clusters

Prajapati, Sabin; Haselbach, David; Wittig, Sabine; Patel, Mulchand S.; Chari, Ashwin; Schmidt, Carla; Stark, Holger; Tittmann, Kai

doi:10.1016/j.str.2019.04.009

Cited by 29 publications

(52 citation statements)

References 63 publications

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“…The PDHc is composed of 1 E2p 60-mer, 4 E3BP trimers, $20 E1p tetramers, and a maximum of 12 E3 dimers PDHc stoichiometry exhibits variations for core component proteins (E2p, E3BP), recently reported for human (Prajapati et al, 2019) and N. crassa (Forsberg et al, 2020) PDHc, observing the substitution (Hiromasa et al, 2004) or the addition model (Sanderson et al, 1996), respectively. E1a, E1b, and E3 decorate the core with diverse stoichiometries (Prajapati et al, 2019;Stoops et al, 1997). Here, we analyzed MS data and retrieved abundance ratios for PDHc components, capturing a distribution with a median of a correct 1:1 stoichiometry for E1p and E1b across fractions (Figure 6E).…”

Section: Reconstructions Of the Pdhc And Other Oadh Complexes Reveal mentioning

confidence: 78%

“…The PDHc or its core structures are produced using icosahedral symmetry (Jiang et al, 2018;Prajapati et al, 2019;Stoops et al, 1997;Yu et al, 2008;Zhou et al, 2001), but non-icosahedrally symmetric parts will be averaged out or eventually manifest as artificial densities, especially for the PDHc, as recently suggested (Forsberg et al, 2020). For the mammalian core, a ''substitution model'' is favored with 40:20 (Brautigam et al, 2009) or 48:12 E2p:E3BP proteins (Hiromasa et al, 2004).…”

Section: Comparison Of Eukaryotic Pdhcs Uncovers Adaptations Of the Nmentioning

confidence: 99%

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Integrative structure of a 10-megadalton eukaryotic pyruvate dehydrogenase complex from native cell extracts

et al. 2021

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Section: Reconstructions Of the Pdhc And Other Oadh Complexes Reveal mentioning

confidence: 78%

Section: Comparison Of Eukaryotic Pdhcs Uncovers Adaptations Of the Nmentioning

confidence: 99%

Integrative structure of a 10-megadalton eukaryotic pyruvate dehydrogenase complex from native cell extracts

et al. 2021

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show abstract

“…In their recent work, Prajapati and collaborators report a non-uniform stoichiometry of the E2/E3BP PDC core. The imbalanced distribution of E2 and E3BP constituents of the trimeric units results into structurally dynamic E1 and E3 clusters [35]. Moreover, for one of the proposed models of E. coli, the PDC core is a fully functional E2 homotrimer operating in a "division-of-labor" mechanism, including binding of the E3 component [35,36].…”

Section: Discussionmentioning

confidence: 99%

Pyruvate dehydrogenase complex deficiency: updating the clinical, metabolic and mutational landscapes in a cohort of Portuguese patients

Pavlu-Pereira

Silva

Florindo

et al. 2020

Orphanet J Rare Dis

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Background The pyruvate dehydrogenase complex (PDC) catalyzes the irreversible decarboxylation of pyruvate into acetyl-CoA. PDC deficiency can be caused by alterations in any of the genes encoding its several subunits. The resulting phenotype, though very heterogeneous, mainly affects the central nervous system. The aim of this study is to describe and discuss the clinical, biochemical and genotypic information from thirteen PDC deficient patients, thus seeking to establish possible genotype–phenotype correlations. Results The mutational spectrum showed that seven patients carry mutations in the PDHA1 gene encoding the E1α subunit, five patients carry mutations in the PDHX gene encoding the E3 binding protein, and the remaining patient carries mutations in the DLD gene encoding the E3 subunit. These data corroborate earlier reports describing PDHA1 mutations as the predominant cause of PDC deficiency but also reveal a notable prevalence of PDHX mutations among Portuguese patients, most of them carrying what seems to be a private mutation (p.R284X). The biochemical analyses revealed high lactate and pyruvate plasma levels whereas the lactate/pyruvate ratio was below 16; enzymatic activities, when compared to control values, indicated to be independent from the genotype and ranged from 8.5% to 30%, the latter being considered a cut-off value for primary PDC deficiency. Concerning the clinical features, all patients displayed psychomotor retardation/developmental delay, the severity of which seems to correlate with the type and localization of the mutation carried by the patient. The therapeutic options essentially include the administration of a ketogenic diet and supplementation with thiamine, although arginine aspartate intake revealed to be beneficial in some patients. Moreover, in silico analysis of the missense mutations present in this PDC deficient population allowed to envisage the molecular mechanism underlying these pathogenic variants. Conclusion The identification of the disease-causing mutations, together with the functional and structural characterization of the mutant protein variants, allow to obtain an insight on the severity of the clinical phenotype and the selection of the most appropriate therapy.

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“…In their recent work, Prajapati and collaborators report a non-uniform stoichiometry of the E2/E3BP PDC core. The imbalanced distribution of E2 and E3BP constituents of the trimeric units results into structurally dynamic E1 and E3 clusters (33). Moreover, for one of the proposed models of E. coli, PDC core is a fully functional E2 homotrimer operating in a "division-of-labor" mechanism, including binding of E3 component (33,34).…”

Section: Discussionmentioning

confidence: 99%

Pyruvate dehydrogenase complex deficiency: updating the clinical, metabolic and mutational landscapes

Pavlu-Pereira

Silva

Florindo

et al. 2020

Preprint

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Background : Pyruvate dehydrogenase complex (PDC) catalyzes the irreversible decarboxylation of pyruvate into acetyl-CoA which ultimately generates ATP. PDC deficiency can be caused by alterations in any of the genes encoding its several subunits, and the resulting phenotype, though very heterogeneous, mainly affects the neuro-encephalic system. The aim of this study is to describe and discuss the clinic, metabolic and genotypic profiles of thirteen PDC deficient patients, thus seeking to establish possible genotype-phenotype correlations. Results : The mutational spectrum revealed that seven patients (54 %) carry mutations in the PDHA1 gene , encoding the E1α subunit, five patients (38 %) carry mutations in the PDHX gene, encoding the E3 binding protein, and the remaining patient (8 %) harbors mutations in the DLD gene, encoding the E3 subunit. These data corroborate PDHA1 mutations as the predominant cause of PDC deficiency, though revealing a notable prevalence of PDHX mutations among Portuguese patients, most of them carrying a seemingly private mutation (p.R284X). The biochemical analyses revealed high lactate and pyruvate plasma levels whereas de ratio L/P was under 16; enzymatic activities, when compared to control values, revealed to be independent from the genotype and ranged from 8.5% to 30% which may be considered a cut-off value for primary PDC deficiency. Concerning the clinical features, all patients displayed developmental delay/psychomotor retardation, the severity of which seems to correlate with the type and localization of the mutation carried by the patient. The therapeutic options essentially go through the administration of a ketogenic diet and supplementation with thiamine, although arginine aspartate intake revealed to be beneficial in some patients. Moreover, the in silico analysis of the missense mutations present in this PDC deficient population allowed to understand the molecular mechanism underlying these pathogenic variants. Conclusion : The identification of the disease-causing mutations, together with the functional and structural characterization of the mutant protein variants, allows to get insight on the severity of the clinical phenotype and the selection of the most appropriate therapy.

show abstract

Structural and Functional Analyses of the Human PDH Complex Suggest a “Division-of-Labor” Mechanism by Local E1 and E3 Clusters

Cited by 29 publications

References 63 publications

Integrative structure of a 10-megadalton eukaryotic pyruvate dehydrogenase complex from native cell extracts

Integrative structure of a 10-megadalton eukaryotic pyruvate dehydrogenase complex from native cell extracts

Pyruvate dehydrogenase complex deficiency: updating the clinical, metabolic and mutational landscapes in a cohort of Portuguese patients

Pyruvate dehydrogenase complex deficiency: updating the clinical, metabolic and mutational landscapes

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