BCKDH-E1a

BCKDH-E1a is the alpha subunit of the mitochondrial branched-chain α-keto acid dehydrogenase (BCKDH) complex in Toxoplasma gondii, which functionally substitutes for the absent mitochondrial pyruvate dehydrogenase by catalysing the conversion of pyruvate to acetyl-CoA in the mitochondrion, thereby fuelling the TCA cycle (PMID:25032958). Genetic deletion of BCKDH-E1a significantly impairs intracellular growth and virulence (PMID:25032958). As the mitochondrial source of acetyl-CoA, the BCKDH complex also supports mitochondrial protein acetylation, and its loss produces an altered TCA cycle and hypo-acetylation of mitochondrial proteins, with parasites surviving through compensatory adaptations at the transcriptional, translational, and post-translational levels (PMID:32546260). Beyond its role in this complex, nothing further is known about BCKDH-E1a in the available corpus.

1. 2014 High

   It was unknown how apicomplexan parasites generate mitochondrial acetyl-CoA lacking a conventional mitochondrial PDH; this showed that the BCKDH complex, including the E1a subunit, catalyses pyruvate-to-acetyl-CoA conversion, establishing BCKDH-E1a as essential for TCA cycle function, growth, and virulence.

   Evidence Genetic deletion of BCKDH-E1a with metabolic profiling and intracellular growth assays in T. gondii (and P. berghei)

   PMID:25032958

   Open questions at the time

   • No structural or enzymatic characterization of the E1a subunit itself
   • Contribution of E1a versus other complex subunits to catalysis not resolved
   • Mechanism of virulence attenuation not defined at the molecular level
2. 2020 High

   It was unknown how parasites tolerate loss of the BCKDH-derived acetyl-CoA pool; multi-omics showed BCKDH is the mitochondrial acetyl-CoA source and that its loss causes an altered TCA cycle and mitochondrial protein hypo-acetylation, with survival enabled by compensatory transcriptional, translational, and post-translational adaptation.

   Evidence Acetylome, transcriptome, proteome, and metabolome analysis of BCKDH-knockout T. gondii

   PMID:32546260

   Open questions at the time

   • The specific compensatory pathways restoring acetyl-CoA are not identified
   • Direct contribution of E1a distinct from the intact complex not isolated
   • Which mitochondrial proteins are functionally affected by hypo-acetylation not established