A pathogenic glutamate-to-aspartate substitution (D296E) in the pyruvate dehydrogenase E1 subunit genePDHA1

Abstract

In a patient with fatal neonatal lactic acidosis due t o pyruvate dehydrogenase deficiency, the only potential mutation detected was c.888C>G in PDHA1, the gene for the E1 α subunit of the complex. This would result in a substitution of glutamate for aspartate (D296E). Pathogenicity of this minor alteration i n amino acid sequence was demonstrated by expression studies. By comparing the mutant sequence with the known structures of the E1 components of pyruvate dehydrogenase and the closely related branched chain α-ketoacid dehydrogenase, an explanation for the profound consequences of the mutation can be proposed.

Molecular detection and analysis of a novel metalloprotease gene of entomopathogenic Serratia marcescens strains in infected Galleria mellonella

“…In Escherichia coli, a single amino acid substitution in the enzymatic domain of cytotoxic necrotizing factor type 1 altered the phenotype to that of the dermonecrotic toxin of Bordetella spp. (McNichol et al 2006), while a glutamine-to-aspartate substitution in the pyruvate dehydrogenase E1 subunit gene PDHA1 is implicated in human fatal neonatal lactic acidosis (Brown et al 2003). The significance of the amino acid differences observed in our study is still to be elucidated.…”

Asp295 Stabilizes the Active-Site Loop Structure of Pyruvate Dehydrogenase, Facilitating Phosphorylation of Ser292 by Pyruvate Dehydrogenase-Kinase

“…In contrast, the same mutations of HsBCKDC E1 did not inhibit phosphorylation [51]. The D296E mutant in HsPDC E1 α was still phosphorylated, although in these analyses the effect of phosphorylation was determined indirectly by measuring the decrease in activity of an already catalytically compromised mutant protein [52]. …”