Characterization of a missense mutation at histidine-44 in a pyruvate dehydrogenase-deficient patient.

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Jacobia SJ, Korotchkina LG, Patel MS

Characterization of a missense mutation at histidine-44 in a pyruvate dehydrogenase-deficient patient.

Biochim Biophys Acta. 2002 Jan 2;1586(1):32-42. doi: 10.1016/s0925-4439(01)00083-7.

PubMed ID

11781147 [ View in PubMed

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Abstract

Genetic defects in pyruvate dehydrogenase complex (PDC) cause lactic acidosis, neurological deficits, and often early death. Most mutations of PDC are localized in the alpha subunit of the pyruvate dehydrogenase (E1) component. We have kinetically characterized a patient's missense mutation alphaH44R in E1alpha by creating and purifying three recombinant human E1s (alphaH44R, alphaH44Q, and alphaH44A). Substitutions at histidine-15 resulted in decreased V(max) values (6% alphaH44R; 30% alphaH44Q; 90% alphaH44A) while increasing K(m) values for thiamine pyrophosphate (TPP) compared to wild-type (alphaH44R, 3-fold; alphaH44Q, 7-fold; alphaH44A, 10-fold). This suggests that the volume of the residue at site 15 is important for TPP binding and substitution by a residue with a longer side chain disrupts the active site more than the TPP binding site. The rates of phosphorylation and dephosphorylation of alphaH44R E1 by E1-kinase and phospho-E1 phosphatase, respectively, were similar to that of the wild-type E1 protein. These results provide a biochemical basis for altered E1 function in the alphaH44R E1 patient.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Cocarboxylase	Pyruvate dehydrogenase E1 component	Protein	Escherichia coli (strain K12)	Unknown	Not Available	Details