Biochemical characterization of two mutants of human pyruvate dehydrogenase, F205L and T231A of the E1 alpha subunit

Wu, YG, Chen, WY, Zhang, ZW, Yang, GZ, Li, W and Duggleby, RG (2003) Biochemical characterization of two mutants of human pyruvate dehydrogenase, F205L and T231A of the E1 alpha subunit. Journal of Inherited Metabolic Disease, 26 7: 671-674. doi:10.1023/B:BOLI.0000005628.16515.01


Author Wu, YG
Chen, WY
Zhang, ZW
Yang, GZ
Li, W
Duggleby, RG
Title Biochemical characterization of two mutants of human pyruvate dehydrogenase, F205L and T231A of the E1 alpha subunit
Journal name Journal of Inherited Metabolic Disease   Check publisher's open access policy
ISSN 0141-8955
Publication date 2003
Sub-type Article (original research)
DOI 10.1023/B:BOLI.0000005628.16515.01
Volume 26
Issue 7
Start page 671
End page 674
Total pages 4
Place of publication The Netherlands
Publisher Kluwer
Collection year 2003
Language eng
Subject C1
320305 Medical Biochemistry - Proteins and Peptides
730107 Inherited diseases (incl. gene therapy)
Abstract Mutations in the E1alpha subunit of the pyruvate dehydrogenase multienzyme complex may result in congenital lactic acidosis, but little is known about the consequences of these mutations at the enzymatic level. Here we characterize two mutants (F205L and T231A) of human pyruvate dehydrogenase in vitro, using the enzyme expressed in Escherichia coli. Wild-type and mutant proteins were purified successfully and their kinetic parameters were measured. F205L shows impaired binding of the thiamin diphosphate cofactor, which may explain why patients carrying this mutation respond to high-dose vitamin B-1 therapy. T231A has very low activity and a greatly elevated K-m for pyruvate, and this combination of effects would be expected to result in severe lactic acidosis. The results lead to a better understanding of the consequences of these mutations on the functional and structural properties of the enzyme, which may lead to improved therapies for patients carrying these mutations.
Keyword Endocrinology & Metabolism
Genetics & Heredity
Deficiency
Complex
Mutations
Enzymes
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2004 Higher Education Research Data Collection
School of Chemistry and Molecular Biosciences
 
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Created: Wed, 15 Aug 2007, 01:21:46 EST