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Human Molecular Genetics, 2000, Vol. 9, No. 7 1041-1048
© 2000 Oxford University Press

Sequential deletion of C-terminal amino acids of the E1{alpha} component of the pyruvate dehydrogenase (PDH) complex leads to reduced steady-state levels of functional E1{alpha}2ß2 tetramers: implications for patients with PDH deficiency

Agnieszka Seyda, Gillian McEachern, Richard Haas1 and Brian H. Robinson+

Department of Biochemistry, University of Toronto, and Metabolism Research Programme, Research Institute, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada and 1Departments of Neurosciences and Paediatrics, University of California—San Diego, San Diego, CA, USA

Human pyruvate dehydrogenase (PDH) complex deficiency is an extremely heterogeneous disease in its presentation and clinical course. We have characterized novel mutations that affect the C-terminal portion of the PDH-E1{alpha}-coding sequence. Although the molecular defects underlying these mutations are different, both effectively produce a stop codon prematurely three amino acids from the C-terminus. The clinical and biochemical consequences of these mutations are unusual in that the affected individuals are very long-term survivors with PDH complex deficiency despite having low (<20%) activity in skin fibroblasts. These findings prompted us to investigate the C-terminus of E1{alpha} in greater detail. We constructed and expressed a series of PDH-E1{alpha} deletion mutants in a cell line with zero PDH complex activity due to a null E1{alpha} allele. Sequential deletion of the C-terminus by one, two, three and four amino acids resulted in PDH complex activities of 100, 60, 36 and 14%, respectively, compared with wild-type E1{alpha} expressed in PDH complex-deficient cells. The immunodetectable protein was decreased by the same amount as the activity, suggesting that the stability and/or assembly of the E1{alpha}2ß2 heterotetramer might depend on the intactness of the PDH-E1{alpha} C-terminus. In addition, we compared the somatic and the testis-specific isoforms of E1{alpha} and concluded that they are biochemically equivalent.

+ To whom correspondence should be addressed. Tel: +1 416 813 5989; Fax: +1 416 813 8700; Email: bhr@sickkids.on.ca


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L. G. Korotchkina, S. Sidhu, and M. S. Patel
Characterization of Testis-specific Isoenzyme of Human Pyruvate Dehydrogenase
J. Biol. Chem., April 7, 2006; 281(14): 9688 - 9696.
[Abstract] [Full Text] [PDF]


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