Cryptic proteolytic activity of dihydrolipoamide dehydrogenase

Ngolela Esther Babady, Yuan-Ping Pang, Orly Elpeleg, Grazia Isaya

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

The mitochondrial enzyme, dihydrolipoamide dehydrogenase (DLD), is essential for energy metabolism across eukaryotes. Here, conditions known to destabilize the DLD homodimer enabled the mouse, pig, or human enzyme to function as a protease. A catalytic dyad (S456-E431) buried at the homodimer interface was identified. Serine protease inhibitors and an S456A or an E431A point mutation abolished the proteolytic activity, whereas other point mutations at the homodimer interface domain enhanced the proteolytic activity, causing partial or complete loss of DLD activity. In humans, mutations in the DLD homodimer interface have been linked to an atypical form of DLD deficiency. These findings reveal a previously unrecognized mechanism by which certain DLD mutations can simultaneously induce the loss of a primary metabolic activity and the gain of a moonlighting proteolytic activity. The latter could contribute to the metabolic derangement associated with DLD deficiency and represent a target for therapies of this condition.

Original languageEnglish (US)
Pages (from-to)6158-6163
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number15
DOIs
StatePublished - Apr 10 2007

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Dihydrolipoamide Dehydrogenase
Point Mutation
Mutation
Serine Proteinase Inhibitors
Enzymes
Eukaryota
Energy Metabolism
Peptide Hydrolases
Swine

Keywords

  • Frataxin
  • Friedreich ataxia
  • Mitochondria
  • Moonlighting enzymes
  • Protease

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Cryptic proteolytic activity of dihydrolipoamide dehydrogenase. / Babady, Ngolela Esther; Pang, Yuan-Ping; Elpeleg, Orly; Isaya, Grazia.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 15, 10.04.2007, p. 6158-6163.

Research output: Contribution to journalArticle

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