title: Cryptic proteolytic activity of dihydrolipoamide dehydrogenase.
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.
authors.affiliation: Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Ngolela Esther
authors.initials: NE
authors.lastname: Babady
authors.forename: Yuan-Ping
authors.initials: YP
authors.lastname: Pang
authors.forename: Orly
authors.initials: O
authors.lastname: Elpeleg
authors.forename: Grazia
authors.initials: G
authors.lastname: Isaya
mesh_terms: D000818:Animals; D008058:Dihydrolipoamide Dehydrogenase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D019281:Dimerization; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D011487:Protein Conformation; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000378:metabolism; D034421:Sus scrofa
chemical_list: D015842:Serine Proteinase Inhibitors; D008058:Dihydrolipoamide Dehydrogenase; D012697:Serine Endopeptidases