A novel mutation in the dihydrolipoamide dehydrogenase E3 subunit gene (DLD) resulting in an atypical form of α-ketoglutarate dehydrogenase deficiency

Odièvre, Marie‐Hélène; Chrétien, Dominique; Münnich, Arnold; Robinson, Brian H.; Dumoulin, R.; Masmoudi, Sahben; Kadhom, Noman; Rötig, Agnès; Rustin, Pierre; Bonnefont, Jean‐Paul

doi:10.1002/humu.9319

Cited by 78 publications

(65 citation statements)

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“…In humans, DLD mutations that affect the DLD activity are linked to a severe metabolic disorder (23). We analyzed a pathogenic mutation (D444V) in the DLD homodimer interface previously hypothesized to result in loss of DLD activity by perturbing the stability of the homodimer (24).…”

Section: Resultsmentioning

confidence: 99%

“…It has been proposed that moonlighting proteins can enhance the phenotypic variability of single-gene disorders (14). In this respect, it is noteworthy that patients with point mutations at the DLD homodimer interface (D444V or R447G) were affected with hypertrophic cardiomyopathy, which is one of the manifestations of Friedreich ataxia (47) and has not been observed in association with other DLD mutations (23). Conversely, partial DLD deficiency was observed in a subset of Friedreich ataxia patients (48,49).…”

Section: Discussionmentioning

confidence: 99%

“…In humans, mutations in DLD are linked to a severe disorder of infancy with failure to thrive, hypotonia, and metabolic acidosis, which result from deficient activity of all three ␣-ketoacid dehydrogenases (15)(16)(17)(18)(19). However, the clinical manifestations of DLD deficiency show a great degree of variability (16,(20)(21)(22)(23), which has been attributed to varying effects of different DLD mutations on the stability of the protein (20) as well as its ability to dimerize (23,24) or interact with other components of the three ␣-ketoacid dehydrogenase complexes (25). Our results suggest a previously unrecognized mechanism by which mutations that alter the stability of the DLD homodimer may not only result in a decrease in the primary metabolic activity of the enzyme but at the same time cause an increase in its moonlighting proteolytic activity.…”

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Cryptic proteolytic activity of dihydrolipoamide dehydrogenase

Babady¹,

Pang

Elpeleg

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

111

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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.is a f lavindependent oxidoreductase required for the complete reaction of at least five different multienzyme complexes. In the mitochondrial matrix, the DLD homodimer functions as the E3 component of the pyruvate, ␣-ketoglutarate, and branchedchain amino acid-dehydrogenase complexes and the glycine cleavage system. In the context of these four multienzyme complexes, DLD utilizes dihydrolipoic acid and NAD ϩ to generate lipoic acid and NADH (1). The opposite reaction, from lipoic acid and NADH to dihydrolipoic acid and NAD ϩ , is catalyzed by the DLD homodimer in the context of the NAD ϩ -dependent peroxidase-peroxinitrate reductase of Mycobacterium tuberculosis (2). In addition, DLD has diaphorase activity, being able to catalyze the oxidation of NADH to NAD ϩ by using different electron acceptors such as O 2 , labile ferric iron (3), nitric oxide (4), and ubiquinone (5, 6). In this capacity, DLD is believed to primarily have a prooxidant role, achieved by reducing O 2 to a superoxide radical or ferric to ferrous iron, which in turn catalyzes production of hydroxyl radical through Fenton chemistry (3). However, the ability to scavenge nitric oxide and to reduce ubiquinone to ubiquinol suggests that the diaphorase activity of DLD may also have an antioxidant role (4-6). The oligomeric state of DLD can change from dimeric to monomeric or tetrameric depending on the pH in the mitochondrial matrix, and changes in the oligomeric state of the protein have been shown to correlate with a shift from DDL activity (only present in dimeric and tetrameric DLD) to diaphorase activity (present in both oligomeric and monomeric forms of the protein) (7,8). Thus, DLD represents a highly versatile oxidoreductase with multiple critical roles in energy metabolism and redox balance (2,7,(9)(10)(11)(12).Here, we found that DLD can also function as a moonlighting protease. Moonlighting enzymes are a growing category of molecules that can accomplish multiple functions through a variety of mechanisms including, among other...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Cryptic proteolytic activity of dihydrolipoamide dehydrogenase

Babady¹,

Pang

Elpeleg

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

111

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“…Clinical complications generally appear at the neonatal age and often lead to premature death [32,[34][35][36][37][38][39][40][41][42][43][44]. Pathogenic mutations of LADH reside mostly either in the cofactor-binding sites, or in the disulfide active center or in the dimerization surface [27,32].…”

Section: Introductionmentioning

confidence: 99%

Molecular dynamics study of the structural basis of dysfunction and the modulation of reactive oxygen species generation by pathogenic mutants of human dihydrolipoamide dehydrogenase

Ambrus

Ádám-Vizi

2013

Archives of Biochemistry and Biophysics

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Human dihydrolipoamide dehydrogenase (LADH, E3) is a component in the pyruvate-, alpha-ketoglutarate-and branched-chain ketoacid dehydrogenase complexes and in the glycine cleavage system. The pathogenic mutations of LADH cause severe metabolic disturbances, called E3 deficiency that often involve cardiological and neurological symptoms and premature death. Our laboratory has recently shown that some of the known pathogenic mutations augment the reactive oxygen species (ROS) generation capacity of LADH, which may contribute to the clinical presentations. A recent report concluded that elevated oxidative stress generated by the above mutants turns the lipoic acid cofactor on the E2 subunits dysfunctional. In the present contribution we generated by molecular dynamics (MD) simulation the conformation of LADH that is proposed to be compatible with ROS generation. We propose here for the first time the structural changes, which are likely to turn the physiological LADH conformation to its ROS-generating conformation. We also created nine of the pathogenic mutants of the ROS-generating conformation and again used MD simulation to detect structural changes that the mutations induced in this LADH conformation. We propose the structural changes that may lead to the modulation in ROS generation of LADH by the pathogenic mutations.

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“…One mutation found in patients with low E3 activity is the Arg-447 to Gly mutation. 5 Patients with this mutation suffer from neurological deterioration and generally die within 3 years. Figure 2 presents the sequence alignment of the sequence around the Arg-447 region of human E3 with the corresponding regions of E3s from a range of sources, such as pigs, yeast, Escherichia coli, and Pseudomonas fluorescens.…”

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confidence: 99%

Characterization of a Naturally Occurring Mutation (Arg-447 to Gly) in Human Dihydrolipoamide Dehydrogenase of Patients with Neurological Deterioration

Kim¹

2016

Journal of the Korean Chemical Society

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A novel mutation in the dihydrolipoamide dehydrogenase E3 subunit gene (DLD) resulting in an atypical form of α-ketoglutarate dehydrogenase deficiency

Cited by 78 publications

References 28 publications

Cryptic proteolytic activity of dihydrolipoamide dehydrogenase

Cryptic proteolytic activity of dihydrolipoamide dehydrogenase

Molecular dynamics study of the structural basis of dysfunction and the modulation of reactive oxygen species generation by pathogenic mutants of human dihydrolipoamide dehydrogenase

Characterization of a Naturally Occurring Mutation (Arg-447 to Gly) in Human Dihydrolipoamide Dehydrogenase of Patients with Neurological Deterioration

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