CONGENITAL LACTIC ACIDOSIS, Α‐KETOGLUTARIC ACIDURIA AND VARIANT FORM OF MAPLE SYRUP URINE DISEASE DUE TO a SINGLE ENZYME DEFECT: DIHYDROLIPOYL DEHYDROGENASE DEFICIENCY

Münnich, Arnold; Saudubray, Jean‐Marie; Taylor, Jennifer; Charpentier, C.; Marsac, Cécile; Rocchiccioli, F.; Amédée-Manesme, O; Coudé, F. X.; Frézal, J; Robinson, Brian H.

doi:10.1111/j.1651-2227.1982.tb09393.x

Cited by 56 publications

(20 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This suggests that the affinity of whatever the central factor is for the branched-chain keto acid dehydrogenase is greater than those for pyruvate and 2-oxoglutarate dehydrogenase. It is consistent with what has been encountered in E3 deficiency in which elevated levels of alanine are regularly encountered (4,15), in contrast to maple syrup urine disease where they are depressed, and levels of leucine, isoleucine, and valine were normal or only slightly elevated (5,7,12,15,18).…”

Section: Discussionsupporting

confidence: 63%

Effect of Lipoic Acid in a Patient with Defective Activity of Pyruvate Dehydrogenase, 2-Oxoglutarate Dehydrogenase, and Branched- Chain Keto Acid Dehydrogenase

et al. 1990

View full text Add to dashboard Cite

ABSTRACT. Lactic acidosis and accumulation of 3-hydroxybutyrate and other citric acid cycle intermediates were found in an infant with a lethal syndrome of metabolic acidosis and renal tubular acidosis. Nevertheless, the patient was relatively well for 4 mo of life. The activity of the pyruvate dehydrogenase complex, 2-oxoglutarate dehydrogenase, and branched-chain keto acid dehydrogenase were all reduced to levels 9 to 29% of control. In contrast, the activity of lipoamide dehydrogenase was normal. The conversion of 1-14C-leucine and 1-I4C-valine to I4CO2 and of U-L-14C-valine to its major metabolic product 3-hydroxyisobutyric acid by fibroblasts derived from the patient was less than 5% of control. Cultivation of the patient's fibroblasts in medium enriched with lipoic acid markedly improved these in vitro conversions of leucine and valine. Lactic acidemia is encountered in a variety of clinical situations and a number of inborn errors of metabolism including defects in the PDHC (1). The associated accumulation of 2-ketoglutarate suggests defective activity in 2-ketoglutarate dehydrogenase as we11 (2). The PDHC consists fundamentally of three components that act sequentially to catalyze the oxidative decarboxylation of pyruvate. They are El, E2, and E3. The E3 enzyme also serves the same function in the 2-oxoglutarate dehydrogenase and in the third enzyme complex involved in oxidative decarboxylation, branched-chain keto acid dehydrogenase.Defective activity of all three enzyme complexes suggests the presence of a defect in E3, and a small number of patients with E3 deficiency has been reported (3-6). We describe a patient in whom defective activity of these three enzyme complexes was associated with normal activity of E3.CASE REPORT E.B. was admitted to the University of California San Diego Medical Center at 8 mo of age for evaluation of lactic acidosis. He had not developed acute symptomatic acidosis until 2 wk before admission, although he had appeared weak, sucked poorly, and gained weight slowly from birth. He was born in Venezuela, weighing 2250 g, of a 22-y-old mother and a 32-y-old father. The parents were first cousins. At 4 mo of age he began to vomit. He gained no weight during the 6th mo. During the next month he was brought to the United States and admitted to a children's hospital where he was found to have a low serum bicarbonate and large amounts of lactic acid in the urine. He was treated with 12 mEq/kg NaHC03 and transferred to San Diego (Table 1 ).Physical examination on admission revealed an alert but relatively inactive male infant who did not appear acutely ill. The pulse was 132 and the respirations 28/min, and the blood pressure was 80/40. The weight was 5250 g (50th percentile for 2 mo). The height was 64 cm (50th percentile for 4 mo), and the head circumference 18 cm (2nd percentile). The anterior fontanel was 4 x 4 cm. He was markedly hypotonic and unable to raise his head or to sit upright without support. The liver was palpable 2 cm below the right costal margin.The serum concent...

show abstract

Section: Discussionsupporting

confidence: 63%

Effect of Lipoic Acid in a Patient with Defective Activity of Pyruvate Dehydrogenase, 2-Oxoglutarate Dehydrogenase, and Branched- Chain Keto Acid Dehydrogenase

et al. 1990

View full text Add to dashboard Cite

show abstract

“…The latter is an FAD-and NADH-dependent activity believed to mainly have a prooxidant role (3). These findings together suggest that, under physiological conditions, DLD primarily functions as a DLD, playing a central role in the maintenance of energy metabolism (9)(10)(11)(12). Conversely, the moonlighting proteolytic activity of DLD could arise under pathological conditions, including the presence of dimer-destabilizing mutations or the acidification of the mitochondrial matrix (7).…”

Section: Discussionmentioning

confidence: 99%

“…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 others, localization to different cellular compartments, binding of different cofactors, and changes in oligomerization state (13).…”

mentioning

confidence: 99%

Cryptic proteolytic activity of dihydrolipoamide dehydrogenase

Babady¹,

Pang

Elpeleg

et al. 2007

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

109

View full text Add to dashboard Cite

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...

show abstract

“…A deficiency, therefore, in this enzyme results in blocking of oxidative decarboxylation not only of pyruvate and a-ketoglutarate but of branched-chain ctketoacids, and causes serious neurological disease [6,7,9,10,13]. Therapeutic measures for this disease have been unsuccessful, with the exception of a large dose of lipoic acid, to which one patient partially responded [6].…”

Section: Introductionmentioning

confidence: 92%

Dihydrolipoyl dehydrogenase deficiency: a therapeutic trial with branched-chain amino acid restriction

et al. 1986

View full text Add to dashboard Cite

A patient with a deficiency of dihydrolipoyl dehydrogenase and neurological disease is described. The patient was placed on a branched-chain amino acid-restricted regimen. After the introduction of the regimen, there were some biochemical improvements and he achieved some developmental milestones, in contrast to previously reported patients whose neurological disease was progressive. Restriction of the branched-chain amino acids is worth trying among therapeutic measures for this disease, although restriction of the amino acids alone may not totally prevent progression of neurological disease.

show abstract

CONGENITAL LACTIC ACIDOSIS, Α‐KETOGLUTARIC ACIDURIA AND VARIANT FORM OF MAPLE SYRUP URINE DISEASE DUE TO a SINGLE ENZYME DEFECT: DIHYDROLIPOYL DEHYDROGENASE DEFICIENCY

Cited by 56 publications

References 14 publications

Effect of Lipoic Acid in a Patient with Defective Activity of Pyruvate Dehydrogenase, 2-Oxoglutarate Dehydrogenase, and Branched- Chain Keto Acid Dehydrogenase

Effect of Lipoic Acid in a Patient with Defective Activity of Pyruvate Dehydrogenase, 2-Oxoglutarate Dehydrogenase, and Branched- Chain Keto Acid Dehydrogenase

Cryptic proteolytic activity of dihydrolipoamide dehydrogenase

Dihydrolipoyl dehydrogenase deficiency: a therapeutic trial with branched-chain amino acid restriction

Contact Info

Product

Resources

About