The Enzymatic Carboxylation of Butyryl Coenzyme A

Hegre, C. S.; Halenz, Donald R.; Lane, M. Daniel

doi:10.1021/ja01533a055

Cited by 49 publications

(12 citation statements)

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“…Neither excreted ethylmalonate. This absence of ethylmalonate could be expected in a patient with propionyl-CoA carboxylase deficiency if we assume that ethylmalonate is formed via ethylmalonic acid semialdehyde~ butyryl-CoA~ carboxylation of butyryl-CoA catalyzed by propionylCoA carboxylase (Stern et al, 1959;Hegre et al, 1959) in parallel to valine degradation via methylmalonic acid semialdehyde~ propionyl-CoA~ methylmalonyl-CoA (Tanaka et al, 1975).…”

Section: Discussionmentioning

confidence: 91%

Propionyl-CoA carboxylase deficiency with overflow of metabolites of isoleucine catabolism at all levels

et al. 1979

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An 11-year old girl with spastic paraplegia and mental retardation has suffered from attacks of metabolic acidosis since the age of 18 months. "Ketotic hyperglycinemia" was diagnosed when she was 3 years old. Reinvestigation at 9 1/2 years included a two-day load with L-isoleucine, and propionyl-CoA carboxylase assay in cultured fibroblasts. The following compounds increased following the load: 3-hydroxypropionic acid, 2-methyl-3-hydroxybutyric acid, 2-ethylhydracrylic acid, 3-hydroxy-n-valeric acid, 3-oxo-n-valeric acid, 2-methyl-3-oxobutyric acid, 2-oxo-3-methylvaleric acid, 2-methyl-3-oxovaleric acid, N-tiglylglycine, methylcitric acid and butanone. Small amounts of alloisoleucine appeared in plasma. Propionyl-CoA carboxylase deficiency was suggested by this metabolite pattern and demonstrated in cultured fibroblasts.

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Section: Discussionmentioning

confidence: 91%

Propionyl-CoA carboxylase deficiency with overflow of metabolites of isoleucine catabolism at all levels

et al. 1979

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“…Deficient SCAD enzyme activity leads to accumulation of butyryl-CoA, which is converted to ethylmalonic acid (EMA) (Hegre et al 1959) and/or butyryl-carnitine (Coates et al 1988;Wanders et al 1999). Elevation of EMA (>18-20 mmol/ mol creatinine), however, has been observed in various other metabolic disorders with neurological disease manifestations, e.g., ethylmalonic encephalopathy (OMIM 602473) (Burlina et al 1994;Tiranti et al 2004;Tiranti et al 2005), multiple acyl-CoA dehydrogenation deficiency (MADD; OMIM 231680) (Gregersen 1985;Rhead et al 1987;Rinaldo et al 1991), and respiratory chain disorders (Christensen et al 1993;Hoffmann et al 1990; Lehnert and Ruitenbeek 1993).…”

Section: Introductionmentioning

confidence: 99%

Antioxidant dysfunction: potential risk for neurotoxicity in ethylmalonic aciduria

Pedersen

Zolkipli

Vang

et al. 2010

J of Inher Metab Disea

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Mitochondrial dysfunction and oxidative stress are central to the molecular basis of several human diseases associated with neuromuscular disabilities. We hypothesize that mitochondrial dysfunction also contributes to the neuromuscular symptoms observed in patients with ethylmalonic aciduria and homozygosity for ACADS c.625G>A-a common variant of the short-chain acyl-coenzyme A (CoA) dehydrogenase (SCAD) enzyme in the mitochondrial fatty acid oxidation pathway. This study sought to identify the specific factors that initiate cell dysfunction in these patients. We investigated fibroblast cultures from 10 patients with neuromuscular disabilities, elevated levels of ethylmalonic acid (EMA) (>50 mmol/mol creatinine), and ACADS c.625G>A homozygosity. Functional analyses, i.e., ACADS gene and protein expression as well as SCAD enzyme activity measurements, were performed together with a global nano liquid chromatography tandem mass spectroscopy (nano-LC-MS/MS)-based screening of the mitochondrial proteome in patient fibroblasts. Moreover, cell viability of patient fibroblasts exposed to menadione-induced oxidative stress was evaluated. Loss of SCAD function was detected in the patient group, most likely due to decreased ACADS gene expression and/or elimination of misfolded SCAD protein. Analysis of the mitochondrial proteome in patient fibroblasts identified a number of differentially expressed protein candidates, including reduced expression of the antioxidant superoxide dismutase 2 (SOD2). Additionally, patient fibroblasts demonstrated significantly higher sensitivity to oxidative stress than control fibroblasts. We propose that reduced mitochondrial antioxidant capacity is a potential risk factor for ACADS c.625G>A-associated ethylmalonic aciduria and that mitochondrial dysfunction contributes to the neurotoxicity observed in patients.

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“…The most frequent symptoms are chronic and episodic neuromuscular disabilities, including cognitive and muscular developmental delay, hypotonia, and seizures. All patients reported with documented SCAD deficiency excrete increased levels of ethylmalonic acid in the urine, originating from the accumulation of butyryl-CoA, the substrate for SCAD (14). SCAD deficiency is inherited in an autosomal recessive fashion due to variations in both alleles of the SCAD gene.…”

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confidence: 99%

Misfolding, Degradation, and Aggregation of Variant Proteins

Pedersen

Bross

Winter

et al. 2003

Journal of Biological Chemistry

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Short chain acyl-CoA dehydrogenase (SCAD) deficiency is an inborn error of the mitochondrial fatty acid metabolism caused by rare variations as well as common susceptibility variations in the SCAD gene. Earlier studies have shown that a common variant SCAD protein (R147W) was impaired in folding, and preliminary experiments suggested that the variant protein displayed prolonged association with chaperonins and delayed formation of active enzyme. Accordingly, the molecular pathogenesis of SCAD deficiency may rely on intramitochondrial protein quality control mechanisms, including degradation and aggregation of variant SCAD proteins. In this study we investigated the processing of a set of disease-causing variant SCAD proteins (R22W, G68C, W153R, R359C, and Q341H) and two common variant proteins (R147W and G185S) that lead to reduced SCAD activity. All SCAD proteins, including the wild type, associate with mitochondrial hsp60 chaperonins; however, the variant SCAD proteins remained associated with hsp60 for prolonged periods of time. Biogenesis experiments at two temperatures revealed that some of the variant proteins (R22W, G68C, W153R, and R359C) caused severe misfolding, whereas others (R147W, G185S, and Q341H) exhibited a less severe temperaturesensitive folding defect. Based on the magnitude of in vitro defects, these SCAD proteins are characterized as folding-defective variants and mild folding variants, respectively. Pulse-chase experiments demonstrated that the variant SCAD proteins either triggered proteolytic degradation by mitochondrial proteases or, especially at elevated temperature, aggregation of non-native conformers. The latter finding may indicate that accumulation of aggregated SCAD proteins may play a role in the pathogenesis of SCAD deficiency.

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The Enzymatic Carboxylation of Butyryl Coenzyme A

Cited by 49 publications

References 0 publications

Propionyl-CoA carboxylase deficiency with overflow of metabolites of isoleucine catabolism at all levels

Propionyl-CoA carboxylase deficiency with overflow of metabolites of isoleucine catabolism at all levels

Antioxidant dysfunction: potential risk for neurotoxicity in ethylmalonic aciduria

Misfolding, Degradation, and Aggregation of Variant Proteins

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