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At least 19 recordsLinked to original sources
PubMed2025

Odd-Chain Dicarboxylic Acid Feeding Produces a Glutaric Aciduria Type 1-Like Metabolic Signature in Mice.

Glutaric aciduria type-1 (GA1) is an inherited mitochondrial neurometabolic disorder with a poorly understood pathogenesis and unmet medical needs. GA1 can be diagnosed via its hallmark biochemical signature consisting of glutaric aciduria, 3-hydroxyglutaric aciduria, and increased plasma glutarylcarnitine. These glutaryl-CoA-derived metabolites are thought to originate solely in the mitochondria. Here, we demonstrate that wild-type mice fed an 11-carbon odd-chain dicarboxylic acid (undecanedioic acid, DC11) recreate the biochemical phenotype of GA1. Odd-chain dicarboxylic acids like DC11 are not present in food but can arise from several endogenous processes, such as lipid peroxidation and fatty acid ω-oxidation. DC11 is chain-shortened in peroxisomes to glutaryl (DC5)-CoA, which then gives rise to the GA1-like pattern of DC5 metabolites in urine, tissues, and blood. Glutaric acid released from peroxisomes during DC11 chain-shortening can enter mitochondria for reactivation by the enzyme succinyl-CoA:glutarate-CoA transferase (SUGCT) and become substrate for glutaryl-CoA dehydrogenase (GCDH), the enzyme that is deficient in GA1. Our data provide proof-of-concept that the generation of dicarboxylic acids by ω-oxidation, which is stimulated during the same catabolic states known to trigger acute encephalopathy in GA1, may exacerbate disease by increasing the glutaryl-CoA substrate load in mitochondria.

Animals↗
PubMed1977

Glutaric aciduria: clinical and laboratory findings in two brothers.

In two siblings with dystonic cerebral palsy the urinary metabolic profiles of organic acids were dominated by glutaric acid, a metabolite not normally present in urine. The exretion of glutaric acid amounted to several grams per day. The urinary excretion of beta-OH-glutaric acid and glutaconic acid was also enhanced. Imparied metabolism of glutaryl-CoA by leukocytes indicates that the patients suffer from an inborn error of lysine, tryptophan, and hydroxylysine metabolism. A defective oxidation of glutaryl-CoA to crotonyl-CoA, probably due to a deficiency of glutaryl-CoA dehydrogenase, is consistent with these findings.

Amino Acid Metabolism, Inborn Errors↗
PubMed1979

Recurrent hypoglycemia associated with glutaric aciduria type II in an adult.

Repeated episodes of hypoglycemia accompanied by elevated serum concentrations of free fatty acid without ketosis, fatty infiltration of the liver, hepatic dysfunction, and proximal myopathy in a 19-year-old woman, prompted us to analyze her urine for organic acids. Greatly increased quantities of glutaric acid, ethylmalonic acid, dicarboxylic acids with six to 10 carbons, and isovalerylglycine were consistently found in her urine. The ability of cultured skin fibroblasts from the patient to oxidize [1(-14)C]butyrate and [2(-14)C]lysine was reduced. These urinary and in vitro findings indicated defective activity of several acyl coenzyme A dehydrogenases, including glutaryl, isovaleryl, and butyryl coenzyme A dehydrogenases -- establishing a diagnosis of glutaric aciduria Type II. Carnitine concentrations in the skeletal muscle and liver were moderately reduced, but carnitine deficiency was considered a secondary biochemical abnormality. Although glutaric aciduria Type II has previously been described only in a neonate, the disease must be considered in the differential diagnosis of hypoglycemia in adults.

Adult↗
PubMed1977

[Primary photosynthetic reactions in isolated chloroplasts fixed by glutaric aldehyde].

The primary photosynthetic reactions in isolated pea chloroplasts with the structures fixed by increasing concentrations of glutaric aldehyde were studied. It was shown that under chloroplast fixation by 5--25 mM of glutaric aldehyde, a significant inhibition of processes responsible for energy transformation in biological membranes was observed. The highest sensitivity was observed for the phosphorylation reactions, photo-induced changes in absorption at 520 nm, photo-induced quenching of atebrin fluorescence and slow component of delayed light emission. The photo-induced proton uptake was found to be less sensitive to fixation by glutaric aldehyde. It was also shown that on chloroplast fixation the extent of the steady-state P700 oxidation and the lifetime of the photosystem I and II chlorophyll fluorescence are both increased, a fact is indicating of loss in the effectiveness of light energy transfer from the antenna molecules to the reaction centres. Presumably the conformational changes play an essential role at the initial steps of light energy transformation.

Aldehydes↗
PubMed1979

L-Glutaric acidemia: investigation of a patient and his family.

A 5-month-old infant had an unusual combination of clinical signs and symptoms. These consisted of irritability, dystonia, lack of head control, grimacing, opisthotonos, choreoathetoid movements, delayed development, and severe metabolic acidosis. Metabolic investigation by gas-liquid chromatography/mass spectrometry detected urinary organic acids. This confirmed the diagnosis of L-glutaric aciduria. The concentration of L-glutaric acid in the patient's plasma was 2.5 mg/dl (normal range, 0 to 0.1 mg/dl), and in the patient's urine was 4.6 mg/mg of creatinine (normal range, 0 to 0.05 mg/mg of creatinine), but the concentration was not elevated in the plasma and urine of the infant's parents nor of two other family members. No glutaryl-CoA dehydrogenase activity was found in leukocytes taken from the patient. Three of the four family members, including the parents, demonstrated 38%, 42%, and 42% activity, respectively, compared with the activity of normal controls. These findings are consistent with an autosomal recessive disorder involving the metabolism of glutaryl-CoA to crotonyl-Co-a. Dietary restriction was instituted on two separate occasions. First, a low protein diet of 1.6 gm/kg of body weight per day was given, then a low lysine intake of 50 mg/kg/day. These dietary manipulations caused a decrease in the plasma and urine concentrations of L-glutaric acid and beta-hydroxyglutaric acid. However, no effect on the clinical manifestations of the disease was noted.

Amino Acid Metabolism, Inborn Errors↗
PubMed1978

Studies on glutaryl-CoA dehydrogenase in leucocytes, fibroblasts and amniotic fluid cells. The normal enzyme and the mutant form in patients with glutaric aciduria.

Three patients with glutaric aciduria have been shown to possess a partial but severe defect of the enzyme glutaryl-CoA dehydrogenase in isolated leucocytes and cultured skin fibroblasts. They could readily be distinguished from heterozygotes by measuring the activity of this enzyme, as shown in a study of the two families involved. The activity of glutaryl-CoA dehydrogenase in normal cultured amniotic fluid cells was comparable to the activity in normal cultured skin fibroblasts indicating the possibility of prenatal diagnosis. Without flavin adenine dinucleotide added to the assay mixture, the activity of glutaryl-CoA dehydrogenase in fibroblasts from normal individuals was very much reduced and similar to the activity in the patients, but after addition of flavin adenine dinucleotide to saturation the activity increased 20-fold in normal subjects while only a very slight increase could be demonstrated in the patients. The Michaelis constant for the substrate glutaryl-CoA was similar for both normal and patient cell lines. The optimum assay conditions for the enzyme in cultured fibroblasts from normal individuals have been established. In contrast to our patients, we found no activity in a fibroblast cell line from a patient with glutaric aciduria diagnosed elsewhere.

Amniotic Fluid↗
PubMed1979

Treatment of glutaryl-CoA dehydrogenase deficiency (glutaric aciduria). Experience with diet, riboflavin, and GABA analogue.

The autosomal recessive inherited disorder glutaryl-CoA dehydrogenase deficiency (glutaric aciduria) runs a progressive course with severe choreoathetosis and dystonia, eventually leading to total helplessness and early death. Theree patients were observed during therapeutic trials with a protein-low diet, riboflavin and GABA analogue. Diet and riboflavin had a slight-to-moderate effect on the clinical symptoms; the excretion of glutaric acid and 2-amino-adipic acid decreased considerably during treatment. Regression of neurologic symptoms was observed during treatment with GABA analogue. It is concluded that the patients should be treated as early as possible with protein-low diet, riboflavin, and GABA analogue.

2-Aminoadipic Acid↗
PubMed1977

The allosteric mechanism of bovine liver glutamate dehydrogenase. Evidence from circular-dichroism studies for a conformational change in the ternary complex enzyme-(oxidized nicotinamide-adenine dinucleotide)-glutarate.

1. Computer averaging of multiple scans was used to refine the circular dichroism spectrum of bovine liver glutamate dehydrogenase, revealing well-defined structure in the aromatic region. 2. The circular dichroism of NAD+ bound to glutamate dehydrogenase is strongly negative at 260nm, probably owing to immobilization of the adenosine moiety. Loss of the characteristic adenine-nicotinamide interaction suggests that the coenzyme is bound in an unstacked conformation. 3. Glutarate and succinate, substrate analogues that are both inhibitors competitive with glutamate, do not significantly perturb the circular-dichroism spectrum of the enzyme in the absence of NAD+. 4. In the presence of NAD+, 150nM-succinate decreases the negative circular dichroism corresponding to bound coenzyme, but does not affect the protein circular dichroism. However, ISOmM-glutarate causes profound alternations of the circular-dichroism spectra of the bound NAD+ and of the enzyme, indicative of a protein conformational change. This direct evidence of conformational change specifically promoted by C5 dicarboxylates confirms the previous inference from protection studies. 5. The conformational change is discussed in relation to the allosteric mechanism of glutamate dehydrogenase.

Allosteric Regulation↗
PubMed1979

[Glutaric aciduria. 1 new case].

A 4 year old girl with mild mental retardation presented with convulsions, coma and hepatomegaly. She died rapidly. The main biochemical findings were hypoglycaemia, metabolic acidosis, generalised aminoaciduria, elevation of the plasma and urine alpha-amino adipic acid, massive urine excretion of glutaric and glutaconic acids with traces of alpha-hydroxyglutaric acid. The diagnosis of glutaric aciduria was confirmed by the low activity of glutaryl CoA dehydrogenase in liver tissue. This diagnosis should be considered in children with progressive neurological disorders (dystonia, choreoathetosis) and in children with an illness similar to Reye's syndrome.

Amino Acid Metabolism, Inborn Errors↗
PubMed1977

Glutaric aciduria: biochemical and morphologic considerations.

Biochemical and morphologic studies on a patient with glutaric aciduria are presented. Generalized aminoaciduria, alpha-aminoadipic aciduria, and saccharopinuria were noted just prior to death, as well as glutaconic aciduria greater than beta-hydroxyglutaric aciduria. Mutant liver mitochondria did not oxidize glutaryl-CoA to glutaconyl-CoA, indicating deficiency of glytaryl-CoA dehydrogenase. Autopsy revealed cerebral edema, ischemic neuronal changes, and striatal degeneration in the brain with fatty changes in liver, kidney, and myocardium.

Amino Acid Metabolism, Inborn Errors↗
PubMed1977

Intermittently progressive dyskinetic syndrome in glutaric aciduria.

A case of glutaric aciduria, a recently discovered inborn error of tryptophan-lysine metabolism, is reported. Development was normal during the first year of life. Signs of dyskinesia and dystonia associated with developmental regression occurred twice during gastrointestinal disease. By two years of age, a dystonic syndrome with a severe motor and language disability had resulted.

Amino Acid Metabolism, Inborn Errors↗
PubMed1978

Glutaric aciduria in progressive choreo-athetosis.

The clinical symptoms in a 10-year-old girl with progressive dystonic cerebral palsy are described. The biochemical findings were dominated by large amounts of glutaric acid in the urine. The disorder is caused by impairment of the degradation of glutaryl-CoA. A survey is given of the clinical and biochemical symptoms, based on the five cases reported so far. It is concluded that patients with progressive dystonic palsy should be examined for disorders in the metabolism of organic acids.

Acyl Coenzyme A↗
PubMedDate not supplied

Effectiveness of N-N-bis-P-chlorophenyl-3p-tolyl glutaric acid diamide (SRC-3605) as a hypocholesterolaemic compound in hypercholesterolaemic female weanling and adult rats.

SRC-3605, N-N-bis-P-chlorophenyl 3-p-tolyl glutaric acid diamide, was studied for its hypocholesterolaemic effect on serum and liver cholesterol in hypercholesterolaemic weanling and adult female rats. Weanlings were administered doses of SRC-3605 ranging from 100 to 300 mg/kg body weight for 4 or 8 consecutive days. The greatest hypocholesterolaemic effect was observed with doses of 150, 200 and 250 mg, although a progressive decreases in serum cholesterol was noted with increasing doses. Hepatic cholesterol decreases supported the serum data, but were inconsistent. Hypercholesterolaemic adult animals received 50, 100, 150 or 200 mg/kg body weight of either SRC-3605 or clofibrinic acid for 4 days. A decrease in serum cholesterol levels was observed only with the 200 mg SRC-3605. No clear-cut influence of the either compounds was found on hepatic cholesterol. The results indicated that SRC-3605 possesses the property to reduce both serum and liver cholesterol in hypocholesterolaemic weanling female rats.

Animals↗
PubMed1979

Transport of C5 dicarboxylate compounds by Pseudomonas putida.

Induced glutarate and 2-oxoglutarate uptake and transport by Pseudomonas putida were investigated in whole cells and membrane vesicles, respectively. Uptake of 2-oxoglutarate, but not glutarate, was against a concentration gradient to 1.7-fold greater than the initial extracellular concentration. Membrane vesicles transported 2-oxoglutarate and glutarate against gradients to intramembrane concentrations fivefold greater than the initial extravesicle concentrations. The rates of transport of both compounds were greatest in the presence of the artificial electron donor system phenazine methosulfate-ascorbate. Malate and D-lactate were the only naturally occurring compounds that served as electron donors. Uptake and transport were inhibited by KCN, NaN3, and 2,2-dinitrophenol. Kinetic parameters of transport were: glutarate, apparent Km--1.22 mM, Vmax--400 nmol/min per mg of membrane protein; 2-oxoglutarate, apparent Km--131 microM, Vmax--255 nmol/min per mg of membrane protein. Studies of competitive inhibition indicated a common system for transport of five C5 dicarboxylate compounds. The apparent Km and Ki values with 2-oxoglutarate as a substrate placed the substrate affinity for transport in the order 2-oxoglutarate greater than glutarate greater than D-2-hydroxyglutarate and L-2-hydroxyglutarate greater than glutaconate.

Biological Transport↗
PubMed1977

Catabolism of L-lysine by Pseudomonas aeruginosa.

Pseudomonas aeruginosa PACI grows poorly on L-lysine as sole source of carbon but mutant derivatives which grow rapidly were readily isolated. Studies with one such mutant, P. aeruginosa PAC586, supported the existence of a route for L-lysine catabolism which differes from those reported previously in other species of Pseudomonas. The postulated route, the cadaverine or decarboxylase pathway, is initiated by the decarboxylation of L-lysine and involves the following steps: L-lysine leads to cadverine leads to I-piperideine leads 5-aminovalerate leads to glutarate semialdehyde leads glutarate. Evidence for this pathway is based on the characterization of the pathway reactions and the induction of the corresponding enzymes by growth on L-lysine. The first three enzymes were also induced by growth on cadaverine and to a lesser extent by 5-aminovalerate. No evidence was obtained for the presence of pathways involving L-lysine 2-monooxygenase or L-pipecolate dehydrogenase, but another potential route for L-lysine catabolism initiated by L-lysine 6-aminotransferase was detected. Studies with mutants unable to grow on L-lysine supported the existence of more than one catabolic pathway for L-lysine in this organism and indicated that all routes converge on a pathway for glutarate catabolism which generates acetyl-CoA. Pipecolate catabolism also appeared to converge on the glutarate pathway in P. AERUGINOSA. The results suggested that the growth rate of the parental strain is limited by the rate of transport and/or decarboxylation of L-lysine. The cadaverine pathway was present, but not so highly induced, in the parental strain P. aeruginosa PACI. Pseudomonas fluorescens contained enzymes of both the cadaverine (decarboxylase) and oxygenase pathways, strains of P. putida (biotypes A and B) contained enzymes of the oxygenase pathway but not the decarboxylase pathway and P. multivorans appeared deficient in both. All these species possessed L-lysine aminotransferase activity.

Cadaverine↗