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PubMed2005

Structure of Escherichia coli glutamate decarboxylase (GADalpha) in complex with glutarate at 2.05 angstroms resolution.

Glutamate decarboxylase (GAD) is a pyridoxal enzyme that catalyzes the conversion of L-glutamate into gamma-aminobutyric acid and carbon dioxide. The Escherichia coli enzyme exists as two isozymes, referred to as GADalpha and GADbeta. Crystals of the complex of the recombinant isozyme GADalpha with glutarate as a substrate analogue were grown in space group R3, with unit-cell parameters a = b = 117.1, c = 196.4 angstroms. The structure of the enzyme was solved by the molecular-replacement method and refined at 2.05 angstroms resolution to an R factor of 15.1% (R(free) = 19.9%). The asymmetric unit contains a dimer consisting of two subunits of the enzyme related by a noncrystallographic twofold axis which is perpendicular to and intersects a crystallographic threefold axis. The dimers are related by a crystallographic threefold axis to form a hexamer. The active site of each subunit is formed by residues of the large domains of both subunits of the dimer. The coenzyme pyridoxal phosphate (PLP) forms an aldimine bond with Lys276. The glutarate molecule bound in the active site of the enzyme adopts two conformations with equal occupancies. One of the two carboxy groups of the glutarate occupies the same position in both conformations and forms hydrogen bonds with the N atom of the main chain of Phe63 and the side chain of Thr62 of one subunit and the side chains of Asp86 and Asn83 of the adjacent subunit of the dimer. Apparently, it is in this position that the distal carboxy group of the substrate would be bound by the enzyme, thus providing recognition of glutamic acid by the enzyme.

Escherichia coli↗
PubMed1998

Glutaric aciduria type I with high residual glutaryl-CoA dehydrogenase activity.

Two brothers with dystonia and slight MRI changes in the basal ganglia had normal urinary glutaric acid excretion, but slightly increased 3-hydroxyglutarate and conjugated glutarate excretions. Both siblings have high residual glutaryl-CoA dehydrogenase activity, and are compound heterozygotes for two mutations - R227P and V400M reported to be disease-causing in patients with glutaric aciduria type I.

Amino Acid Metabolism, Inborn Errors↗
PubMed1987

Recent progress in understanding glutaric acidemias.

Glutaric acidemia, which is due to inherited deficiency of glutaryl-CoA dehydrogenase, is characterized clinically by progressive dystonia and dyskinesia in childhood, and pathologically by degeneration of the caudate and putamen. Results using newer imaging techniques (computer tomography and magnetic resonance image scanning) suggest that neurological involvement in this condition begins before birth, and that gliosis of the basal ganglia is a relatively late event. Glutaric acidemia type II is usually due to inherited deficiency of electron transfer flavoprotein (ETF) or ETF:ubiquinone oxidoreductase, but some patients with typical disease may have another, to date undefined, abnormality. There may also be a clinical phenotype of glutaric acidemia type II which, like glutaryl-CoA dehydrogenase deficiency, is characterized by a movement disorder and by degeneration of the basal ganglia.

Child, Preschool↗
PubMed1984

Glutaric aciduria type II: evidence for a defect related to the electron transfer flavoprotein or its dehydrogenase.

Incubation of intact fibroblasts from a patients with glutaric aciduria type II with [2-14C]riboflavin showed normal synthesis of flavin mononucleotide and flavin adenine dinucleotide. This is taken as evidence for normal transport of riboflavin into the cells and normal activity of riboflavin kinase (EC 2.7.1.26) and flavin mononucleotide adenylyltransferase (EC 2.7.7.2). The ability of intact fibroblasts to oxidize 1-14C-fatty acids and [6-14C]lysine is impaired in the patient which together with the urinary excretion pattern of organic acids indicates a defective dehydrogenation of fatty acid acyl-CoAs and glutaryl-CoA. However, dehydrogenation of (C6-C10) fatty acid acyl-CoA derivatives and glutaryl-CoA was normal when the dehydrogenases were measured in fibroblast homogenate with artificial electron acceptors. In vivo, these dehydrogenases transfer their electrons to CoQ10 in the main electron transport chain via electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase. Glutaric aciduria type II fibroblasts showed very diminished activity when the glutaryl-CoA dehydrogenase activity was measured without artificial electron acceptor but with intact endogenous electron transport system. As the NADH and succinate oxidation seems normal in glutaric aciduria type II patients, this is strong evidence for a defect in either the electron transfer flavoprotein or the electron transfer flavoprotein dehydrogenase.

Amino Acid Metabolism, Inborn Errors↗
PubMed1991

Prenatal diagnosis and neonatal monitoring of a fetus with glutaric aciduria type II due to electron transfer flavoprotein (beta-subunit) deficiency.

The prenatal diagnosis of a male fetus with glutaric aciduria type II and the time course of metabolite urinary excretion, starting immediately after birth, are described. Prenatal diagnosis was undertaken at the 17th wk of gestation by immunoblot analysis and pulse labeling experiments of amniocytes and, retrospectively, by stable isotope dilution analysis of six metabolites in amniotic fluid. The results were as follows: 1) The immunochemical analysis on cultured amniocytes showed that the fetus, as the previous index case in this family, was affected with a deficiency of the beta-subunit of electron transfer flavoprotein. 2) Glutarate concentration was significantly increased in the cell-free supernatant of the amniotic fluid. In the postnatal period, most of the organic acids and acylglycines characteristic of the disorder appeared in urine within a week, although an increased excretion of hexanoylglycine was the only biochemical abnormality detectable in the first urine sample collected at 9 h after birth. Growth and development of this infant were normal during the following 6 mo of life, when he was receiving oral supplementation with L-carnitine and riboflavin. It should be underscored that transient abnormalities in routine blood tests (glutamic oxaloacetic transaminase, lactate dehydrogenase, and creatine phosphokinase) were present soon after birth, despite his asymptomatic clinical course. Early detection and aggressive treatment could be effective in such a form of glutaric aciduria type II.

Amniotic Fluid↗
PubMedDate not supplied

Bilateral arachnoid cysts of the temporal fossa in four children with glutaric aciduria type I.

Glutaric aciduria type I is an uncommon inborn error of metabolism. It is a serious disease, often with a fatal outcome. This study reports the presence of bilateral temporal fluid collections, probably bilateral arachnoid cysts, in association with glutaric aciduria type I. The CT and, when available, MR studies from five patients with this disorder were reviewed. Four of the patients had findings consistent with bilateral arachnoid cysts of the temporal fossa. This is a rare occurrence, with only 11 such cases reported in the literature. The observed association between temporal fluid collections and glutaric aciduria type I suggests that patients with bilateral arachnoid cysts should be investigated for this metabolic disorder.

Amino Acid Metabolism, Inborn Errors↗
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↗
PubMed1993

[Glutaric aciduria type I].

We report three patients with glutaric aciduria type I. The biochemical diagnosis of two cases was revealed by determination of free glutaric acid in urine, by using the CG/EM method. In the third patient, however, these levels were only slightly increased and the diagnosis was attained by the determination of total glutaric acid and glutaryl-carnitine. Serum carnitine levels were decreased in two cases. Clinical symptoms of this type of organic acidemia are highlighted by an acute or subacute presentation with signs of dysfunction of the neostriatum, simulating a cerebral paralysis with extrapyramidal signs. Homozygous patients have been reported with the same biochemical and enzymatic activity findings, but these patients were neurologically asymptomatic throughout life. Other features suggestive of the disease are macrocephaly associated with a widening of the subarachnoid spaces. Riboflavin and carnitine administration to these patients seems to prevent new bouts of neurological dysfunction.

Amino Acid Metabolism, Inborn Errors↗
PubMed1977

Glutarate semialdehyde dehydrogenase of Pseudomonas. Purification, properties, and relation to L-lysine catabolism.

The lysine-induced glutarate semialdehyde dehydrogenase of Pseudomonas was purified to electrophoretic homogeneity from a mutant strain lacking delta-aminovalerate transaminase. The properties of the enzyme, including molecular weight, amino acid composition, electrophoretic behavior, and kinetic features, distinguish it from similar dehydrogenases induced in the same cell strain by hydroxyproline or by glucarate. Enzyme induction patterns and the growth behavior of a mutant deficient in glutarate semialdehyde dehydrogenase clearly relate this enzyme to the so-called delta-aminovalerate pathway of L-lysine catabolism. Induction studies also indicate that delta-aminovalerate is a better inducer of the dehydrogenase than L-lysine. Cells of a mutant strain lacking delta-aminovalerate transaminase contained higher levels of the dehydrogenase, presumably as a result of the accumulation of delta-aminovalerate, making this mutant a useful preparative source of the enzyme. The marked reduction of lysine-inducible glutarate semialdehyde dehydrogenase in a mutant strain permitted assessment of the basal levels of hydroxyproline/glucarate-inducible ketoglutarate semialdehyde dehydrogenases not possible in wild type cells.

Aldehyde Oxidoreductases↗
PubMedDate not supplied

Microparticles of BSA substituted with deoxycholic acid and triethylene glycol glutarate. Correlations between the physico-chemical properties of the matrix and the release kinetics.

Bovine serum albumin or bovine serum albumin covalently linked to deoxycholic acid and triethylene glycol glutarate were used for the preparation of microspheres loaded with indomethacin. The presence of these residues on the bovine serum albumin molecule increased the loading levels. The kinetic analysis of release evidenced a zero order release period from the start of release in the microparticles obtained by bovine serum albumin linked to deoxycholic acid and triethylene glycol glutarate, followed by a decreasing rate release and a first Anomalous period followed by a zero order period in the albumin microparticles. These different release behaviours were correlated to the modifications induced by deoxycholic acid and triethylene glycol glutarate on the drug diffusivity and solubility in the matrix undergoing erosion.

Chemical Phenomena↗
PubMed1998

Glutaryl-CoA dehydrogenase mutations in glutaric acidemia (type I): review and report of thirty novel mutations.

Glutaric acidemia type I (GA1) is caused by mutations in the gene encoding the enzyme glutaryl-CoA dehydrogenase (GCD). Sixty-three pathogenic mutations identified by several laboratories are presented, 30 of them for the first time, together with data on expression in Escherichia coli and relationship to the clinical and biochemical phenotype. In brief, many GCD mutations cause GA1, but none is common. There is little if any relationship between genotype and clinical phenotype, but some mutations, even when heterozygous, seem especially common in patients with normal or only minimally elevated urine glutaric acid.

Amino Acid Metabolism, Inborn Errors↗
PubMed2000

Recurrent and novel mutations of GCDH gene in Chinese glutaric acidemia type I families.

Glutaric acidemia type I is caused by mutations of the glutaryl-CoA dehydrogenase (GCDH) gene resulting in loss of GCDH enzyme activity. Patients present with progressive dystonia and lesions in basal ganglia. Dietary treatment, when instituted from the early neonatal period, markedly reduces dystonia and morbidity. Early diagnosis and prenatal diagnosis will be facilitated by knowledge of locally prevalent GCDH mutations. Several common GCDH mutations have been found in different ethnic groups. GCDH mutations were studied in 5 Chinese glutaric acidemia type I families. We detected two novel recurrent mutations (A219T and IVS10-2A>C) which were found in two unrelated families. An asymptomatic carrier of IVS10-2A>C was also found on screening of 120 individuals. Other mutations were identified, including two other novel (R386G & IVS3+1G>A) and two known mutations (G178R & R355H). Fibroblasts from patients carrying the novel mutations were confirmed to be deficient for GCDH activity. This is the first report of GCDH mutations describing recurrent mutations in Chinese patients. The carrier rate of IVS10-2A>C may be particularly high in Chinese.

Alternative Splicing↗
PubMed1987

Characterization of new diagnostic acylcarnitines in patients with beta-ketothiolase deficiency and glutaric aciduria type I using mass spectrometry.

Direct analysis of unpurified urine from patients with beta-ketothiolase deficiency and glutaryl-coenzyme A dehydrogenase deficiency was carried out by methylation and fast atom bombardment mass spectrometry. Previously unidentified signals consistent with unusual acylcarnitines were detected. In the former disease, thermospray liquid chromatography/mass spectrometry analysis confirmed the identification of tiglylcarnitine and differentiated it from a biological isomer, 3-methylcrotonylcarnitine. In glutaric aciduria, glutarylcarnitine was confirmed by detection of glutaric acid liberated upon base hydrolysis of a purified acylcarnitine fraction. The discovery of these metabolites suggests that L-carnitine therapy might be beneficial for the enhanced excretion of toxic metabolites that accumulate in patients with these disorders.

Acetyl-CoA C-Acyltransferase↗
PubMed2001

Metal-assisted esterification: glutaric acid-iron(II) complexes in the gas phase.

Transition metal ions are routinely used to assist organic reactions; however, direct detection of the intermediates in such reactions is uncommon. Here, we demonstrate a transition metal ion-assisted reaction between glutaric acid (L) and methanol, using electrospray ionization mass spectrometry (ESI-MS). Esterification of glutaric acid does not occur in aqueous methanol solution under ESI conditions, but the FeII-bound acid cluster, [FeII L2 - H]+, adds methanol and dehydrates to give rise to an abundant product ion with a 14 Da increased mass. The occurrence of methyl esterification is supported by collision-induced dissociation and isotopic labeling data, which indicate that the sequence by which the product ion is generated is loss of water, followed by the addition of methanol. Electrospray ionization conditions, specifically the tube lens offset voltage, strongly affect the reaction efficiency, presumably through control of the dehydration process. Other transition metal ions, such as NiII, ZnII, CoII and CuII, also show distinctive metal-assisted reactions.

Cobalt↗
PubMed2002

Outcome of the first 3-years of a DNA-based neonatal screening program for glutaric acidemia type 1 in Manitoba and northwestern Ontario, Canada.

Glutaric acidemia type 1 (GA1) is overrepresented in the aboriginal population of Island Lake, Manitoba, and northwestern Ontario who speak the Ojibway-Cree (Oji-Cree) dialect. The carrier frequency in these communities has been predicted to be as high as 1 in 10 individuals. Prior to beginning newborn screening for GA1 in May 1998, 18 of 20 affected patients diagnosed at this center have been from these high-risk communities. Most have followed an acute encephalopathic course with permanent neurologic sequelae and high mortality. They excrete small amounts of glutaric acid and 3-hydroxyglutaric acid and have significant residual enzyme activity. A single homozygous mutation in glutaryl-CoA-dehydrogenase (GCDH IVS-1 + 5g right arrow t) has been identified in this population. DNA-based newborn screening targeted to our high-risk communities was begun in order to provide presymptomatic detection and treatment of affected patients. Of the first 1176 newborns screened, 4 affected infants were identified and treated with a low-protein diet, carnitine, and riboflavin. All 4 infants have required numerous hospitalizations for treatment of intercurrent illnesses. Eventually, 3 infants presented with acute dystonic encephalopathy and seizures along with permanent neurological sequelae. One of these infants died unexpectedly at home at 18 months of age. The fourth, now 9 months old, has had a gastrostomy tube placed to facilitate fluid replacement in addition to a standard treatment protocol and is doing well. The reasons for our initial disappointing outcomes in the first 3 of 4 affected babies are likely multiple. Based on our early experience and that of other centers screening newborns for GA1, current therapeutic strategies may be insufficient in preventing the occurrence of neurologic sequelae in some children. An incomplete understanding of the neurotoxic mechanisms underlying this devastating disorder hampers effective management.

Canada↗
PubMed1986

Glutaric aciduria type 1: biochemical investigations and postmortem findings.

Glutaric aciduria type 1 (GA1; deficiency of glutaryl - CoA dehydrogenase) was diagnosed in a 6.5-month-old female infant. Despite a good biochemical response to dietary reduction of lysine and tryptophan, there was no clinical response to diet nor to riboflavin therapy and her neurological condition deteriorated progressively until her death at 10.5 months. At postmortem examination only mild neuropathological abnormalities were found in contrast to previous reports of this condition. High levels of glutarate were found in liver, skeletal muscle, heart muscle and aqueous humor. Eye fluid which is readily available, may be a useful material for the postmortem diagnosis of this, and other organic acidurias when urine is not available.

Brain↗
PubMed1996

Subdural hemorrhage as an initial sign of glutaric aciduria type 1: a diagnostic pitfall.

The case of a 9-month-old girl with glutaric aciduria type 1 (GA 1) is reported. On initial presentation at 6 months of age, the patient demonstrated bilateral subdural hemorrhages and widening of the basal cisterns. After neurosurgical intervention the subdural effusions regressed; their etiology remained unclear. At the age of 9 months the patient presented again because of progressive loss of psychomotor abilities and a dystonic movement disorder. Cerebral MRI revealed regressive subdural hematoma, but marked frontotemporal atrophy as well. Because of a suspected metabolic disorder, urinary analysis of organic acids was performed. This repeatedly showed marked excretion of glutaric acid, 3-hydroxyglutaric acid and glutaconic acid, indicating a diagnosis of GA 1. Considering our patient's history, we recommend the inclusion of GA 1 in the differential diagnosis of patients with unexplained subdural hematoma and neurological deficits.

Amino Acid Metabolism, Inborn Errors↗