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PubMed2002

A survey of Japanese patients with mitochondrial fatty acid beta-oxidation and related disorders as detected from 1985 to 2000.

A clinical survey of Japanese patients with mitochondrial fatty acid beta-oxidation and related disorders (FAODs) was performed with questionnaires sent to 187 institutions, where inborn errors of metabolism could be managed in Japan, including a search of related literature published between 1985 and 2000. Sixty-four patients with ten types of FAODs were found. Carnitine palmitoyltransferase 2 deficiency and glutaric aciduria type 2 were most common (17 and 14 patients, respectively). As of 2000, there were no patients with medium-chain acyl-CoA dehydrogenase deficiency, which is common in Caucasians. Age at onset was under 2 years in 38 (59%) of the patients. Eight (13%) patients had neonatal onset. Twenty-one (55%) of the 38 children with an initial attack under 2 years of age had acute encephalopathy or a Reye syndrome-like illness. Half of the patients presented within 2 years of birth died or were handicapped. On the other hand, 19 (79%) of the 24 with onset after 2 years of age had muscle symptoms and 23 (96%) of the 24 grew and developed normally. Though the precise incidence of FAODs in Japan is still unknown, as a consequence of the development of diagnostic procedures the number of FAOD cases being diagnosed appears to have increased. Mass screening for FAODs during the neonatal period will greatly aid in prevention of attacks and related effects.

Acyl-CoA Dehydrogenases↗
PubMed1999

Defluvibacter lusatiae gen. nov., sp. nov., a new chlorohenol-degrading member of the alpha-2 subgroup of proteobacteria.

The two Gram-negative bacterial strains S1 and S4 were isolated from activated sludge of an industrial waste water treatment plant and exhibited a stable capability to degrade 2,4-dichlorophenol, 4-chloro-2-methylphenol, 4-chlorophenol and phenol. The cells were short rods with a polar flagellum, being mesophilic, strictly aerobic, oxidase-positive, and chemoorganotrophic. They utilized a range of amino acids, but only a restricted number of carbohydrates. Reassociation experiments with DNA from strains S1 and S4 revealed high interstrain similarity, indicating, that both strains belong to the same species. The phylogenetic position was determined by comparison of the almost complete 16S rDNA sequence of strain S1 with sequences of related bacteria. Strain S1 clustered with members of the alpha-2 subgroup of the Proteobacteria by forming a separate lineage within the radiation of Mesorhizobium, Phyllobacterium and Sinorhizobium. Both strains can be differentiated from members of related taxa by a set of physiological and chemotaxonomic properties including the ability to grow with norvaline, L-tryptophan, putrescine, glutarate and malonate, and by the presence of spermidine as major polyamine and of 12:0 3OH as fatty acid. Strain S1 is described as type strain of a new species and assigned to a new genus with the proposed name Defluvibacter lusatiae.

Base Sequence↗
PubMedDate not supplied

The Colorado mental retardation and developmental disabilities research center.

The Colorado MRRC was one of the original MRRCs funded and has maintained its focus on genetic and nutritional causes of mental retardation and developmental disabilities. Significant discoveries of the center have included a number of metabolic disorders, including glutaric academia types I and II, electron transport flavoprotein (ETF) deficiency, ETF dehydrogenase deficiency, glycerol kinase deficiency, sphingolipidoses, genetic linkages in dyslexia, phonological deficits in dyslexia, and the importance of the trace mineral Zn in early development. Current research at the center is supported by program of projects grants on inborn errors of metabolism, Down syndrome (DS), autism, and dyslexia.

Academic Medical Centers↗
PubMed1998

"Atypical" neuromodulatory profile of glutapyrone, a representative of a novel 'class' of amino acid-containing dipeptide-mimicking 1,4-dihydropyridine (DHP) compounds: in vitro and in vivo studies.

Glutapyrone, a disodium salt of 2-(2,6-dimethyl-3,5-diethoxycarbonyl-1,4-dihydropyridine-4-carboxamido)- glutaric acid, is a representative of a novel 'class' of amino acid-containing 1,4-dihydropyridine (DHP) compounds developed at the Latvian Institute of Organic Synthesis, Riga, Latvia. Conceptually, the glutapyrone molecule can be regarded as a dipeptide-mimicking structure formed by the "free" amino acid (glutamate) moiety and "crypto" (built into the DHP cycle) amino acid ("GABA") elements. Both of these amino acids are joined by the peptide bond. This compound unlike classical DHPs lacks calcium antagonistic or agonistic properties. Our previous studies revealed a profound and long-term anticonvulsant, stress-protective and neurodeficit-preventive activities of glutapyrone. In view of structural properties the role of glutamatergic mechanisms in the mediation of central effects of glutapyrone was considered. In the present study glutapyrone at the concentration range of 1 microM(-1) mM failed to effect both NMDA ([3H]TCP) and non-NMDA ([3H]KA and [3H]AMPA) receptor ligand binding in the rat cortical membranes in vitro. The compound markedly enhanced motor hyperactivity induced by the NMDA antagonist PCP and the dopamine releasing compound D-amphetamine in the rats. Glutapyrone displayed activity in a variety of animal models relevant for affective/depressive disorders in humans i.e. reserpine-induced ptosis and hypothermia, forced swimming test and open field test. These data indicate that the unusually "broad" pharmacological spectrum of glutapyrone might involve concomitant actions on multiple neurotransmitter systems, particularly, GABA-ergic and the catecholamines. It is discussed whether these functional properties are secondary to action on intracellular events, predominantly, G protein-related since glutapyrone appears to lack direct interactions with a number of receptors including ionotropic glutamate and GABA(A)/Bzd receptors.

Analysis of Variance↗
PubMedDate not supplied

Metabolic signaling between neurons and glial cells: a short review.

There is convincing evidence that astrocytes transform blood-born glucose to lactate, alpha-Keto-glutarate and alanine and supply the neurons. There is a tight regulation of this metabolic coupling by means of chemical signals released by functioning neurons. Previous, pioneer, studies have explored several signals-candidates the major being K(+), Ca(++) and several neuromodulators. However, recent results of numerous studies identify glutamate as the major signal that traffics between excited neurons and astrocytes. The excited neurons also produce and release NH(4)(+) in the extracellular space. Both glutamate and ammonium are taken up preferentially by astrocytes and form glutamine. Ammonia fixation by glutamine synthase controls the amount of lactate, glutamine and alanine produced and released by Muller cells in the extracellular space and then taken up by neurons. Thus, there is a tight coupling between function and metabolism in the central neurons system.

Animals↗
PubMed2006

Tandem mass neonatal screening in Taiwan--report from one center.

BACKGROUND/PURPOSE: Neonatal screening using tandem mass spectrometry (MS/MS) started in Taiwan in 2000. We evaluated the efficacy of this system by analyzing the frequency of diseases and the outcome of the patients identified. METHODS: Between August 2001 and July 2004, 199, 922 neonates were screened for 10 amino acids and acylcarnitines using MS/MS in a single center. RESULTS: In total, 29 cases of inborn errors of metabolism were detected. The overall prevalence was one per 6894 births. The most common inborn error found was 3-methylcrotonyl CoA carboxylase deficiency (10 cases, 34.5%), but none of the cases needed aggressive treatment. There were two cases of type I glutaric aciduria, two cases of maple syrup urine disease, and one case of type II citrullinemia, and early therapeutic intervention was effective for all of them. CONCLUSION: We found that MS/MS neonatal screening was valuable in the early diagnosis of severe and treatable inborn errors of metabolism such as organic acidemias and urea cycle disorders. It also detected less severe disorders that required only observation.

Amino Acids↗
PubMed1991

Ultrastructural immunolocalization of osteopontin in metaphyseal and cortical bone.

The ultrastructural localization of osteopontin in bone was determined especially focussing on the relationship to bone forming cells, i.e. osteoblasts and osteocytes. Thus, rat metaphyseal and cortical bone was fixed in a mixture of low concentration glutar- and paraformaldehyde and embedded at low temperature in Lowicryl K11M. Polyclonal antibodies raised against rat osteopontin fusion protein were incubated on ultrathin sections and protein G coated with 5-nm colloidal gold was used for detection. The results demonstrate most intensive labeling in the mineralization front of newly formed bone; whereas lower concentration of label was found in the osteoid both in metaphyseal and cortical bone. The concentration of marker was substantially higher in newly formed bone near osteoblasts compared to bone constituting the osteocyte lacuna. Intracellularly the prevailing localization of label was to large Golgi vesicles in osteoblasts. Only focally local accumulation of marker was seen at the cell/osteoid surface. The observations suggest a function of osteopontin also in the mineral turnover of newly formed bone.

Animals↗
PubMed1998

Prolyl hydroxylase activity in tissue homogenates of annelids from deep sea hydrothermal vents.

Tissue homogenates of the deep sea annelids Alvinella caudata and Alvinella pompejana were found to contain enzyme activity resembling vertebrate prolyl 4-hydroxylase. The release of 3H2O from [3,4-(3)H]proline labeled, under-hydroxylated chicken protocollagen type I depended on the presence of the cofactors 2-oxoglutarate, ascorbate, Fe2+ and O2. The release of 3H2O could be inhibited by the prolyl 4-hydroxylase inhibitors zinc, 2,2'-dipyridyl, 3,4-dihydroxybenzoic acid and pyridine-2,4-dicarboxylate, as well as by the synthetic peptide (Pro-Pro-Gly)10. This synthetic peptide could also serve as substrate, because it enhanced the decarboxylation of 2-oxo[5-(14)C]glutarate. Alvinella prolyl hydroxylase appeared to be related to type II vertebrate enzyme because of its lack of affinity for poly (L-proline) and resistance to inactivation by an irreversible peptide inhibitor of chicken prolyl 4-hydroxylase. Maximal enzyme activity was observed in solutions with less than 10% oxygen saturation. By contrast, chicken enzyme was most active at saturating oxygen concentrations. Further data suggest that the Alvinella enzymes are able to accept the 2-oxo acids pyruvate, oxaloacetate and 2-oxoadipinate as substitutes of the cosubstarate 2-oxoglutarate. The data explain the high hydroxylation of Alvinella collagens despite the low oxygen concentrations around hydrothermal vents.

Animals↗
PubMed2002

Design, synthesis and pharmacological evaluation of novel pyrazolo[3,4-b]thieno[2,3-d]pyridine acid derivatives: a new class of anti-inflammatory and anti-platelet agents.

A series of pyrazolo[3,4-b]thieno[2,3-d]pyridine alkanoic acid derivatives has been synthesized and evaluated as thromboxane synthetase inhibitors and leukotriene D(4) receptor antagonists. The glutaric acid derivative LASSBio341 (6) was shown to be active in arachidonic acid-induced platelet aggregation (IC(50)=0.14 microM) and inhibition of the contraction of guinea pig tracheal strip induced with LTD(4) (IC(50) = 43.7 microM), displaying still in vivo anti-inflammatory profile.

Animals↗
PubMed2000

Non-peptidic, non-prenylic bisubstrate farnesyltransferase inhibitors. Part 3: structural requirements of the central moiety for farnesyltransferase inhibitory activity.

Recently, we have described non-peptidic, non-prenylic bisubstrate analogues as a novel type of farnesyltransferase inhibitor composed of a farnesyl-mimetic, a linker and an AAX-peptidomimetic substructure. With this study, we showed that the amide function connecting the farnesyl-mimetic and the linking substructures of our inhibitors is crucial for their activity. We suggest that the amide is bound to the essential zinc ion in the farnesyltransferases active center. We identified succinic and glutaric acid, respectively, in addition to the initially used 1-alanyl moiety as suitable linking structures. Glycine can also be used in this function provided the distance between the alpha-amide group and the center of the peptidomimetic substructure is enlarged by introduction of an additional methylene unit into the peptidomimetic substructure.

Alkyl and Aryl Transferases↗
PubMed1999

Continuous indirect electrochemical regeneration of galactose oxidase.

The development of an indirect anaerobic electrochemical regeneration of galactose oxidase (GOase) allows the prevention of the undesired production of the enzyme inhibitor hydrogen peroxide, which is generated under aerobic regeneration conditions during synthetic applications of GOase. The pH optimum for the electrochemical regeneration of GOase with polyethyleneglycol-modified ferrocene mediators in carbonate buffer is 10.8. Total turnover numbers achieved by either electrochemical or aerobic regeneration of GOase are almost the same. The electrochemical regeneration is half as fast as the aerobic regeneration. It is not necessary to work under anaerobic conditions, because at pH 10.8 the aerobic regeneration of GOase is prevented. The enzyme can be stabilized most effectively by immobilization on an aminopropylated polysiloxane (DELOXAN) via the glutaric dialdehyde procedure with good activity yields up to 37%. Buffers containing amino groups proved to be fatal for long-term GOase stability.

Buffers↗
PubMed1996

Risks of Virus Transmission During Diagnostic Hysteroscopy

The high frequency of asymptomatic carriers of viral infections represents a major risk for transmission. Viral agents can be transmitted through blood or biologic fluids during diagnostic hysteroscopy. Routine disinfection methods to clean hysteroscopes cannot be considered adequate to prevent transmission. Hepatitis C and B viruses require 1-hour sterilization in glutaric aldehyde or gas sterilization (ethylene oxide) to be decontaminated. Human immunodeficiency virus decontamination of instruments is easier and safer. Blood test screening of patients positive for hepatitis B and C should be performed in all candidates for endoscopic gynecologic procedures to avoid the possibility of virus transmission.

Journal Article↗
PubMed2003

Pathogenic mutations in the carboxyl-terminal domain of glutaryl-CoA dehydrogenase: effects on catalytic activity and the stability of the tetramer.

Inherited defects in glutaryl-CoA dehydrogenase cause the neurometabolic disease, glutaric acidemia type I. Five of over 80 mutations that have been identified are located in a carboxyl-terminal domain. The five mutations were generated by site directed mutagenesis and expressed in Escherichia coli. The mutant dehydrogenases were purified and characterized by circular dichroism and fluorescence spectroscopy, analytical size exclusion chromatography, thermal stability, and steady state kinetic analysis. There is no significant change in the alpha-helical content of the mutant proteins and little effect on tertiary structure; however, spectral properties of the mutant proteins indicate that the FAD prosthetic group can dissociate from the mutant proteins. Size exclusion chromatography shows that four mutant proteins dissociate to dimers or a mixture of monomers and dimers. Steady state kinetic analyses show that K(m) for glutaryl-CoA is affected by the mutations, but there is little effect on k(cat) compared with the wild type dehydrogenase. The lack of effects of the mutations on the K(m) for the electron acceptor, electron transfer flavoprotein, and on secondary structure suggests that the mutations do not result in long-range structural effects. The crystal structures of the acyl-CoA dehydrogenases show that their overall folding patterns are very similar and that the carboxyl-terminal domain is involved in substrate binding, FAD binding and intersubunit interactions. Investigations of mutations in the carboxyl-terminal domain of glutaryl-CoA dehydrogenase clearly illustrate these multiple roles of this domain. The results also indicate that a primary effect of the mutations is to cause alterations that promote aggregation.

Chromatography, Gel↗
PubMed2002

Evaluation of filter paper collection of urine samples for detection and measurement of organic acidurias by capillary electrophoresis.

There is little doubt that mental retardation has been prevented in most babies diagnosed by newborn screening programs for inborn errors and the cost-benefit ratios of these programs have been reported as highly positive. In a previous work we optimised a CE method for quick profiling of organic acidurias, which characterize a large number of inborn errors, so that it permits the separation, detection and even identification in less than 15 min of 22 organic acids in urine samples related to a wide range of metabolic disorders. In the present work we have studied the adequacy of filter paper collection of urine samples to simplify this step, always difficult in babies, when it is not performed by training personnel. The studied parameters were: media and conditions for re-extraction to give the best sensitivity and a more simple procedure when the samples are measured by CE, interferences coming from the diaper, recoveries obtained, possible correction of recoveries with creatinine and stability of the compounds. The whole method we report has the advantages of easy sample collection, easy shipping or delivery, and rapid analysis. Moreover, this method of collection and analysis allows the identification and quantitation of fumaric, methylmalonic, N-acetylaspartic, pyroglutamic and homogentisic acids, as well as glutaric acid for which screening is considered especially advisable.

Acids↗
PubMed2004

Sonographic appearance of the normal and abnormal insula of Reil.

Three planes are discerned during ultrasonographic screening of the insula in parasagittal view: opercular, insular, and fissural. Six newborn infants with normal brain anatomy, including two each of 28, 34, and 40 weeks' gestation, were selected for a description of the evolution of these parasagittal planes. Opercularization of the insula begins to be detected on a sonogram at about the 24th gestational week and progresses cranially. On coronal section the insular space forms a shallow groove at 24 weeks, becoming a slit at 28 weeks that grows longer and develops branches after 32 weeks. At 28 weeks the ascending anterior branch of the circular groove and the lateral fissure at the bottom of the insula are clearly seen in parasagittal section. Subsequent change consists of undulation and bifurcation of the lateral fissure, together with elongation of the anterior margin. Secondary gyri become visible in the insular dome between 28 and 34 weeks, forming short anterior and long posterior insular gyri. Five term newborn infants with perisylvian polymicrogyria were observed with both neonatal ultrasound and magnetic resonance imaging: two of unknown cause, and one each due to cytomegalovirus, bifunctional peroxisomal protein deficiency, and monozygous twinning. With polymicrogyria, on parasagittal sonographic examination at fissural level the anterior margin of the circular groove is a short rudiment. In insular view, only rudimentary sulci ascend from the lateral fissure; short and long gyri are not seen. In opercular view, no secondary branches are seen from the lateral fissure, an image akin to that seen at 28 weeks. A complete insular triangle is not recognized in any of these sections. A deep abnormal sulcus may prolong the lateral fissure when schizencephaly is associated with polymicrogyria. The insula in glutaric aciduria type II has no secondary gyri at term and is reduced to a simple and small triangle. Not all instances of polymicrogyria lead to macroscopically recognizable alteration of insular gyri.

Brain Diseases↗
PubMed2005

Acute bilateral striatal necrosis with rotavirus gastroenteritis and inborn metabolic predisposition.

We present a 9-month-old male with acute rotavirus gastroenteritis who developed an acute encephalopathy with focal seizures and developmental regression. Magnetic resonance imaging showed bilateral striatal necrosis and raised glutarylcarnitine levels on tandem mass spectrometry of a (crisis) blood spot, and chromatography of organic acids revealed increased urinary excretion of dicarboxylic acid. Skin biopsy demonstrated a partial decrease in glutaryl-CoA dehydrogenase activity. The case was not typical for either rotavirus encephalitis/rotavirus-associated encephalopathy or for glutaric aciduria type I. The patient has developmental delay and continues to receive physiotherapy, speech therapy, and local developmental follow-up.

Brain Diseases, Metabolic, Inborn↗
PubMed2002

Integration of enzymes and electrodes: spectroscopic and electrochemical studies of chitosan-enzyme films.

A new film-forming solution was developed for the efficient immobilization of enzymes on solid substrates. The solution consisted of a biopolymer, chitosan (CHIT), that was chemically modified with a permeability-controlling agent, Acetyl Yellow 9 (AY9), using glutaric dialdehyde (GDI) as a molecular tether. A model enzyme, glucose oxidase (GOx), was mixed with the CHIT-GDI-AY9 solution and cast on the surface of platinum electrodes to form robust CHIT-GDI-AY9-GOx films for glucose biosensing. UV-visible and infrared spectroscopies were used to determine the composition of the films. The optimized films contained on average 1 molecule of AY9/3 glucosamine units of chitosan and 25 free GDI tethers/1 molecule of GOx. The electrochemical assays of the films indicated both a very high efficiency of enzyme immobilization (approximately 99%) and large enzyme activity (60 units cm(-2)). The latter translated into a high sensitivity (42 mA M(-1) cm(-2)) of the Pt/CHIT-GDI-AY9-GOx biosensor toward glucose. The biosensor operated at 0.450 V, had a fast response time (t90% < or = 3 s), and was free of typical interferences, and its dynamic range covered 3 orders of magnitude of glucose concentrations. The lowest actually detectable concentration was 10 microM glucose. In addition, the biosensor displayed a practical shelf life and excellent operational stability, e.g. its response was stable during 24-h testing under continuous polarization and continuous flow of 5.0 mM glucose solution. The proposed approach to enzyme immobilization is simple, efficient, and cost-effective and should be of importance in the development of biosensors based on other enzymes that are more expensive than glucose oxidase.

Biosensing Techniques↗
PubMed2004

Carbon nanotube-chitosan system for electrochemical sensing based on dehydrogenase enzymes.

Multiwalled carbon nanotubes (CNT) were solubilized in aqueous solutions of a biopolymer chitosan (CHIT). The CHIT-induced solubilization of CNT facilitated their manipulations, including the modification of electrode surfaces for sensor and biosensor development. The colloidal solutions of CNT-CHIT were placed on the surface of glassy carbon (GC) electrodes to form robust CNT-CHIT films, which facilitated the electrooxidation of NADH. The GC/CNT-CHIT sensor for NADH required approximately 0.3 V less overpotential than the GC electrode. The susceptibility of CHIT to chemical modifications was explored in order to covalently immobilize glucose dehydrogenase (GDH) in the CNT-CHIT films using glutaric dialdehyde (GDI). The stability and sensitivity of the GC/CNT-CHIT-GDI-GDH biosensor allowed for the interference-free determination of glucose in the physiological matrix (urine). In pH 7.40 phosphate buffer solutions, linear least-squares calibration plots over the range 5-300 microM glucose (10 points) had slopes 80 mA M(-1) cm(-2) and a correlation coefficient 0.996. The detection limit was 3 microM glucose (S/N = 3). The CNT-CHIT system represents a simple and functional approach to the integration of dehydrogenases and electrodes, which can provide analytical access to a large group of enzymes for wide range of bioelectrochemical applications including biosensors and biofuel cells.

Biosensing Techniques↗