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PubMed2000

MALDI-TOF MS analysis of a library of polymerizable cyclodextrin derivatives.

Polymerizable cyclodextrin derivatives (PCDs) have been proposed as candidates for use in dental therapeutics (Bowen, 1996; Bowen and Reed, 1997). Here, PCD "libraries" were synthesized by quasi-random reactions of 6 moles of methacrylic anhydride plus 6 moles of cyclic glutaric anhydride per mole of beta-cyclodextrin (BCD) in solution. BCD has 21 reactive sites on each of its molecules. These proportions were based on probability calculations, which predicted that the products should have a minimum of 2 polymerizable substituents and acidic ligand groups on practically every one of the diverse product molecules. Matrix-assisted laser desorption/ionization (MALDI) time of flight (TOF) mass spectrometry (MS) gave valuable information regarding the masses of molecular ions representing the molecules that made up the PCD libraries. For the MALDI-TOF MS analyses, small samples were analyzed by the successive application of 3 solutions to the sample holder: the matrix in acetone, the products in water, and sodium trifluoroacetate in water. The resulting spectra had > 40 envelopes of mass peaks above background. The ionic-abundance peak heights had quasi-Gaussian configurations, with central peaks having masses in the neighborhood of 2000 g/mol (Daltons). Regardless of structural permutations within each peak, the range of these peaks was between about 1500 g/mol and 2900 g/mol. This range of masses was in accord with, but perhaps somewhat more narrow than, that predicted by the statistical method, which was based on equal reactivity of all hydroxyl groups. Analysis by MALDI-TOF MS gave valuable data regarding the masses, structures, and characteristics of the products formed and provided unanticipated information to facilitate improvements in future PCD syntheses.

Acetone↗
PubMed1982

Oxidation of fatty acids in cultured fibroblasts: a model system for the detection and study of defects in oxidation.

A number of recently described inherited disorders interfere with the oxidation of fatty acids. In these disorders at least three different metabolic steps may be affected: (1) transport of long chain fatty acids into the mitochondria as in carnitine deficiency and carnitine palmitoyl transferase deficiency (CPT); (2) multiple acyl CoA dehydrogenase deficiency or glutaric aciduria type II (GAII) due presumably to a defective common electron transfering flavoprotein or iron sulfur flavoprotein; (3) specific long or medium chain fatty acyl CoA dehydrogenase deficiency as in inherited dicarboxylic aciduria. In order to develop a system for the detection and the study of the consequences of defects such as these on the oxidation of fatty acids, we investigated the metabolism of oleate (18 carbons), octanoate (eight carbons) and butyrate (four carbons) in intact cultured fibroblasts from patients with CPT deficiency, GAII, and dicarboxylic aciduria. In CPT deficient cells there was a markedly deficient ability to oxidize [1-14C] and [U-14C] oleate (19 and 5% of normal, respectively), whereas oxidations of [1-14C] octanoate and [1,4-14C] succinate were significantly increased (150 and 222%, respectively), and [1-14C] butyrate oxidation was normal. GAII cells displayed a nearly complete defect in the oxidation of [1-14C] and [U-14C] oleate (8 and 1%, respectively), as well as of [1-14C] octanoate and [1-14C] butyrate (8 and 5% of normal, respectively). The oxidation of [1,4-14C] succinate by GAII cells was normal. Cells from a patient with dicarboxylic aciduria showed a significant reduction in [14CO2] production from [U-14C] oleate (57%) and [1-14C] octanoate (31%) and a normal oxidation of [1-14C] oleate, [1-14C] butyrate, and [1,4-14C] succinate. These observations are consistent with available information on the normal metabolism of fatty acids in liver and muscle and also with the hypothesis about the molecular localization of the defects in GAII and inherited dicarboxylic aciduria. They demonstrate that intact cultured skin fibroblasts represent a reliable and convenient model for the investigation of fatty acid oxidation in man. Many aspects of the human acyl CoA dehydrogenases and their physiologic functions remain unknown, among them the problem of their acyl chain length specificity. Studies in cultured fibroblasts from patients with presumed mutations affecting the metabolism of fatty acids provide a means for the elucidation of these defects and at the same time give information on normal metabolic functions. It appears likely that a number of previously unrecognized defects in this area of metabolism remain to be found. The availability of a model system for their study in cultured fibroblasts should facilitate their discovery.

Carnitine O-Palmitoyltransferase↗
PubMed1991

Octenylsuccinic aciduria in children fed protein-hydrolysate formulas containing modified cornstarch.

The excretion of 2-(2'-octenyl)succinic acid (OSA) and several metabolites of OSA was studied by gas chromatography/mass spectrometry in 17 infants and children fed one of three proprietary elemental or protein-hydrolysate formulas that use OSA-modified cornstarch as an emulsifying agent. Variable but often large amounts (up to 2500 mg/g creatinine) of the fatty acid-like OSA and its metabolites were found in the urine of these children, and levels of OSA in their blood ranged from 9.5 to 57.9 mumol/L. Apparently secondary abnormalities, such as increased urinary levels of glutaric acid and 2-ketoglutaric acid, were also found in more than half of the urine specimens. The molecular weight and mass fragmentation patterns of the nine compounds associated with the excretion of OSA are consistent with the proposal that OSA is metabolized in human infants and children by a combination of omega-, omega-1-, and beta-oxidation steps, similar to the metabolism of another branched-chain fatty acid, valproic acid. The urinary organic acid pattern of children fed elemental formulas containing OSA-modified starch often was dominated by OSA and its metabolites, and in several children the OSA-related changes were mistaken for a primary metabolic disease. Physicians and laboratories evaluating children for suspected metabolic diseases should be aware of the possibility of abnormal organic acid studies associated with OSA-containing formulas.

Child↗
PubMed2002

Ca(2+) and Na(+) dependence of 3-hydroxyglutarate-induced excitotoxicity in primary neuronal cultures from chick embryo telencephalons.

Glutaryl-CoA dehydrogenase deficiency (also known as glutaric aciduria type I) is an autosomal, recessively inherited neurometabolic disorder with a distinct neuropathology characterized by acute encephalopathy during a vulnerable period of brain development. Neuronal damage in this disease was demonstrated to involve N-methyl-D-aspartate (NMDA) receptor-mediated neurotoxicity of the endogenously accumulating metabolite 3-hydroxyglutarate (3-OH-GA). However, it remained unclear whether NMDA receptors are directly or indirectly activated and whether 3-OH-GA disturbs the intracellular Ca(2+) homeostasis. Here we report that 3-OH-GA activated recombinant NMDA receptors (e.g. NR1/NR2A) but not recombinant alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors (e.g. GluR-A/GluR-B) in HEK293 cells. Fluorescence microscopy using fura-2 as Ca(2+) indicator revealed that 3-OH-GA increased intracellular Ca(2+) concentrations in the presence of extracellular Ca(2+) in cultured chick neurons. Similar to glutamate-induced cell damage, 3-OH-GA neurotoxicity was modulated by extracellular Na(+). The large cation N-methyl-D-glucamine, which does not permeate NMDA receptor channels, enhanced 3-OH-GA-induced Ca(2+) increase and cell damage. In contrast, 3-OH-GA-induced neurotoxicity was reduced after replacement of Na(+) by Li(+), which permeates NMDA channels but does not affect the Na(+)/Ca(2+) exchanger in the plasma membrane. Spectrophotometric analysis of respiratory chain complexes I-V in submitochondrial particles from bovine heart revealed only a weak inhibition of 3-OH-GA on complex V at the highest concentration tested (10 mM). In conclusion, the present study revealed that NMDA receptor activation and subsequent disturbance of Ca(2+) homeostasis contribute to 3-OH-GA-induced cell damage.

Adenosine Triphosphatases↗
PubMed1986

Systemic carnitine deficiency due to lack of electron transfer flavoprotein:ubiquinone oxidoreductase.

A child with myopathy and systemic carnitine deficiency died at age 8 years in an acute metabolic attack. He had glutaric aciduria type II, and his cultured fibroblasts contained normal activity of four different acyl CoA dehydrogenases, but there was deficiency of electron transfer flavoprotein:ubiquinone oxidoreductase (ETF-QO). This enzyme is thought to reduce coenzyme Q in the respiratory chain, funneling reducing equivalents from seven flavoproteins in the beta-oxidation of acyl CoAs. There was massive urinary excretion of the short-chain acylcarnitines that accumulated in mitochondria as a result of the ETF-QO defect. Carnitine therefore acts as a buffer for excessive accumulation of intramitochondrial acyl CoAs, and defective beta-oxidation can cause carnitine insufficiency.

Acetylcarnitine↗
PubMed1990

Electron transfer flavoprotein: ubiquinone oxidoreductase (ETF:QO) deficiency in an adult.

A 19-year-old woman with mild myopathic symptoms from age 6 and fasting intolerance presented with a Reye-like syndrome and a myopathy. Investigations disclosed a lipid storage myopathy, type II glutaric acidemia, and carnitine deficiency in skeletal muscle. Riboflavin and carnitine treatment corrected the metabolic abnormalities and she improved clinically. She later died from pulmonary complications secondary to aspiration. Subsequent studies established electron transfer flavoprotein: ubiquinone oxidoreductase (ETF:QO) deficiency (fibroblast ETF:QO activity was 2.9 mU/mg, normal range is 14.1 +/- 3.8 mU/mg) as the cause of her illness. This is the first documented case of ETF:QO diagnosed in an adult.

Acidosis↗
PubMed1993

The disposition of serum proteins as drug-carriers in mice bearing Sarcoma 180.

The tumor distribution and the disposition of serum proteins, such as albumin, fetuin, transferrin, and IgG, were investigated in mice bearing Sarcoma 180. Serum proteins labeled with fluoresceinisothiocyanate (FITC) were administered to the mice. The FITC-labeled proteins acylated with glutaric anhydride were also administered to the mice in order to investigate the effect of chemical modification. The plasma concentration of each glutarylated serum protein was significantly lower, about 15 to 46-fold, in comparison to that of the non-acylated protein at 24 h after administration. The tissue distributions of the glutarylated serum proteins were also decreased compared to those of the non-acylated proteins. Especially, the hepatic distribution of albumin and IgG was significantly reduced with glutarylation. The urinary excretion of albumin and transferrin, and fecal excretion of IgG, were significantly increased with glutarylation. The serum proteins were accumulated effectively in the tumor tissue in mice bearing Sarcoma 180. It was found that the tumor distributions were not impaired by the glutarylation, except involving fetuin. It was suggested, therefore, that the glutarylated serum proteins were valuable for relative tumor-selectivity and might be utilized in a macromolecular carrier system for antitumor drugs.

Anhydrides↗
PubMed1997

[Pharmacological approach to control American foulbrood of honeybees].

In this review, I will describe honeybee biology from my prospective as a veterinary pharmacologist and will provide a summary of my research project to search for effective drugs to control American foulbrood, a bacterial disease of honeybees. In conclusion, mirosamicin, a macrolide antibiotic, as a preventive and glutaral, an alkylating agent, as a disinfectant were the most promising drugs.

Alkylating Agents↗
PubMed2004

Human organic anion transporter 4 is a renal apical organic anion/dicarboxylate exchanger in the proximal tubules.

Human organic anion transporter OAT4 is expressed in the kidney and placenta and mediates high-affinity transport of estrone-3-sulfate (E1S). Because a previous study demonstrated no trans-stimulatory effects by E1S, the mode of organic anion transport via OAT4 remains still unclear. In the present study, we examined the driving force of OAT4 using mouse proximal tubular cells stably expressing OAT4 (S2 OAT4). OAT4-mediated E1S uptake was inhibited by glutarate (GA) (IC50:1.25 mM) and [14C]GA uptake via S2 OAT4 was significantly trans-stimulated by unlabeled GA (5 mM) (P<0.001). [3H]E1S uptake via S2 OAT4 was significantly trans-stimulated by preloaded GA (P<0.001) and its [14C]GA efflux was significantly trans-stimulated by unlabeled E1S in the medium (P<0.05). In addition, both the uptake and efflux of [14C]p-aminohippuric acid (PAH) and [14C]GA via S2 OAT4 were significantly trans-stimulated by unlabeled GA or PAH. The immunoreactivities of OAT4 were observed in the apical membrane of proximal tubules along with those of basolateral organic anion/dicarboxylate exchangers such as hOAT1 and hOAT3 in the same tubular population. These results indicate that OAT4 is an apical organic anion/dicarboxylate exchanger and mainly functions as an apical pathway for the reabsorption of some organic anions in renal proximal tubules driven by an outwardly directed dicarboxylate gradient.

Animals↗
PubMed2001

Cationic amino acids involved in dicarboxylate binding of the flounder renal organic anion transporter.

Three conserved cationic amino acids in predicted transmembrane domains 1, 8, and 11, respectively, of the flounder renal organic anion transporter, fROAT, were changed by site-directed mutagenesis and the resulting mutants functionally characterized in Xenopus laevis oocytes. Uptake of p-aminohippurate (PAH) in oocytes that expressed mutant H34I, K394A, or R478D was markedly reduced compared with oocytes that expressed wild-type fROAT, but was still several-fold higher than that in water-injected control oocytes. Immunocytochemically, no decrease in cell surface expression of the mutants could be detected. Only mutant R478D appeared to have a lower PAH affinity than the wild type. Similar to wild-type-dependent PAH transport, uptake induced by mutant H34I was sensitive to glutarate (GA) cis-inhibition. In contrast, mutants K394A and R478D could not be significantly affected by up to 10 mM GA, although the cRNA-dependent PAH uptake could still be almost completely suppressed by probenecid. Moreover, again in contrast to the wild type, neither PAH influx nor PAH efflux mediated by these two mutants could be trans-stimulated by GA, nor did they induce GA transport. These data suggest that amino acids K394 and R478 in fROAT are required for dicarboxylate binding and PAH/dicarboxylate exchange.

Amino Acids↗
PubMed1992

A potential blood substitute from a tetronic polyol and a modified hemoglobin.

This investigation reports a new potential blood substitute. An acellular fluid is formed between a Tetronic polyol and a modified hemoglobin. It was possible to stabilize the hemoglobin with glutaric acid. The subsequent reaction with the alcohols of the Tetronic polyol resulted in a useful resuscitative fluid. Exchange transfusion experiments in rats was possible at the 75% replacement level with an excellent survival rate. This was apparently possible because of the effective transport properties of this material. Histological sections of the liver, kidney and lungs showed little or no permanent damage to the organs. The Tetronic polyol - modified hemoglobin complex was not excreted in the urine in contrast to the modified hemoglobin by itself and a solution of unmodified hemoglobin. These preliminary studies indicate that this combination of a polymer and modified hemoglobin has a potential use as a red cell substitute.

Alcohols↗
PubMed1975

Biological studies of amiclenomycin.

The action of amiclenomycin (AM) in inhibiting growth of microorganisms is specific against mycobacteria in vitro, but the antibiotic does not show a therapeutic effect against tubercle bacilli in vivo. The action of AM is reversed by biotin, desthiobiotin (DTB) and 7,8-diaminopelargonic acid (DAPA), but not by 7-keto-8-aminopelargonic acid (KAPA), pimelic acid and glutaric acid. In the presence of AM, cultures of Mycobacterium smegmatis and Bacillus sphaericus accumulated KAPA, whereas the formation of DTB decreased. Therefore, AM is thought to inhibit KAPA-DAPA transamination in biotin biosynthesis. In M. smegmatic and B. sphaericus the conversions of KAPA to DAPA and of DTB to biotin were rate limiting in biotin synthesis. Accordingly, the synergistic antibiotic activity of AM, inhibiting the former, and actithiazic acid, inhibiting the latter reaction, would be simply explained.

Amino Acids, Diamino↗
PubMed1999

Mitochondrial fatty acid oxidation disorders and cyclic vomiting syndrome.

Inherited fatty acid oxidation (FAO) disorders represent a relatively new group of inborn errors of metabolism. Although our understanding of the biochemical and molecular bases of these disorders has improved dramatically in recent years, many patients remain undetected or are given other diagnoses, cyclic vomiting syndrome (CVS) being one of them in a few known cases. Medium chain acyl-CoA dehydrogenase deficiency and the late-onset form of glutaric acidemia type II have been anecdotally misdiagnosed as CVS. In addition, short chain acyl-CoA dehydrogenase deficiency (either true defects or polymorphism-related phenotypes) and particularly short-chain 3-hydroxy acyl-CoA dehydrogenase deficiency may present with clinical and biochemical features that closely resemble CVS. However, the collective role played by FAO and probably other metabolic disorders among the causes of CVS in unknown. Guidelines for a diagnostic approach to FAO disorders at the biochemical level are being presented and discussed. Hopefully, a better understanding and an awareness of FAO disorders could improve the diagnostic evaluation of patients with CVS.

Acyl-CoA Dehydrogenases↗
PubMedDate not supplied

[Bilateral hypodensity of the basal ganglia. Clinico-evolutionary correlation in children].

INTRODUCTION: The presence in neuroimaging of areas of symmetrical bilateral hypodensity in the basal ganglia (SBHBG) is a striking and unusual finding. OBJECTIVE: To determine the aetiology, clinical significance and evolution of a group of paediatric patients with SBHBG. PATIENTS AND METHODS: We made a study of 21 patients with neuroimaging studies (CT or MR) showing SBHBG. The affected area was related to the aetiology, clinical features and evolution. RESULTS: The ages varied between 4 months and 16 years. In 7 cases Leigh s disease was diagnosed, 5 had had acute hypoxia, 4 type I glutaric aciduria, and 1 case each of methylmalonic aciduria, Ia gluconeogenesis, CO intoxication, acute striatal necrosis and bacterial meningitis. The putamen was affected in 6 cases, globus pallidus in 4 cases and the lenticular nucleus was damaged in the rest. Three cases also had lesions in the caudate nucleus. MR was better than CT for localization of the precise area involved. Clinically, 13 cases had extrapyramidal signs. We found no relation between the size, localization of the lesion and the prognosis, which was more dependent on the aetiology, only one patient (CO intoxication) recovered and eight died (Leigh s disease and 1 case of hypoxia). CONCLUSIONS: The presence of SBHBG in a patient makes extensive study necessary to find the aetiology. It is a nonspecific finding, usually of metabolic origin and with little correlation with the clinical condition. Its presence implies a poor prognosis and raises suspicion of the presence of certain neurological disorders.

Adolescent↗
PubMed1992

[Nuclease conjugates with ligand-free serum albumin].

In order to obtain nuclease and human serum albumin (HSA) conjugates with a high enzyme content it is proposed to use a ligand-free HSA. The ligands are removed with the help of a strong anion exchanger. A two-stage procedure of conjugate preparation is proposed. It consists in the complexation of ligand-free HSA and enzyme and subsequent co-condensation of protein molecules of the poly-complex with the aid of glutaric aldehyde. When the conjugates are administered to rabbits intravenously, the RNAase activity is manifested in blood for 3-5 days. Moreover, in the case of conjugates with a molecular weight of 80 kDa, the prolongation time is greater than for conjugate with a higher molecular weight.

Animals↗
PubMedDate not supplied

[Chemical suturing of myosin and actin to capron fiber].

Immobilization of myosin, actin, actomyosin and subfragment S1 on kapron fibre was achieved with the help of glutaric aldehyde. The ATPase activity of myosin and its ability to interact with actin is preserved; while the ATPase activity of S1 subfragment decreases considerably. The immobilization on kapron fibre changes the pH-dependance of ATPase activity of myosin and that of subfragment S1, shifting the maximum to low pH zone (pH 5.5), and increases the thermostability of the enzyme. The ions of Ca++ in all cases act as an activating agent on ATPase while the ions of Mg++ either do not affect myosin and subfragment S1 at all, or increase the activity in the case of the immobilized of actomyosin but to a lesser degree than the ions of Ca++. The immobilized actin preserves its ability to form actomyosin complex.

Actins↗
PubMed1977

3-Hydroxy-3-methylgutaryl-CoA synthase. Participation of acetyl-S-enzyme and enzyme-S-hydroxymethylgutaryl-SCoA intermediates in the reaction.

Acetyl-CoA reacts stoichiometrically with a cysteinyl sufhydryl group of avian liver 3-hydroxy-3-methylglutaryl (HMG)-CoA synthase to yield acetyl-S-enzyme (Miziorko H.M., Clinkenbeard, K.D., Reed, W.D., and Lane, M.D. (1975) J. Biol. Chem. 250, 5768-5773). Evidence that acetyl-S-enzyme condenses with the second substrate, acetoacetyl CoA, to form enzyme-S-HMG-SCoA has been obtained by trapping and characterizing this putative intermediate. [14C]Acetyl-S-enzyme was incubated briefly at -25 degrees with acetoacetyl-CoA, precipitated with trichloroacetic acid, and the labeled acylated enzyme species were isolated. Performic acid oxidation of the precipitated [14C]acyl-S-enzyme intermediates produced volatile [14C]acetic acid from unreacted [14C]acetyl-S-enzyme and nonvolatile [14C]3-hydroxy-3-methyl glutaric acid from enzyme-S-[14C]HMG-SCoA. Condensation of unlabeled acetyl-S-enzyme with [14C]aceto-acetyl-CoA or acetoacetyl-[3H]CoA also produced labeled enzyme-S-HMG-SCoA. Thus, the acetyl moiety from acetyl-CoA and the acetoacetyl and CoA moieties from acetoacetyl-CoA all are incorporated into the HMG-CoA which is covalently-linked to the enzyme. Enzyme-S-[14C]HMG-SCoA was subjected to proteolytic digestion under conditions favorable for intramolecular S to N acyl transfer in the predicted cysteine-S-[14C]HMG-SCoA fragment. Performic acid oxidation of the protease-digested material yields N-[14C]HMG-cysteic acid indicating that HMG-CoA had been covalently bound to the enzyme via the -SH of an active site cysteine. An isotope trapping technique was employed to test the kinetic competence of acetyl-S-enzyme as an intermediate in the HMG-CoA synthase-catalyzed reaction. Evidence is presented which indicates that the rate of condensation of acetoacetyl-CoA with acetyl-S-enzyme to form enzyme-S-HMG-SCoA is more rapid than either the acetylation of the synthase by acetyl-CoA or the overall forward reaction leading to HMG-CoA. These observations, together with indirect evidence that hydrolysis of enzyme-S-HMG-SCoA is extremely rapid, suggest that acetylation of synthase is the rate-limiting step in HMG-CoA synthesis.

Acetates↗
PubMed1977

[Some physicochemical properties of modified trypsin].

Physico-chemical properties of trypsin covalently bound with human serum albumin by glutaric aldehyde have been studied. The modification of the enzyme practically caused no changes in the pH optimum of trypsin. The inhibition of modified trypsin by inhibitors from soy beans and human blood serum has been also studied. The apparent inhibition constants have been calculated. The modification has been shown to result in a deceleration of autolytic degradation. The autolysis rate constants have been calculated at 50 degrees C.

Chemical Phenomena↗