Ketotic episodes in glutaryl-CoA dehydrogenase deficiency (glutaric aciduria).
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Acidosis↗
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[Acidity and acidimetric titration of medically used glutaric acid imide].
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Hydrogen-Ion Concentration↗
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↗
Microbial metabolism of the pyridine ring. Metabolic pathways of pyridine biodegradation by soil bacteria.
1. Two bacteria, a Bacillus sp. and a Nocardia sp. (strain Z1) were isolated from soil by enrichment with 0.1 percent (v/v) pyridine and grew rapidly on this compound as sole C, N and energy source. The monohydroxypyridines, tetrahydropyridine, piperidine and some other analogues were not utilized for growth or oxidized by washed suspensions of either bacterium. 2. Cell-free extracts were unable to metabolize pyridine even after supplementation with a variety of cofactors or protecting agents. Treatment of cells with toluene led to rapid loss of the ability to oxidize pyridine. 3. In the presence of 10mM-semicarbazide at pH 6.0, Nocardia Z1 accumulated a semialdehyde idenditied as its 2,4-dinitrophenylhydrazone by chromatography, mixed melting point, mass spectrometry and isotope trapping from [2,6(-14)C]pyridine as glutarate semialdehyde. 4. Extracts of this bacterium prepared from cells grown with pyridine or exposed to the gratuitous inducer 2-picoline, contained high activities of a specific glutarate semialdehyde dehydrogenase. 5. Cells grown with pyridine or glutarate also contained a glutaric dialdehyde dehydrogenase, an acyl-CoA synthetase and elevated amounts of isocitrate lyase but no glutaryl-CoA dehydrogenase. 6. Bacillus 4 accumulated in the presence of 10mM-semicarbazide several acidic carbonyl compounds from pyridine among which was succinate semialdehyde. Extracts of this bacillus after growth of the cells with pyridine contained an inducible succinate semialdehyde dehydrogenase in amounts at least 50-fold over those found in succinate-grown cells. 7. Two mutants of this bacillus, selected for their inability to grow on pyridine were deficient in succinate semialdehyde dehydrogenase. 8. In the presence of 0.2mM-KCN, washed suspensions of Bacillus 4 accumulated formate and possibly formamide from pyridine. The use of [14C]pyridine showed that formate was derived from C-2 of the pyridine ring. 9. The organism had a specific formamide amidohydrolase cleaving formamide quantitatively to formate and NH3. 10. Formate was further oxidized by the particle fraction. There was no soluble formate dehydrogenase in extracts.
Aldehyde Oxidoreductases↗
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↗
Ethylmalonic-adipic aciduria. In vivo and in vitro studies indicating deficiency of activities of multiple acyl-CoA dehydrogenases.
The mechanisms underlying ethylmalonic-adipic aciduria were studied in a 5-yr-old girl. Oxidation of radioactive substrates by cultured skin fibroblasts from the proband and asymptomatic family members was also determined and compared to that by normal fibroblasts and that by cells from a patient with glutaric aciduria type II. Feeding medium-chain triglycerides promptly induced vomiting and lethargy accompanied by a pronounced increase of urinary ethylmalonate. Significant increases of serum isovalerate and urinary isovalerylglycine were observed after leucine feeding, but urinary glutarate increased only slightly after lysine feeding. Thus, the results from clinical investigation remained equivocal as to whether pathways other than fatty acid oxidation were blocked in our patient. Oxidation of [1-(14)C]butyrate by cultured skin fibroblasts from the proband was reduced to 14% of control. In vitro oxidation of [2-(14)C]lysine and [2-(14)C]leucine was also reduced to 28 and 23% of control, respectively. Much more severe reduction in oxidation of these three substrates (3, 9, and 9%, respectively) was observed in glutaric aciduria type II cells. These results indicated that in the proband, degradative pathways of fatty acids, lysine, and leucine are blocked at the steps of butyryl-CoA, glutaryl-CoA, and isovaleryl-CoA dehydrogenases, respectively, as in the case of glutaric aciduria type II. Because activities of multiple acyl-CoA dehydrogenases are reduced, a deficiency of electron-transferring flavoprotein, which serves as a hydrogen-acceptor for these dehydrogenases, is postulated as the underlying mechanisms of these two diseases, but a genetic heterogeneity was indicated by significant differences in the residual activities in these two types of cells. The hypothesis of more than one mutant allele of an autosomal recessive gene was also suggested by the study on cells from asymptomatic members of the family.
Acidosis↗
Studies on the effects of saturated and unsaturated short-chain monocarboxylic acids on the energy metabolism of rat liver mitochondria.
The effect of eight branched-chain amino acid metabolites, four metabolites from the beta-oxidation, and the unphysiologic acid 4-pentenoic acid on the oxygen consumption rate of liver mitochondria oxidizing pyruvate, 2-oxo-glutarate, and L-palmitoylcarnitine has been investigated. The 12 metabolites are: propionic, isobutyric, 2-Me-butyric, isovaleric, acrylic, Me-acrylic, tiglic, Me-crotonic, butyric, hexanoic, crotonic, and 2-hexenoic acids. The oxidation rate of pyruvate was strongly inhibited by propionic, 4-pentenoic, and isovaleric acids at 0.1, 0.1, and 1.0 mM, respectively. With 2-oxo-glutarate as substrate, the oxygen consumption rate was strongly inhibited at 0.1 mM of propionic, 4-pentenoic, and isovaleric acids. The L-palmitoyl-carnitine oxidation rate was very strongly inhibited by 0.1 mM 4-petenoic acid, whereas butyric and hexanoic acids exerted a moderate inhibition at 0.1 mM. Propionic acid inhibited L-palmitoylcarnitine oxidation slightly at 1.0 mM. It is argued that propionyl-CoA and isovaleryl-CoA inhibit pyruvate and 2-oxo-glutarate dehydrogenases directly, and the significance of the results for ketotic episodes in organic acidurias is discussed.
Amino Acids, Branched-Chain↗
[Effect of chemical modification on thermal stability of horseradish peroxidase].
Soluble preparations of horse radish peroxidase are obtained by means of its amino groups modification with glutaric aldehyde, maleic anhydride and inert proteins including albumin. The enzyme activity is found to decrease under the modification with glutaric aldehyde and to be unchanged at all other cases. Thermal stability of the enzyme preparations obtained is studied within the temperature range from 56 to 80 degrees C. Thermostability of glutaric aldehyde-modified peroxidase is approximately 2.5-fold decreased at 56 degrees C. Thermostability of other preparations exceeds the stability of native peroxidase in 25--90 times at 56 degrees C. Thermodynamic parameters of activation for the process of irreversible thermoinactivation of native and modified enzyme are calculated. A strong compensation effect between activation enthalpy and entropy values is observed, which were changed in 1.5--2 times, while the free activation energy is changed by 2--3 kcal/mol only. Possible mechanism of the change of the enzyme thermal stability under its chemical modification is discussed.
Chemical Phenomena↗
The influence of different fixatives and osmolality on the ultrastructure of the cochlear neuroepithelium.
To investigate which fixative is most suitable for the preservation of cochlear hair cells three main groups of fixatives were used: 1. 3% glutar aldehyde in various buffers (osmolality altered). 2. Glutar aldehyde/paraform aldehyde combination (ad modum Karnovsky). 3. Osmic acid solutions (OsO4) in veronal acetate buffer according to Rhodin (1954). The 2% osmic acid fixative (350--370mosm/kg) resulted in an excellent ultrastructural preservation; an acceptable result was obtained with a 3% glutar aldehyde fixative in 0.1 M sodium phosphate buffer, 600--700 mosm/kg and the Karnovsky's fixative.
Animals↗
[Production of immobilized alpha-amylase and its properties].
Active immobilized alpha-amylase was obtained when applying AE-cellulose chromatography and glutaric dialdehyde. The time of the enzyme interaction with the carrier, amount of glutaric dialdehyde necessary for binding, optimal enzyme: carrier ratio as well as the methods for desiccation of the immobilized amylase preparations were specified. Conditions are selected for alpha-amylase stabilization with the presence of glutaric aldehyde. Immobilized amylase as compared to free enzyme is shown to be more pH-stable in the acid and alkaline zones of pH (2.0-3.5 and 10.5-12.0), thermostable (within a temperature range of 20-60 degrees C) and resistant to the effect of 5.5 M urea.
Amylases↗
Low molecular weight organic acids in the urine of the newborn.
The urinary excretion of seven selected low molecular weight organic acids in normal neonates was measured by gas chromatography. First and third to fourth day of life excretion of the following compounds was significantly unchanged: 3-OH-butyric acid (less than 13 mumol/mmol creatinine), succinic acid (approx. 43 mumol/mmol creatinine), adipic acid (approx. 12 mumol/mmol creatinine), 2-OH-glutaric acid (approx. 23 mumol/mmol creatinine), 3-OH-3-Me-glutaric acid (approx. 25 mumol/mmol creatinine) and citric acid (approx. 115 mumol/mmol creatinine). The excretion of 4-OH-phenyl-acetic acid increased during the first four days of life (from less than 8 mumol/mmol creatinine to approx. 20 mumol/mmol creatinine). It is postulated that urinary orgainc acid excretion in the neonate, which is clearly different from the adult urinary pattern, is a reflection of the specific neonatal metabolic situation, including a high fatty acid utilisation and a low protein catabolism.
Adipates↗
[Inner and outer immobilization of chloroplasts].
The effects of glutaric aldehyde on pea leave chloroplasts and their inactivation kinetics were studied. Optimization of the chloroplasts fixation by glutaric aldehyde resulted in a 5-fold increase of stability of the chloroplasts. Immobilization of the chloroplasts in agar-agar gels was performed; the ability of chloroplasts for photooxidation of H2O was thereby retained. Immobilization did not actually affect the stability of chloroplasts. The inactivation kinetics of fixed and immobilized chloroplasts are in good agreement with the previously described model for inactivation of native chloroplasts.
Aldehydes↗
Prevention of oxalate urolithiasis by some compounds.
Male Wistar rats were fed a basal diet, Purina Laboratory Chow, and an oxalate calculi-producing diet (CPD). The CPD was the basal diet containing 3 per cent glycolic acid. Sodium pyruvate, DL-alanine, alpha-keto glutaric acid, thiamine pyrophosphate, and L-glutamic acid were added to the CPD to determine their effectiveness in preventing calculi formation. The effectiveness of methyl glyoxal was determined by adding it to the drinking water. Rats fed CPD for 4 weeks developed calculi in the ureters, bladder, renal tubules, and/or renal pelvis and papilla. Rats in groups fed alanine and/or pyruvate had no calculi in their renal tubules or ureters; additionally, these rats had a significant reduction in incidence and amount of deposits in the renal pelvis and bladder. Rats in groups fed alpha-keto glutaric acid, thiamine pyrophosphate, L-glutamic acid, and methyl glyoxal developed equally or more severe oxalate urolithiasis than those on CPD alone. Results of this study show that either pyruvate or alanine at appropriate levels may be beneficial in preventing oxalate urolith formation.
Alanine↗
[Modification of the carboxyl and amine groups of the cellulolytic enzymes of Aspergillus awamori].
The activity and stability of some enzymes of Asp. awamori cellulolytic complex were studied as affected by chemical modification of carboxylic groups with N,N'-dicyclohexyl carbodiimide (DCCD) and amine groups with glutaric aldehyde. The carboxylic groups are established to be necessary for manifestation of the activities of C1- and C2-cellulases, Cx-exo- and Cx-endoglucanases. Their role is negligible in the action of beta-glucosidase. The activity of individual cellulases was studied as affected by nucleophilic substitution of DCCD-activated COOH-groups by various reagents (glycine amide, leucine amide, tyrosine amide and N-benzoyl-l-arginine-methyl ether-hydrochloride). Tyrosine amide is the least inacting reagent for all the enzymes, glycine amide is somewhat more activating. Essential differences are shown in the chemical and catalytic properties of Cx-exoglucanase and beta-glucosidase. It is found (under the effect of glutaric aldehyde) that amino groups are significant for manifestation of the activities of C1- and C2-cellulases and Cx-endoglucanase and to a less extent for that of Cs-exoglucanase and beta-glucosidase. It is supposed that electrostatic interactions of the carbolytic and amine groups might be an essential factor for stability of C1- and C2-cellulases and Cx-endoglucanase.
Amines↗
[Utilization of luminescent monospecific sera against human immunoglobulins G, A and M for diagnostic purposes].
A method for obtaining luminescent sera, consisting in isolation of pure antigens G, A, M from human gamma-globulin and blood serum from patients with myeloma disease is suggested. A native antiserum was obtained by immunization of rabbits with water-insoluble polycondensate of antigens "sewn" with glutaric aldehyde. Adsorption of antisera as well as specific antigens was carried out with antigen- and antibodyimmunosorbent, the latter being obtained with the help of both glutaric aldehyde and sefarose 4B treated with cyanogen bromide. The sera had a specific titre in the precipitation reaction against their own antigens 1:32 and were highly specific. A globulin fraction was obtained by sedimentation with polyethylene-glycol. Marking of the specific protein with fluoresceine isothiocyanate was carried out using the dialysis method with subsequent purification on sefadex and DEAE-cellulose. The application of the abovementioned sera made it possible to ascertain the character of distribution of deposits of immunoglobulins in glomeruli in systemic lupus erythematodes, glomerulonephritis and in the cells of the synovial fluid sediment in rhematoid arthritis.
Animals↗
[Pronase E and P immobilization on aminoorganosilica surface].
Immobilization of pronase E and P was performed on sylochrome modified by gamma-aminopropyltrietoxysilane using cyanuric chloride, 2,4--toluylenediisocyanate, glutaric aldehyde and also on sylochrome by means of titanium tetrachloride. The esterase and caséinolytic activities of the immobilized preparations and their stability during storage were determined. The increased thermostability of the immobilized preparation is established. The influence of the enzyme: carrier ratio on the immobilization process and activity of the enzymes was studied. It is shown that application of glutaric aldehyde favours the best retention of the esterase activity (73%), whereas the caseinolytic activity is better retained (31%) when titanium tetrachloride was used.
Drug Stability↗
[Study of the role of arginine residues in aspartate transaminase from chicken heart cytosol].
Reaction of 1,2-cyclohexanedione with chicken heart cytosolic aspartate transaminase results in loss of enzyme activity complying to first order kinetics up to 70% inactivation. The inactivation rate is markedly decreased in the presence of alpha-ketoglutarate, glutarate or alpha-methylaspartate. The number of arginine residues modified per subunit was approximately two (in enzyme preparations which retained 30% residual activity). The diketone-modified enzyme nearly completely loses affinity for alpha-methylaspartate and glutarate; in contrast, its ability to bind alpha-alanine and catalyze its transamination half-reaction with the bound coenzyme remains unimpaired. From these data it can be inferred that a functional arginine residue is the cationic binding site for the distal carboxyl group of the substrates. The transaminase apoenzyme was inactivated with cyclohexanedione at the same rate as reconstituted holoenzyme. Measurements of circular dichroism showed that the modified apoenzyme is capable to bind pyridoxal-P. No evidence was obtained for the presence of an arginine residue in the coenzyme binding site.
Alanine↗
Effects of 3-hydroxy-3-methylglutaric acid on plasma and low-density lipoprotein cholesterol levels in familial hypercholesterolemia.
Different doses of 3-hydroxy-3-methyl-glutaric acid (HMG) on plasma lipids were studied in a double-blind trial in 36 patients with familial hypercholesterolemia (type IIa or hyper-beta-lipoproteinemia). The patients were randomly assigned to five groups, and each group received one of the following treatments: placebo, or HMG 750 mg, 1500 mg, 2250 mg, or 3000 mg per day. As compared to placebo, the mean plasma cholesterol levels during the eight-week treatment period were 11 and 13 per cent lower in the 2250-mg and 3000-mg HMG-treated groups (P less than 0.034 and less than 0.021, respectively). At the same dosage levels LDL cholesterol was decreased by 8 per cent. HMG had no significant effect on plasma triglycerides as compared to placebo. Discontinuation of the medication did not result in a rebound of plasma cholesterol. There were no clinical or biologic adverse effects due to the administration of HMG, and all patients maintained excellent compliance to the medication. Because of its lack of toxicity, HMG may be useful as an adjunct to diet in the treatment of familial hypercholesterolemia.
Adult↗