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At least 19 recordsLinked to original sources
PubMed1991

Amino acid sequence of long chain alpha-hydroxy acid oxidase from rat kidney, a member of the family of FMN-dependent alpha-hydroxy acid-oxidizing enzymes.

The complete amino acid sequence of rat kidney long chain alpha-hydroxy acid oxidase has been determined by microsequencing, using a number of standard enzymatic and chemical cleavages. Peptides were purified by high pressure liquid chromatography or by gel electrophoresis followed by electrotransfer. The sequence comprises 352 residues and ends with a peroxisomal targeting sequence SRL. The present work definitely establishes that hydroxy acid oxidase is a member of the family of FMN-dependent alpha-hydroxy acid-oxidizing enzymes. The family includes lactate oxidase, short chain alpha-hydroxy acid oxidase (glycolate oxidase), flavocytochrome b2, and mandelate dehydrogenase. There are altogether 45 totally conserved positions among the six sequences known. The sequence similarities are analyzed in light of the known three-dimensional structure of flavocytochrome b2 and glycolate oxidase. It is concluded that long chain hydroxy acid oxidase should be folded as a beta 8 alpha 8 barrel and should dehydrogenate alpha-hydroxy acids according to the same chemical mechanism as other enzymes of the family, in spite of a Tyr----Phe substitution at the active site.

Alcohol Oxidoreductases↗
PubMed1990

In vivo characteristics of low molecular weight copolymers composed of L-lactic acid and various DL-hydroxy acids as biodegradable carriers for drug delivery systems.

Low molecular weight and amorphous copolyesters composed of 70 mol% L-lactic acid and 30 mol% DL-hydroxy acids such as DL-lactic acid, DL-alpha-hydroxy-n-butyric acid, DL-alpha-hydroxyisovaleric acid and DL-alpha-hydroxyisocaproic acid were synthesized by direct copolycondensation in the absence of catalysts, to evaluate their in vivo capabilities as biodegradable carriers for drug delivery systems. For this purpose, the copolyester was moulded into a small cylindrical specimen under melt-pressing technique and implanted subcutaneously in the back of male adult rats. The in vivo degradation pattern can be subdivided into three types: the formations of parabolic type (L-LA/DL-HBA copolymer), linear type (L-LA/DL-LA copolymer) and S type (L-LA/DL-HIVA and L-LA/DL-HICA copolymers). A luteinizing hormone-releasing hormone agonist, des-Gly10-(D-Leu6)-LH-RH ethylamide monoacetate (LH-RH agonist), was incorporated into the small cylinders of copolyester formulations, of which the strongest pharmacological influence was observed in a copoly(L-LA/DL-HICA) formulation system, resulting in the maintenance of effective pharmacological influence throughout an experimental period of 15 wk, at which the in vivo release rate of LH-RH agonist was held constant at approximately 45 micrograms/d.

Animals↗
PubMed1989

Synergistic antifungal action of 8-quinolinol and its bischelate with copper(II) and with mixed ligand chelates composed of copper(II), 8-quinolinol, and aromatic hydroxy acids.

Antifungal studies were made of mixtures of minimal inhibitory concentrations (MICs) of 8-quinolinol and its bischelates with copper(II), zinc(II), and manganese(II) and with mixed ligand chelates composed of 8-quinolinol, copper(II) and a second ligand including salicylic acid, 3-hydroxy-2-naphthoic acid, 3,5-diiodosalicylic acid, and 4-bromo-3-hydroxy-2-naphthoic acid. Mixtures of the MICs of the bischelates of 8-quinolinol with copper(II) and zinc(II) and copper(II) and manganese(II), as well as 7-iodo-8-quinolinol and its bischelate with copper(II), and 8-quinolinol and 5-iodo-8-quinolinol were also studied against six fungi: Aspergillus niger, Aspergillus oryzae, Trichoderma viride, Myrothecium verrucaria, Mucor cirinelloides, and Trichophyton mentagrophytes. With the exceptions of the mixtures of 8-quinolinol and (8-quinolinolato)(3,5-diiodosalicylato)copper(II) and (8-quinolinolato)(4-bromo-3-hydroxy-2-naphthoato)copper(II) against M. cirinelloides, all of the test organisms were inhibited by 40% or less of each mixture containing 8-quinolinol. Bischelates of 8-quinolinol with copper(II) and zinc(II) and copper(II) and manganese(II) inhibited five fungi at 50% of the mixtures of the MICs. Mucor cirinelloides was not inhibited by bis(8-quinolinolato)copper(II), bis(8-quinolinolato)zinc(II), or by bis(7-iodo-8-quinolinolato)copper(II).(ABSTRACT TRUNCATED AT 250 WORDS)

Antifungal Agents↗
PubMed1975

Mechanistic studies on the rat kidney flavoenzyme L-alpha-hydroxy acid oxidase.

The falvoenzyme L-alpha-hydroxy acid oxidase from rat kidney [T.H Cromartie and C.T. Walsh (1975), Biochemistry 14, 2588] fails to catalyze the elimination of HCl form D,L-beta-chlorolactate, although this compound is a substrate for oxidation by the enzyme. Deuterium isotope effects demonstrate that proton removal from the alpha carbon of alpha-hydroxy acids is fully rate limiting, a finding in agreement with observations on L-lactate dehydrogenase from yeast [F. Lederer (1974), Eur. J. Biochem. 46, 393] which also does not promote elimination from D,L-beta-chlorolactate. Both D-alpha-hydroxy acid oxidase were found to be rapidly and irreversibly inactivated by the acetylenic substrate 1-hydroxy-3-butynoate. The partially purified dehydrogenase was observed to be inactivated within 10 min by 6.8 times 10(-8) M hydroxybutynoate. For the more extensively studied oxidase, inactivation was found to occur after 25 catalytic events, inactivation occurring by covalent addition of the inactivator to the coenzyme. A stoichimometry of one molecule of hydroxybutynoate per flavine was found, and the time course of inactivation was unaffected by the presence of thiols. The oxidase could also be inactivated by prolonged incubation of the enzyme with 2-hydroxy-3-butenoate, and inactivation which could be completely prevented by the presence of thiolds. Since the inactivation with hydroxybutenoate also left the flavine coenzyme unaltered, the inactivation was attributed to Michael addition of nucleophiles on the enzyme of the ketobutenoate product. Several 4-alkyl-substitued 2-hydroxy-3-butynoates were also observed to inactivate the oxidase by both coenzyme modification and random addition to the apoenzyme. It is proposed that the inactivation may occur by nucleophilic addition of a C4 allenic carbanion to the oxidized flavine coenzyme.

Alcohol Oxidoreductases↗
PubMed1977

Significance and taxonomic value of iso and anteiso monoenoic fatty acids and branded beta-hydroxy acids in Desulfovibrio desulfuricans.

The fatty acids obtained from extractable lipids of the anaerobic sulfate bacterium Desulfovibrio desulfuricans were identified. Saturated and monoenoic iso (C15-C19) and anteiso (C15, C17) fatty acids and saturated normal (C14-C18) and monoenoic normal (C16, C18) fatty acids were shown to be shown to be present by capillary gas chromatography-mass spectrometry. Iso and anteiso beta-hydroxy fatty acids were analyzed as trimethylsilyl ethers in the same way. The position of methyl branches in the monoenoic fatty acids was determined from characteristic fragment ions in the mass spectra of their methyl esters. Disilyloxy methyl esters, prepared by derivatization of the mono unsaturated methyl esters and analyzed by capillary gas chromatography-mass spectrometry, provided the position of double bonds. The monoenoic fatty acids identified in this way were normal (delta7-C16:1, delta9-C16:1, delta9-C18:1, delta11-C18:1), iso (delta7-C15:1, delta9-C16:1, delta9-C17:1, delta11-C18:1, delta11-C19:1), and anteiso (delta7-C15:1, delta9-C17:1). Iso delta9-C17:1 fatty acid is present as the major component. The occurrence of these monoenoic fatty acids in this bacterium is of taxonomical importance.

Chromatography, Gas↗
PubMed1989

Alpha hydroxy acids: procedures for use in clinical practice.

Alpha hydroxy acids and alpha keto acids applied topically in lower concentrations reduce the thickness of hyperkeratotic stratum corneum by reducing corneocyte cohesion at lower levels of the stratum corneum. This property permits efficient clinical control of dry skin, ichthyosis, follicular hyperkeratosis, and other conditions characterized by retention of stratum corneum. Applied topically in higher concentrations, these acids cause epidermolysis. This property provides a new alternative for treating seborrheic keratoses, keratoses commonly known as "age spots," actinic keratoses, and verrucae vulgares; all of which lesions involve distinct epidermal hyperplasia as well as retention of stratum corneum. Facial wrinkles can be modified with topical alpha hydroxy acids, applied in higher concentrations as office procedures, and concomitant daily home application of lower concentrations.

Acne Vulgaris↗
PubMedDate not supplied

Quantitation of multiple pathways for the metabolism of nephrotoxic cysteine conjugates using selective inhibitors of L-alpha-hydroxy acid oxidase (L-amino acid oxidase) and cysteine conjugate beta-lyase.

In this study, we have established the selectivity of inhibitors for rat kidney cysteine conjugate beta-lyase and L-alpha-hydroxy acid oxidase (L-amino acid oxidase) and have used these inhibitors to explore the relative roles of these two enzymes in the metabolism of nephrotoxic cysteine conjugates by rat kidney homogenate. In addition, we have investigated the relationship between structure and the metabolism of toxic cysteine conjugates by purified rat kidney L-alpha-hydroxy acid oxidase. With purified enzyme, S-(1,2,3,4,4-pentachlorobutadienyl)-L-cysteine (PCBDC) was about four times more active than S(1,2-dichlorovinyl)-L-cysteine (DCVC). Three alkyl conjugates were less active than DCVC. Purified L-alpha-hydroxy acid oxidase was not inhibited by the beta-lyase inhibitor aminooxyacetic acid but was inactivated by 2-hydroxy-3-butynoate. PCBDC metabolism in rat kidney homogenate was inhibited 74% by aminooxyacetic acid and 42% by 2-hydroxy-3-butynoate, whereas DCVC metabolism was inhibited 77% by aminooxyacetic acid and 28% by 2-hydroxy-3-butynoate. However, only aminooxyacetic acid inhibited the binding of 35S label from [35S]DCVC. Based on these results we have reached three conclusions. First, L-alpha-hydroxy acid oxidase plays a significant role in the metabolism of some cysteine conjugates. Second, metabolism of DCVC by L-alpha-hydroxy acid oxidase does not contribute directly to covalent binding. Third, as much as 65% of DCVC may be metabolized to its corresponding alpha-keto acid. The results are discussed with regard to the nephrotoxicity of cysteine conjugates.

Amino Acid Oxidoreductases↗
PubMed1991

Method for separation and determination of lactone and hydroxy acid forms of a new HMG CoA reductase inhibitor (RG 12561) in plasma.

The new drug RG 12561 (I) is a lactone that is undergoing clinical evaluation for its cholesterol lowering effect based on potent HMG CoA reductase inhibitory activity displayed by its open hydroxy acid form. To determine the dispositional characteristics of the drug, a method was developed for determination of the two forms in plasma. A 0.25-ml aliquot of plasma was deproteinized with 0.5 ml of methanol, and the lactone was extracted with hexane-ethyl acetate (75:25, v/v). The methanolic plasma was then acidified followed by extraction of the hydroxy acid with hexane-ethyl acetate. The extracts were dried, reconstituted and analyzed by isocratic, reversed-phase high-performance liquid chromatography using ultraviolet absorbance at 254 nm. The separations were performed utilizing a C18 column with mobile phase consisting of acetonitrile, 2-propanol and 0.1 M acetate buffer (pH 5), the proportions of which differed depending on the form of drug analyzed. The method was found to be selective and a quantitation limit of 50 ng/ml was established. Validation studies demonstrated that the method was sufficiently accurate and precise for determining disposition of the drug in the dog.

Animals↗
PubMed1992

Facile synthesis of chiral 2-hydroxy acids catalyzed by a stable duck epsilon-crystallin with endogenous L-lactate dehydrogenase activity.

Duck epsilon-crystallin, an abundant structural protein in lenses of some avian species, was shown to possess a genuine and stable L-lactate dehydrogenase (L-LDH; EC 1.1.1.27) activity suitable for the application to enzyme technology as a catalyst for the synthesis of chiral alpha-hydroxy acids. Two pharmaceutically important intermediates, 2-hydroxy acids (S)-2-hydroxybutanoic acid (S)-2-hydroxypentanoic acid have been synthesized in high yields and optical purity utilizing an in situ NADH regeneration system of duck epsilon-crystallin coupled with formate/formate dehydrogenase. This enzyme system is also shown to offer some advantages over the conventional L-LDH sources from several mammalian species.

Animals↗
PubMed1975

Rat kidney L-alpha-hydroxy acid oxidase: isolation of enzyme with one flavine coenzyme per two subunits.

L-alpha-Hydroxy acid oxidase (listed as EC 1.4.3.2, L-amino acid: O2 oxidoreductase) has been purified 100-fold from rat kidney to apparent homogeneity by gel electrophoresis. A subunit molecular weight of 47,500 was found by sodium dodecyl sulfate gel electrophoresis, but in contrast to previous reports, the enzyme has been found to have a molecular weight of ca. 200,000 by Sephadex gel filtration and by dodecyl sulfate gel electrophoresis of the enzyme cross-linked with dimethyl suberimidate. A somewhat higher value was found by sedimentation equilibrium, but a tetrameric structure for the active enzyme is definitely established. The enzyme was found to contain the FMN coenzyme at a concentration of one FMN/102,000 daltons or one flavine/two subunits, a highly unusual finding. This ratio was determined from spectroscopic analysis of the FMN in lyophilized samples of the enzyme and by titration of the coenzyme with the flavine specific enzyme inactivator 2-hydroxy-3-butynoate. The enzyme has the same specific activity as a crystalline sample of the enzyme reported to have twice as much flavine/milligram.

Amino Acid Oxidoreductases↗
PubMed1975

Ultrastructural localization of L-alpha-hydroxy acid oxidase in rat liver perioxisomes.

The localization of L-alpha-hydroxy acid oxidase in rat liver peroxisomes was studied using slight modifications of the Shnitka and Talibi (1971) method. Best results were obtained with formaldehyde fixation and incubation with glycolate as substrate. Following incubation the copper ferrocyanide reaction product was amplified with 3,3'-diamino-benzidine according to Hanker et al. (1972a,b). Dense reaction product was visible in hepatocyte peroxisomes by light and electron microscopy. Some diffusion of enzyme and/or reaction product into the adjacent cytoplasm occurred around the peroxisomes. Apparent non-specific deposits occurred on the plasmalemma, in the nucleus, and occasionally over mitochondria. Glutaraldehyde fixation severely inhibited enzymatic activity, and the enzyme showed less activity toward L-lactate and DL-alpha-hydroxybutyrate.

Alcohol Oxidoreductases↗
PubMed1976

Ultrastructural localization of catalase and L-alpha-hydroxy acid oxidase in microperoxisomes of Hydra.

The ultrastructural localization of catalase and L-alpha-hydroxy acid oxidase (LalphaHAO) was studied in two species of Hydra. Diaminobenzidine reaction product of catalase activity was present in small round or elongated bodies resembling microperoxisomes in the epitheliomuscular, digestive and gland cells. They were closely related to the endoplasmic reticulum, and were often found in proximity to deposits of lipid and glycogen. Reaction product of LalphaHAO activity was also associated with the microperoxisomes. With rapidly oxidized substrates, such as L-lactic acid, reaction product diffused into the cytoplasm around the microperoxisomes. With slowly oxidized substrates, such as DL-alpha-hydroxyisovaleric acid, reaction product was restricted to the matrix of the microperoxisomes. No reaction product was present in the microperoxisomes in the absence of substrate or with D-lactic acid. The rate of substrate oxidation measured biochemically roughly paralleled the amount of cytochemical reaction product deposited with different substrates. Microperoxisome-like bodies reactive for LalphaHAO were also found in the epidermal cnidoblasts; however, catalase could not be demonstrated in them. This study provides the first cytochemical evidence for the presence of an H2O2-producing oxidase in microperoxisomes.

Alcohol Oxidoreductases↗
PubMed1978

Effects of dihydroxy bile acids and hydroxy fatty acids on the absorption of oleic acid in the human jejunum.

Perfusion studies of the normal human jejunum were performed to test whether dihydroxy bile acids and hydroxy fatty acids inhibit the absorption of oleic acid, since previous reports documented their inhibitory effects on the absorption of several other organic solutes. 3 mM deoxycholate and 7 mM glycodeoxycholate inhibited the absorption of 3 mM oleic acid in isotonic micellar solutions while inducing net fluid secretion. Similarly, fractional absorption of oleic acid decreased in the presence of hydroxy fatty acids. However, only the changes induced by 2 mM ricinoleic acid could be distinguished from changes induced by an increase in total fatty acid concentration. Under all experimental conditions, close linear relationships existed between net water movement and fractional absorption of glucose, xylose, and fatty acids, as well as between the absorption rates of these solutes. In contrast, net fluid secretion induced by hypertonic D-mannitol (450 mosmol/liter) had no effect on solute absorption. Our data and observations in the literature do not allow formulation of a hypothesis which would adequately define all effects of dihydroxy bile acids and fatty acids on intestinal transport processes. The observations help explain the malabsorption of fat and other nutrients in patients with the blind loop syndrome.

Adult↗
PubMed1978

Genetics and physiological expression of beta-hydroxy acid dehydrogenase in Drosophila.

A mutant Hadnl was induced in Drosophila melanogaster and found to be deficient in beta-hydroxy acid dehydrogenase. This mutation was utilized to study the genetics and physiological expression of Had+ . Had+ was mapped to the X chromosome at 54.4 and seems to be the structural gene for the enzyme. Enzyme activity in male and female flies indicates that the gene shows both dosage compensation independent from dose effect and differential activity during ontogeny. Electrophoretic mobility data indicate that the enzyme is a dimer which forms by random association of subunits. The fact that the mutant shows no detrimental effect implies that the enzyme is dispensable, at least under laboratory conditions. The biological and technical implications of this gene--enzyme system are discussed.

Animals↗
PubMed1992

Evolutionary relationship of NAD(+)-dependent D-lactate dehydrogenase: comparison of primary structure of 2-hydroxy acid dehydrogenases.

A comparison of the primary structures of NAD(+)-dependent D-lactate dehydrogenase with L-lactate dehydrogenase and L-malate dehydrogenase failed to show any sequence similarity. However, D-2-hydroxyisocaproate dehydrogenase from Lactobacillus casei, glycerate dehydrogenase from cucumber, D-3-phosphoglycerate dehydrogenase and erythronate 4-phosphate dehydrogenase from Escherichia coli showed 38%, 24%, 24% and 22% amino acid identity, respectively. The profile analysis of the aligned sequences confirmed their relatedness. The hydropathy profiles of the aligned dehydrogenases were almost identical between residues 100-300 indicating largely preserved folding patterns of their polypeptide chains. The data suggest that L- and D-specific 2-hydroxy acid dehydrogenase genes evolved from two different ancestors and thus represent two different sets of enzyme families.

Alcohol Oxidoreductases↗
PubMed1975

[Ascorbic, keto and hydroxy acid metabolism in the cell nuclei of certain tumors].

The authors report the results of studies on the content of ascorbic acid, pyruvic acid and the activity of malate dehydrogenase decarboxylizing (MDHD) in cell nuclei of uterine fibromyoma, glandular hyperplasia of the endometrium with epithelial proliferation, common ovarian cyst and solid cancer. It was shown that due to the glycolysis inhibited respiration an oxidated form of ascorbic acid is absent in every case, whereas the MDHD activity is not manifested. The amount of a reduced form of ascorbic and pyruvic acid in benign tumors is at the control level, but in malignant growth these indices are markedly increased.

Ascorbic Acid↗