Identification of 2-hydroxystearic acid in spinal cord phrenosine by chromatographic separation of hydroxy fatty acids.
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Cerebrosides↗
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Results for “Hydroxy Acids”
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Aldol-Type Condensation Reactions of Selenothioacetic Acid S-Butyl Ester Leading to beta-Hydroxy Selenothioic Acid S-Esters and Ketene Selenothioacetals.
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Journal Article↗
Identification and quantification of 3-methoxy-4-hydroxyphenyllactic acid (VLA) in cerebrospinal fluid and 3-methoxy-4-hydroxy phenylpyruvic acid (VPA) in the urine of Parkinsonian patients treated with L-DOPA.
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Catechols↗
Pharmacokinetics and pharmacodynamics of topotecan in patients with advanced cancer.
Topotecan, a semisynthetic water-soluble analog of camptothecin, is the first topoisomerase I-directed drug to enter clinical trial in the United States in over 20 yr. In this study, 30-min infusions of topotecan were administered daily for 5 days every 3 weeks at doses ranging from 0.5 to 2.5 mg/m2. Topotecan is reversibly hydrolyzed in a pH-dependent reaction in aqueous solutions to the ring-open hydroxy acid. The disposition of the closed ring lactone has been studied in 26 patients, and the disposition of both lactone and hydroxy acid has been studied in 12 patients. The clearance rate for topotecan lactone was 1220 ml/min/m2, with a range of 300-4760 ml/min/m2. The clearance rate for total topotecan (lactone and hydroxy acid) was 493 ml/min/m2, with a range of 163-815 ml/min/m2. A model for the disposition of lactone and hydroxy acid incorporating both reversible hydrolysis and elimination was developed. We have shown that topotecan is partially hydrolyzed prior to administration in parenteral solutions, and that clearance of the parent compound proceeds in vivo by conversion to hydroxy acid and elimination. Renal clearance accounted for 30 +/- 18% of drug elimination in patients. The relationship between topotecan dose and myelotoxicity is well fit by a sigmoidal Emax model, as is the relationship between total topotecan area under the concentration-time curve and myelotoxicity. The disposition of topotecan was also studied in mice. The clearance rate for total topotecan in mice was 330 ml/min/m2 after administration of topotecan lactone.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Reversible inactivation of vectorial phosphorylation by hydroxybutynoate in Escherichia coli membrane vesicles.
The acetylenic hydroxy acid 2-hydroxy-3-butynoate causes irreversible inactivation of the Escherichia coli membrane-bound flavoenzyme D-lactic dehyrogenase, and thus blocks D-lactate dependent active transport in isolated membrane vesicles [Walsh, C. T., Abeles, R. H., and Kaback H. R. (1972), J. Biol. Chem. 247, 7858]. The inactivator is a suicide substrate for the dehydrogenase, undergoing a small number of turnovers before partitioning between oxidation and inactiviation. It is now demonstrated that reactive product molecules of 2-keto-3-butynoate can diffuse in the membranes to a component of the phosphotransferase system and cause time-dependent and covalent inactivation of phosphoenolpyruvate-dependent hexose uptake. Membrane vesicles from double mutants with low levels of both D- and L-lactic dehydrogenase lose only 30 percent of their hexose uptake capacity on exposure to hydroxybutynoate under conditions sufficient to fully inactivate hexose transport in wild type vesicles. Transport of 1-[14C]hydroxybutynoate into vesicles is followed by rapid covalent labeling of membrane proteins by the reactive, enzymatically generating keto acid oxidation product. Incubation of hydroxybutynoate-inactivated vesicles (5% residual activity) for 20 min in buffer with 10 mM dithiothreitol results in reactivation of 63% of the hexose transport activity, a 12-fold increase in activity. No reactivation occurs if the vesicular phosphotransferase system is inactivated by keto acid derived from membrane oxidation of the olefinic congener 2-hydroxy-3-butenoate. In contrast to thiol reactivation of acetylenic-blocked glucose transport, blockage of D-lactate-stimulated proline uptake is not alleviated, stressing different modes of inactivation of the phosphotransferase system compared to the membranous lactate dehydrogenases.
Biological Transport, Active↗
Composition of long-chain bases in sphingomyelin of the guinea pig Harderian gland.
Sphingomyelin from the guinea pig Harderian gland was isolated and characterized. The purified sphingomyelin gave a broad spot on thin-layer chromatography. The fatty acid composition of the whole sphingomyelin was 71% nonhydroxy acids and 29% 2-hydroxy acids. Methyl-branched fatty acids were only 2% of the total acids. The long-chain bases were composed of straight-chain sphingenines (50%) and sphinganines (6%). Methyl-branched long-chain bases were 44% of the bases. The sphingomyelin was further separated into four fractions (I, II, III, IV) by high-performance liquid chromatography. The ratio of fractions I, II, III, and IV was approximately 2:5:2:1, respectively. The fatty acids of fractions I and II consisted of nonhydroxy acids and those of fractions III and IV were 2-hydroxy acids. The long-chain bases of fractions I and III were sphinganines including 10-, 9-, and 8-methylsphinganines and anteiso-sphinganines. These methyl-branched bases occupied about 70% of the total sphinganines. The long-chain bases of fractions II and IV consisted of sphingenines. The methyl-branched unsaturated bases were only 30% of the total sphingenines, all in the anteiso-form. Thus, the sphingomyelin obtained from guinea pig Harderian gland had complex compositions of fatty acids and long-chain bases, and half the number of long-chain bases had methyl branches. The methyl-branched fatty acids were only a minor component. These characteristics are similar to those of cerebrosides isolated from the same source.
Animals↗
Synthesis of a novel macrolactone by lipase-catalyzed intra-esterification of hydroxy-fatty acid in organic media.
The unsaturations and groups bound to the ring and to the lateral chain of lactones give a large diversity in this class of molecules. In this work we produced enzymatically a macrolactone in organic media. The substrate used was a hydroxy-fatty acid: (+)-coriolic acid and the enzymes tested were free or immobilized microbial lipases. The immobilized lipase from Candida antarctica seems to be the most adequate catalyst offering a high reaction yield. The intra-esterification was studied as a function of temperature and type of solvent. Higher yields were obtained when using diisopropyl-ether at 35 degrees C. This reaction, involving an alcohol group on an internal position on the carbon chain of the substrate hydroxy-acid, produces an original lactone: 13S-octadeca-(9Z,11E)-dienolide. The product was purified and characterized using (1)H nuclear magnetic resonance spectroscopy, mass spectrometry and infrared spectroscopy.
Alkenes↗
A family of single-isomer positively charged cyclodextrins as chiral selectors for capillary electrophoresis: mono-6A-butylammonium-6A-deoxy-beta-cyclodextrin tosylate.
A novel single-isomer positively charged beta-cyclodextrin (beta-CD), mono-6(A)-butylammonium-6(A)-deoxy-beta-cyclodextrin tosylate (BuAM-beta-CD), has been synthesized, characterized, and used for the enantioseparations of alpha-hydroxy acids, carboxylic acids, and ampholytic analytes by capillary electrophoresis in acidic aqueous background electrolytes. The effective mobilities of all studied analytes decreased with increasing concentration of CD. Satisfactory resolutions were obtained for alpha-hydroxy acids over a wide range of chiral selector concentration. The optimum CD concentration was lower than 5 mM for the carboxylic acids, while higher than 20 mM for alpha-hydroxy acids. Inclusion complexation in combination with ion pair interaction seemed to account for the chiral discrimination process. The hydrogen bonding may provide secondary contribution for the chiral resolution of alpha-hydroxy acids. In addition, BuAM-beta-CD was further proved to be an effective chiral selector for anionic analytes by the baseline enantioseparation of a six-acid mixture within 20 min.
Buffers↗
Isolation and characterisation of a new antagonistic Burkholderia strain from the rhizosphere of healthy tomato plants.
A new Burkholderia strain (PVFi5A) which exhibits antagonism towards many bacterial and fungal plant pathogens has been partially characterised. This strain was isolated from the rhizosphere of tomato plants and was referred to the Burkholderia cepacia complex on the basis of cultural, morphological and biochemical characteristics, including determination of the 16S ribosomal DNA sequence and fatty acid profile. Strain PVFi5A is a Gram-negative, aerobic bacterium, oxidase- and catalase-positive, motile with a polar tuft of flagella, able to grow on a variety of media without producing diffusible pigments; it is avirulent to onion, able to grow at 41 degrees C and resistant to several antibiotic substances. Its fatty acid profile contains the hydroxy acids 18:1 20H, 14:0 3OH and 16:0 3OH, but not the hydroxy acids 16:0 2OH. The antagonistic activity of strain PVFi5A is due to its production of various, as yet unidentified, antimicrobial compounds, one or more of which may differ from those reported previously for certain 'B. cepacia' strains. The ability of PVFi5A to suppress the growth of important bacterial and fungal phytopathogens makes this strain a potential biocontrol agent.
Anti-Bacterial Agents↗
Enantiomeric and diastereoisomeric analysis of nonproteinogenic methyl and hydroxy amino acids.
The enantiomeric and diastereoisomeric analysis of nonproteinogenic methyl and hydroxy amino acids, obtained by asymmetric synthesis with the aid of a chiral regenerable reagent, has been carried out by liquid chromatography.
Amino Acids↗
Isolation and characterization of a lipoxygenase from Pseudomonas 42A2 responsible for the biotransformation of oleic acid into ( S )-( E )-10-hydroxy-8-octadecenoic acid.
The isolation of a new lipoxygenase-like (LOX-like) enzyme from Pseudomonas 42A2 and its characterization is described. The enzyme, located in the periplasm of the cell, which contained 0.55 mol of Fe2+ per mol of protein, is monomeric and has a molecular mass of 45 kDa. In the presence of oxygen, the enzyme converts oleic acid into (E)-10-hydroperoxy-8-octadecenoic acid (HPOD), which decomposes to the corresponding (E)-10-hydroxy-8-octadecenoic acid (HOD). The absolute configuration of this acid was determined as S on the basis of exciton-coupled CD data, and specific rotation and NMR analysis of the corresponding p -bromobenzoate derivative. The reaction in vivo leads to the dihydroxy derivative (E)-7,10-dihydroxy-8-octadecenoic acid (DHOD), so that the three hydroxy-fatty acids can be isolated from the culture medium. The activity of the enzyme was optimal between 25 and 30 degrees C and 44% of its activity still remained at 55 degrees C. Its optimal pH is 8.5-9; and the presence of magnesium ions increased LOX activity by 1.5. The activity of the LOX is highest in unsaturated fatty acids containing double bonds in position 9 (oleic, linoleic and linolenic acids), linoleic acid being preferred (100% activity) over linolenic (60.4%) and oleic acids (46%). However, kinetic studies showed that the affinity of the enzyme is similar for the three substrates.
Biotransformation↗
Strong increase in hydroxy fatty acids derived from linoleic acid in human low density lipoproteins of atherosclerotic patients.
Linoleic acid is the most abundant fatty acid in human low density lipoproteins (LDL). Oxidation of LDL transforms linoleic acid to hydroperoxyderivatives. These are converted to 9-hydroxy-10,12-octadecadienoic acid (9-HODE) and 13-hydroxy-9,11-octadecadienoic acid (13-HODE). 9-HODE is much more abundant in oxidized LDL than other lipid peroxidation products and therefore an indicator of lipid peroxidation (LPO). In this study the 9-HODE content in the LDL of 19 obviously healthy volunteers and 17 atherosclerotic patients was investigated. The level of 9-HODE obtained from LDL of young atherosclerotic patients (aged 36-47 years) was increased by a factor of 20 when compared with samples from healthy volunteers of the same age group. The content of 9-HODE in the LDL of atherosclerotic patients aged between 69 and 94 years increased 30-100 fold when compared with young healthy individuals, but when compared with 'healthy' individuals of the same age group it was only 2-3 fold increased. Obviously, as individuals grow older LDL becomes more and more oxidized. Consequently, assuming that LDL oxidation is a precondition for atherosclerosis--older individuals will suffer from atherosclerosis, even if no easy detectable visible signs of this disease are recognizable. According to 9-HODE determination, the onset of the disease starts slowly in most individuals at around 50 years of age.
Adult↗
Establishment of beta-hydroxy fatty acids as chemical marker molecules for bacterial endotoxin by gas chromatography-mass spectrometry.
Selected ion-monitoring gas chromatography-mass spectrometry was used for detection of beta-hydroxy fatty acids as an independent assay for the presence or absence of endotoxin in materials claimed to induce nonspecific activation of Limulus amoebocyte lysate. To this end, suspensions of gram-negative and -positive bacteria, one fungal species, cerebrospinal fluid, and hollow-fiber hemodialyzer rinses were assayed for endotoxin by gas chromatography-mass spectrometry and the Limulus amoebocyte lysate assay. Good qualitative agreement was shown for both methods when suspensions of test organisms were assayed. Two false-negative results were obtained by gas chromatography-mass spectrometry assays of cerebrospinal fluid and were shown to be a result of insufficient endotoxin in the cerebrospinal fluid specimens for detection by gas chromatography-mass spectrometry. Hemodialyzer rinses were Limulus assay positive; however, no beta-hydroxy fatty acids were detected by gas chromatography-mass spectrometry. These data were compared with data obtained from USP rabbit pyrogen tests of the rinse materials (nonpyrogenic) and chemical characterization of the Limulus assay-reactive rinses, which showed the rinses to be cellulosic in nature. It is suggested that beta-hydroxy fatty acids, as assayed by selected ion-monitoring gas chromatography-mass spectrometry, be used as chemical marker molecules for the presence or absence of endotoxin in materials reported to cause nonspecific activation of Limulus amoebocyte lysate.
Candida albicans↗
Salicylic acid peels for the treatment of photoaging.
Several chemical agents are currently used to perform superficial chemical peels of the face. These include trichloracetic acid (15-30%), alpha-hydroxy acids (e.g., glycolic acid, 40-70%), and Jessner's solution (14% lactic acid, 14% resorcinol, and 14% salicylic acid). We have developed salicylic acid, a beta-hydroxy acid, at a higher strength (30% in a hydro-ethanolic vehicle) as an alternative peel. This peel has distinct advantages for resurfacing moderately photodamaged facial skin. We have peeled patients singly and multiply at 4-week intervals. The benefits are fading of pigment spots, decreased surface roughness, and reduction of fine lines.
Adult↗
Enantioselective C-C bond synthesis catalysed by enzymes.
The enantioselective synthesis of C-C bonds is often the pivotal step of a synthesis. Nature has made a variety of versatile enzymes available that catalyse this type of reaction very selectively under mild conditions. Cyanohydrins, acyloins (alpha-hydroxy ketones), alpha-hydroxy acids and aldols (beta-hydroxy ketones) are very efficiently synthesised enantioselectively with the aid of C-C bond forming enzymes, which we discuss in this tutorial review. In the case of the alpha-hydroxy acids the applications of nitrilases in a synthetic dkr even allows a disconnection that has no enantioselective chemical equivalent.
Carbon↗
Extreme pKa displacements at the active sites of FMN-dependent alpha-hydroxy acid-oxidizing enzymes.
Flavocytochrome b2 (or L-lactate dehydrogenase) from baker's yeast is thought to operate by the initial formation of a carbanion, as do the evolutionarily related alpha-hydroxy acid-oxidizing FMN-dependent oxidases. Previous work has shown that, in the active site of the unligated reduced flavocytochrome b2, the group that has captured the substrate alpha-proton has a high pKapp, calculated to lie around 15 through the use of Eigen's equation. A detailed inspection of the now known three-dimensional structure of the enzyme leads to the conclusion that the high pKa belongs to His 373, an active site group that plays the role of general base in the forward reaction and of general acid in the reverse direction. Moreover, consideration of the kinetics of proton transfer during the catalytic cycle suggests that the pKa of the reduced FMN N5 position should be lowered by several pH units compared to its pKa of 20 or more when free. The features of the three-dimensional structure possibly responsible for these pK shifts are analyzed; they are proposed to consist of a network of hydrogen bonds with the solvent and of a mutual electrostatic stabilization of anionic reduced flavin and the imidazolium ion. Finally, it is suggested that similar pK shifts affect the active sites of the alpha-hydroxy acid-oxidizing flavooxidases, which are homologous to flavocytochrome b2. The functional significance of these pK shifts in terms of catalysis and semiquinone stabilization is discussed.
Binding Sites↗
Dietary hydroxy fatty acids are absorbed in humans: implications for the measurement of 'oxidative stress' in vivo.
Lipid peroxidation products formed in vivo or originating from the diet may lead to atherosclerosis. However, little is known about the absorption of these products in man. We studied the absorption of fat (30 g) containing 14-15 mg [U-13C]-labeled hydroxy or dihydroxy triglycerides in two groups of six apparently healthy women aged 40 +/- 2 years. Post-prandial 13C-labeled hydroxy fatty acid concentration increased in a pattern somewhat different from that of plasma triglycerides, with peak levels being reached between 4 and 6 h. However, the amount of 13C-labeled oxidized fat absorbed (area under the curve of plasma concentrations from 0 to 8 h) was related to that of plasma triglycerides: 13C hydroxy vs TG (r = 0.88, p <.02), and 13C dihydroxy vs TG (r = 0.85, p <.05). 13C monohydroxy triglycerides appeared to be absorbed to a greater extent than those of 13C dihydroxy triglycerides. Although low levels of 13C hydroxy lipids could be detected in fasting plasma after 24 h, concentrations were very low. Dietary lipid oxidation products are absorbed. The measurement of hydroxy fatty acids in plasma total lipids may not be a valid marker of lipid peroxidation in vivo when subjects are not fasting.
Adult↗
L-selective amidase with extremely broad substrate specificity from Ochrobactrum anthropi NCIMB 40321.
An industrially attractive L-specific amidase was purified to homogeneity from Ochrobactrum anthropi NCIMB 40321 wild-type cells. The purified amidase displayed maximum initial activity between pH 6 and 8.5 and was fully stable for at least 1 h up to 60 degrees C. The purified enzyme was strongly inhibited by the metal-chelating compounds EDTA and 1,10-phenanthroline. The activity of the EDTA-treated enzyme could be restored by the addition of Zn2+ (to 80%), Mn2+ (to 400%), and Mg2+ (to 560%). Serine and cysteine protease inhibitors did not influence the purified amidase. This enzyme displayed activity toward a broad range of substrates consisting of alpha-hydrogen- and (bulky) alpha,alpha-disubstituted alpha-amino acid amides, alpha-hydroxy acid amides, and alpha-N-hydroxyamino acid amides. In all cases, only the L-enantiomer was hydrolyzed, resulting in E values of more than 150. Simple aliphatic amides, beta-amino and beta-hydroxy acid amides, and dipeptides were not converted. The gene encoding this L-amidase was cloned via reverse genetics. It encodes a polypeptide of 314 amino acids with a calculated molecular weight of 33,870. Since the native enzyme has a molecular mass of about 66 kDa, it most likely has a homodimeric structure. The deduced amino acid sequence showed homology to a few other stereoselective amidases and the acetamidase/formamidase family of proteins (Pfam FmdA_AmdA). Subcloning of the gene in expression vector pTrc99A enabled efficient heterologous expression in Escherichia coli. Altogether, this amidase has a unique set of properties for application in the fine-chemicals industry.
Amidohydrolases↗