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PubMed2006

DFT study on hydroxy acid-lactone interconversion of statins: The case of fluvastatin.

Fluvastatin is a member of the HMG-CoA reductase inhibitor family of drugs, commonly referred to as statins. It is generally known that, under physiological conditions, statins are susceptible to pH-dependent interconversion between their active (hydroxy acid) and inactive (lactone) forms. The mechanism of this interconversion, under both acidic and basic conditions, was investigated theoretically using the density functional theory (DFT) method. Regardless of the conditions, the lactone form was always higher in energy by 6-19 kcal mol(-1). However, under basic conditions, the activation barrier for the hydrolysis was significantly lower (9 kcal mol(-1)) than for the reverse reaction (28 kcal mol(-1)), making the lactone form unstable. The activation barriers under acidic conditions were of comparable height in both directions (22 and 28 kcal mol(-1)), making the occurrence of both forms equally probable. Due to the high activation barrier (>40 kcal mol(-1)), a one-step, direct interconversion between the two forms turned out to be unfavourable. Moreover, the potential energy surface of fluvastatin was briefly inspected, revealing relatively small energetic differences (<5 kcal mol(-1)) between the key conformers.

Computer Simulation↗
PubMed1997

Quantification of ergosterol and 3-hydroxy fatty acids in settled house dust by gas chromatography-mass spectrometry: comparison with fungal culture and determination of endotoxin by a Limulus amebocyte lysate assay.

Ergosterol and 3-hydroxy fatty acids, chemical markers for fungal biomass and the endotoxin of gram-negative bacteria, respectively, may be useful in studies of health effects of organic dusts, including domestic house dust. This paper reports a method for the combined determination of ergosterol and 3-hydroxy fatty acids in a single dust sample and a comparison of these chemical biomarkers determined by gas chromatography-mass spectrometry with results from fungal culture and Limulus assay. Analyses of replicate house dust samples resulted in correlations of 0.91 (ergosterol in six replicates; P < 0.01) and 0.94 (3-hydroxy fatty acids in nine replicates; P < 0.001). The amounts of ergosterol (range, 2 to 16.5 ng/mg of dust) correlated with those of total culturable fungi (range, 6 to 1,400 CFU/mg of dust) in 17 samples, (r = 0.65; P < 0.005). The amounts of endotoxin (range, 11 to 243 endotoxin units/mg of dust) measured with a modified chromogenic Limulus assay correlated with those of lipopolysaccharide (LPS) determined from 3-hydroxy fatty acid analysis of 15 samples. The correlation coefficient depended on the chain lengths of 3-hydroxy acids used to compute the LPS content. The correlation was high (r = 0.88 +/- 0.01; P < 0.001) when fatty acid chains of 10 to 14 carbon atoms were included; the correlation was much lower when hydroxy acids of 16- or 18-carbon chains were included. In conclusion, the results of the described extraction and analysis procedure for ergosterol and 3-hydroxy fatty acids are reproducible, and the results can be correlated with fungal culture and endotoxin activity of organic dust samples.

Bacteriological Techniques↗
PubMed1997

Conversion of beta-methylbutyric acid to beta-hydroxy-beta-methylbutyric acid by Galactomyces reessii.

beta-Hydroxy-beta-methylbutyric acid (HMB) has been shown to increase strength and lean mass gains in humans undergoing resistance-exercise training. HMB is currently marketed as a calcium salt of HMB, and thus, environmentally sound and inexpensive methods of manufacture are being sought. This study investigates the microbial conversion of beta-methylbutyric acid (MBA) to HMB by cultures of Galactomyces reessii. Optimal concentrations of MBA were in the range of 5 to 20 g/liter for HMB production. Preliminary shake flask experiments indicated that HMB yields were sensitive to dissolved oxygen levels and that cell growth decreased significantly as MBA concentrations increased. Degradation of HMB was faster at acidic pH, and pH 7.0 was optimal for HMB production. Resting cells obtained from media without MBA could efficiently convert MBA to HMB. Thus, a two-step, fed-batch fermentation procedure in which biomass was first produced, followed by coaddition of MBA and glucose, while dissolved oxygen was maintained at 20% of saturation, was designed. A maximum HMB concentration of 38 g/liter was obtained after 136 h, and the molar conversion yield was more than 0.50 mol of HMB/mol of MBA during the fermentation.

Butyrates↗
PubMed1992

The cytoplasmic peptidoglycan precursor of vancomycin-resistant Enterococcus faecalis terminates in lactate.

Vancomycin resistance plasmids in enterococci carry the genes vanH and vanA, which encode enzymes catalyzing, respectively, the reduction of 2-keto acids to 2-D-hydroxy acids and the addition of D-hydroxy acids to D-alanine. It has therefore been postulated that resistant cells produce peptidoglycan precursors that terminate in the depsipeptide D-alanine-2-D-hydroxy acid rather than the dipeptide D-alanine-D-alanine, thus preventing vancomycin binding (M. Arthur, C. Molinas, T. D. H. Bugg, G. D. Wright, C. T. Walsh, and P. Courvalin, Antimicrob. Agents Chemother. 36:867-869, 1992). In the present work, a cytoplasmic peptidoglycan precursor was isolated from vancomycin-resistant Enterococcus faecalis and analyzed by mass spectrometry, which suggested the structure UDP-N-acetyl-muramyl-L-Ala-D-Glu-L-Lys-D-Ala-D-lactate.

Amino Acid Sequence↗
PubMed1996

Differential secretion of cathepsins B and L from normal and tumor human lung cells stimulated by 12(S)-hydroxy-eicosatetraenoic acid.

Cathepsins B and L play roles in intracellular and extracellular proteolysis in normal and malignant processes. A directed extracellular proteolysis by regulated secretion could facilitate the process of invasion. We have therefore investigated the effect of the physiological signal mediator 12(S)-hydroxy-eicosatetraenoic acid on the release of cathepsins B and L in normal and malignant human lung cells. Quantitative determinations of cathepsin activities were done by flow cytometry and spectrofluorometry using synthetic dipeptidyl substrates coupled to fluorogens. Most interestingly, a difference in the secretion of cathepsins B and L was found: only release of active cathepsin B was detected. The effect was specific for 12(S)-hydroxy-eicosatetraenoic acid, 12(R)-hydroxy-eicosatetraenoic acid, and 5(S)-hydroxy-eicosatetraenoic acid were ineffective. The response was immediate but a substantial amount of nonreleasable activity remained cell bound. Alveolar macrophages, Wi-38 fibroblasts, and tumor cells derived from large cell carcinomas and adenocarcinomas were sensitive to 12(S)-hydroxy-eicosatetraenoic acid, but cells from undifferentiated squamous cell carcinomas were not. Sensitivity did not parallel malignancy but more likely the degree of differentiation of cells. The investigated tumor cell lines showed no detectable endogenous 12-lipoxy-genase activity to synthesize 12(S)-hydroxy-eicosatetraenoic acid from arachidonate; therefore, we assume a paracrine mechanism for 12(S)-hydroxy-eicosatetraenoic acid action. Protein kinase C alpha, a key enzyme involved in 12(S)-hydroxy-eicosatetraenoic acid-elicited responses, was expressed in all sensitive tumor cells, but insignificantly in a sensitive normal cell line and an insensitive tumor cell line. From our experiments we propose two separate intracellular pools of active cathepsin B: an unreleasable, lysosomal fraction and a fraction available for regulated secretion. Different processing and sorting mechanisms may be responsible for the generation of these cathepsin B-fractions in these pools.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1985

Qualitative and quantitative measurement of hydroxy fatty acids, thromboxanes and prostaglandins using stable isotope dilutions and detection by gas chromatography-mass spectrometry.

Methods for measurement of the metabolites of arachidonic acid (AA), namely prostaglandins (PGs), thromboxanes (TXs) and hydroxy fatty acids, using stable isotope dilution gas chromatography--mass spectrometry are described. With a few exceptions, labelled species of the various AA metabolites are not commercially available and were therefore synthesized in our laboratory. [2H8]AA, produced by deuteration of eicosatetraynoic acid, was used for comparing the metabolism of exogenously added and endogenously present AA in fibroblast cultures. After derivatization and catalytic hydrogenation, structure elucidation and quantification of the different hydroxy fatty acids was carried out by determination of the fragment ions resulting from alpha-cleavage at the site of the hydroxy function. During catalytic hydrogenation a significant hydrogen--deuterium exchange was observed. To eliminate this problem, 18O-labelled standards were prepared by exchanging the oxygen of the carboxylic acid group. The preparation and the use of hydroxy fatty acids, PGs and TXs labelled with 18O is described.

Fatty Acids↗
PubMed1983

A bioluminescent assay for 12-alpha-hydroxy bile acids using immobilized enzymes.

A bioluminescent assay for 12-alpha-hydroxy bile acids was developed using enzymes coimmobilized onto Sepharose 4B. The immobilized enzymes used were a bacterial 12-alpha-hydroxysteroid dehydrogenase, bacterial luciferase, and NADPH:FMN oxidoreductase or bacterial diaphorase. The assay was specific for 12-alpha-hydroxy bile acids and the lower limit of detection was 4 pmol/0.5 ml assay volume with a linear range of 4 to 2000 pmol. Intraassay precision was from 7.8 to 8.2%. Values obtained with this assay showed good agreement with those obtained by gas-liquid chromatography. The system using diaphorase was not stable at 4 degrees C in the absence of added thiol compounds, but could be stabilized by the addition of glutathione (0.5 mM). The assay is a convenient, a rapid, and an extremely sensitive method for the measurement of 12-alpha-hydroxy bile acid concentrations in the serum of patients or experimental animals.

Bile Acids and Salts↗
PubMed2001

Characterization of p-hydroxy-hippuric acid as an inhibitor of Ca2+-ATPase in end-stage renal failure.

Characterization of p-hydroxy-hippuric acid as an inhibitor of Ca2+-ATPase in end-stage renal failure. In patients with end-stage renal failure (ESRF), disturbances of Ca2+ metabolism are common. Besides hormonal changes, inhibition of cellular Ca2+-ATPase was postulated to contribute to uremic toxicity. We purified a potent inhibitor of the Ca2+-ATPase from the ultrafiltrate of patients with ESRF by multiple steps of high-performance liquid chromatography to homogeneity, and identified the isolated inhibitor by mass spectrometric methods as p-hydroxy-hippuric acid. The enzyme used for the Ca2+-ATPase assay system was isolated from red blood cells by cross-flow filtration. The activity of the Ca2+-ATPase was measured spectrophotometrically as the difference in hydrolysis of adenosine 5'-triphosphate (ATP) in the presence and absence of Ca2+ with different concentrations of ATP and p-hydroxyhippuric acid. The Ca2+-ATPase was found to be inhibited by p-hydroxy-hippuric acid at a concentration above 11.7 micromol/L. p-Hydroxyhippuric acid inhibited the erythrocyte Ca2+-ATPase by reducing Vmax and increasing the Km value. The EC50 (log mol/L; mean +/- SEM) for p-hydroxy-hippuric acid was calculated as 4.82 +/- 0.14. In conclusion, p-hydroxy-hippuric acid may play a role in disturbed Ca2+ metabolism in end-stage renal failure.

Calcium-Transporting ATPases↗
PubMed1976

Occurrence of 2- and 3-hydroxy fatty acids in high concentrations in the extractable and bound lipids of Flavobacterium meningosepticum and Flavobacterium IIb.

The major hydroxy fatty acids of cellular lipids in Flavobacterium meningosepticum and Flavobacterium sp. King's group UUb were identified as 2-hydroxy 13-methyltetradecanoic, 3-hydroxy 13-methyltetradecanoic, 3-hydroxy palmitic, and 3-hydroxy 15-methylhexadecanoic acids using gas chromatography-mass spectrometry and GC-mass fragmentography. The concentration of these hydroxy fatty acids comprised up to 30-40% of the total extractable and 20-30% of the bound lipid fatty acids, respectively. From the stability for mild alkaline hydrolysis, 2-hydroxy fatty acids seemed to be attached with ester linkage, and 3-hydroxy fatty acids with amide linkage.

Chromatography, Gas↗
PubMed1997

Characterization of the interaction of Ca2+ with hydroxy and non-hydroxy fatty acid species of cerebroside sulfate by Fourier transform infrared spectroscopy and molecular modeling.

Ca2+-mediated interactions between the carbohydrate groups of glycolipids, including that of cerebroside sulfate (galactosylceramide I3-sulfate), have recently been implicated as a basis of cell recognition and adhesion. Hydroxylation of the fatty acid of this lipid has an effect on these interactions. Therefore, FT-IR spectroscopy was used to study the interaction of Ca2+ with semisynthetic hydroxy (HFA) and non-hydroxy fatty acid (NFA) species of cerebroside sulfate (CBS). Ca2+ caused partial dehydration of the sulfate group and reduced hydrogen bonding of the sugar hydroxyls of both species. The amide I and II bands of the lipids in the absence of Ca2+ (NH4+ salt forms) suggested that the N-H of the HFA species is involved in a bent intramolecular hydrogen bond, probably with the fatty acid hydroxyl group and the glycosidic oxygen, while that of the NFA species is involved in a linear intermolecular hydrogen bond with the C=O and/or other oxygens. Ca2+ caused a rearrangement of the hydrogen-bonding network in the interfacial region of the HFA species involving the amide group. The results suggested increased hydrogen bonding of the C=O and a shift in hydrogen bonding of the N-H of the Ca2+ salt form of the HFA species from a bent intramolecular hydrogen bond to a linear intermolecular hydrogen bond, probably with the C=O of neighboring molecules, similar to the NFA species. The involvement of the fatty acid alpha-hydroxyl group in the rearranged network was indicated by a reduction in mobility of the alpha-CH group of the HFA species, in contrast to that of the NFA species. Participation of the alpha-OH group in hydrogen-bonding networks in the interfacial region of both the NH4+ and Ca2+ salt forms caused a significant increase in the interchain packing, as evident from correlation field splitting of the HFA-CBS methylene scissoring mode, while this did not occur for the NFA species. The absence of intramolecular hydrogen bonding of the N-H with the glycosidic oxygen for both salt forms of the NFA species and for the Ca2+ salt form of the HFA species may destabilize the "bent shovel", bilayer planar conformation of the sugar and cause it to be in the extended, bilayer perpendicular conformation. Calculations of the three-dimensional interaction energy of Ca2+ with CBS showed strong binding around the sulfate and the surface of galactose facing the bilayer in the bent shovel conformation. Ca2+ binding at this surface would disrupt intra- and intermolecular hydrogen-bonding interactions of the head group, thus accounting for its effect in inducing a transition to the extended conformation.

Binding Sites↗
PubMed1996

Structurally homogeneous and heterogeneous synthetic combinatorial libraries.

We have designed and synthesized structurally homogeneous and heterogeneous nonpeptide libraries. Structurally homogeneous libraries are characterized by the presence of one common structural unit, a scaffold, in all library compounds (e.g. cyclopentane, cyclohexane, diketopiperazine, thiazolidine). In structurally heterogeneous libraries different organic reactions (acylation, etherification, reductive amination, nucleophilic displacement) were applied to connect bifunctional building blocks unrelated in structure (aromatic hydroxy acids, aromatic hydroxy aldehydes, amino alcohols, diamines, and amino acids). The focus of this communication is to document the use of bifunctional building blocks for the design and synthesis of structurally heterogeneous libraries of N-(alkoxy acyl)amino acids, N,N'-bis-(alkoxy acyl)diamino acids, N-acylamino ethers, N-(alkoxy acyl)amino alcohols, N-alkylamino ethers, and N-(alkoxy aryl)diamines.

Aldehydes↗
PubMed2003

Distribution of 3-hydroxy fatty acids in tissues after intraperitoneal injection of endotoxin.

BACKGROUND: 3-Hydroxy fatty acids (3-OH FAs) with 10- to 18-carbon chain lengths are constituents of the endotoxin [lipopolysaccharide (LPS)] of gram-negative bacteria. We investigated whether these FAs may be used as chemical markers in measuring endotoxin concentrations in mammalian tissue samples. METHODS: We used gas-liquid chromatography-tandem mass spectrometry to measure 3-OH FAs in serum and tissues (heart, liver, and skeletal muscles) of rats after intraperitoneal injection of Escherichia coli LPS. One group of rats (group I) received a single LPS dose of 20 mg/kg of body weight; group II rats received the same total dose but over the course of 10 days (2 mg/kg each day). Rats receiving saline (group III) were used as controls. RESULTS: 3-OH FAs with chain lengths of 10, 12, 14, 16, and 18 carbons were detected in all studied types of samples. Group I rats had 50-fold and group II rats had 3-fold higher serum concentrations of 3-hydoxytetradecanoic acid (3-OH 14:0, the predominant 3-OH FA of E. coli LPS) than group III rats. Concentrations of 3-OH 14:0 in livers from group I and II rats were similar and fourfold higher than in group III rats, whereas concentrations of the same acid in skeletal and heart tissues did not differ among the three groups of rats. 3-OH 14:0 dominated in heart and liver of group III rats, whereas 3-OH 16:0 (followed by 3-OH 14:0) dominated in skeletal muscles and blood. CONCLUSIONS: 3-OH FAs 10-18 carbons in length, probably originating from endotoxin and mitochondrial beta-oxidation, are abundant in rat liver, skeletal muscles, and heart and can also be detected in blood. The widespread presence of these compounds in mammals limits their usefulness as LPS markers for endotoxin in clinical samples.

Animals↗
PubMed1993

Isolation, structures, and antifungal activities of new aureobasidins.

Aureobasidins are a group of cyclic depsipeptides with antifungal activity and are produced by Aureobasidium pullulans. Aureobasidins are composed of eight amino acids and one hydroxy acid such as 2-hydroxy-3-methylpentanoic acid (Hmp), and highly lipophilic. Five new aureobasidins, S1, S2a, S2b, S3 and S4, which have higher hydrophilicity in reversed phase HPLC than the known aureobasidins A-R, were discovered in a fermentation broth of A. pullulans R106 by means of on-line liquid chromatography/mass spectrometry with electrospray ionization. We identified the structures of the compounds and studied their antifungal activities. Three of the new aureobasidins, S2b, S3 and S4, which have hydroxylated Hmp as the hydroxy acid, were highly active against Candida spp. and Cryptococcus neoformans.

Amino Acid Sequence↗
PubMed2003

[Allelopathic effect of p- and m-hydroxy-phenylacetic acid on soybean (Glycine max L.) germination].

In present work the p-hydroxy-phenylacetic acid (PHPA) and m-hydroxy-phenylacetic acid(MHPA) in rhizospheric soil solutions and decomposed root residues were detected by High Performance Liquid Chromatography (HPLC), and their effects on soybean germination at the level of 0, 30, 60, 150, 300 and 600 mg.kg-1, on melting temperature of DNA at the level of 600 mg.kg-1 and on cytoplasm protein patterns at the level of 0, 30, 150, 300 mg.kg-1 were also studied. PHPA and MHPA were detected in decomposed products of root residue and soil solutions collected from rhizosphere in which soil sickness was occurred, but not detected in soil on which soybean rotated with wheat. The standard samples of PHPA and MHPA were used for bioassay in Petri dish. The main root length and lateral root number of soybean were seriously reduced, even at the level of 30 mg.L-1. Soybean germination and root growth were retarded seriously by MHPA, in contrast with PHPA. At the level of 600 mg.kg-1, the melting temperature (Tm) of soybean DNA was increased sharply from 77 degrees C to 84.5 degrees C with PHPA, and from 77 degrees C to 88.5 degrees C with MHPA. Tm was affected markedly by MHPA, compared to PHPA, and the result was consistent with that of bioassay. The cytoplasm protein patterns of soybean leaves were obtained from SDS-PAGE, showing several low weight molecular proteins were affected, especially on 16. 1 kD and 20.2 kD. The results implied that PHPA and MHPA had allelopathic effect on soybean, and might have a role in soil-sickness of soybean.

DNA, Plant↗
PubMed1991

Estradiol induces proliferation of peroxisome-like microbodies and the production of 3-hydroxy fatty acid diesters, the female pheromones, in the uropygial glands of male and female mallards.

During the mating season the female mallards produce sex pheromones, diesters of 3-hydroxy fatty acids, in their uropygial glands. Subcellular fractionation by sucrose and Nycodenz density gradient centrifugations and electron microscopic examination of the fractions showed that diesters of 3-hydroxy acids and the enzymes that catalyze the formation and esterification of the 3-hydroxy fatty acids are located in the catalase-containing fractions, probably peroxisomes, whereas monoester synthesizing activities are located in the endoplasmic reticulum. Fatty acyl-CoA reductase that would provide fatty alcohol needed for the synthesis of monoester and diester waxes was found both in the peroxisomal and endoplasmic reticulum fraction. Upon daily intramuscular injection of estradiol into the females in the nonmating season, the short chain monoester waxes of the uropygial glands were replaced by long chain monoester waxes, and subsequently the monoester waxes were replaced by diester waxes. Injection of thyroxine with estradiol hastened the induction of the compositional changes including diester synthesis. Similar changes, including the synthesis of the female pheromones, were induced in the uropygial glands by the hormone treatment of males that do not normally produce diesters at any time during their life cycle. The structure and composition of the diesters induced by hormone treatment of both males and females were identical to those of the female pheromones produced during their mating season. Electron microscopic examination of diaminobenzidine-treated glands showed that peroxisomes proliferated in the gland of the females in the mating season and in the estradiol-treated males that produce the diesters.

Animals↗
PubMed1988

Synthesis and mutagenicity of a ring-A-aromatized bile acid, 3-hydroxy-19-nor-1,3,5(10)-cholatrien-24-oic acid.

It has been presumed that ring-A-aromatized bile acids are produced from biliary bile acids by intestinal flora and the acids thus formed participate in the large bowel carcinogenesis. One of these acids is probably 3-hydroxy-19-nor-1,3,5(10)-cholatrien-24-oic acid, judged from the literatures. Consequently, this acid was synthesized from previously prepared 3-methoxy-19-nor-1,3,5(10)-cholatrien-24-ol. The phenolic ether was successively oxidized with pyridinium chlorochromate and wet silver oxide to give 3-methoxy-19-nor-1,3,5(10)-cholatrien-24-oic acid in high yield, which, after successive treatments with methanol containing a catalytic amount of p-toluenesulfonic acid, a combination of aluminum chloride and ethanethiol, and alkali, gave the desired compound in satisfactory yield. The compound was not mutagenic in Salmonella tester strains TA 98 and TA 100, but it increased the mutagenicity of 2-aminoanthracene when both were applied to plates together. When compared with cholic, deoxycholic, and lithocholic acids, the investigated compound exhibited about two to threefold increase of mutagenicity in the latter assay.

Bile Acids and Salts↗
PubMed1982

Sensitive assay, based on hydroxy fatty acids from lipopolysaccharide lipid A, for Gram-negative bacteria in sediments.

Biochemical measures have provided insight into the biomass and community structure of sedimentary microbiota without the requirement of selection by growth or quantitative removal from the sediment grains. This study used the assay of the hydroxy fatty acids released from the lipid A of the lipopolysaccharide in sediments to provide an estimate of the gram-negative bacteria. The method was sensitive to picomolar amounts of hydroxy fatty acids. The recovery of lipopolysaccharide hydroxy fatty acids from organisms added to sediments was quantitative. The lipids were extracted from the sediments with single-phase chloroform-methanol extraction. The lipid-extraction residue was hydrolyzed in 1 N HCl, and the hydroxy fatty acids of the lipopolysaccharide were recovered in chloroform for analysis by gas-liquid chromatography. This method proved to be about fivefold more sensitive than the classical phenol-water or trichloroacetic acid methods when applied to marine sediments. By examination of the patterns of hydroxy fatty acids, it was also possible to help define the community structure of the sedimentary gram-negative bacteria.

Bacillus subtilis↗