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At least 613 records · Page 34Linked to original sources
PubMed1997

A stereo-inverting D-phenylglycine aminotransferase from Pseudomonas stutzeri ST-201: purification, characterization and application for D-phenylglycine synthesis.

D-phenylglycine aminotransferase (D-PhgAT) from a newly isolated soil bacterium, Pseudomonas stutzeri ST-201, was purified to electrophoretic homogeneity and characterized. The molecular weight (M(r)) of the native enzyme was estimated to be 92,000. It is composed of two subunits identical in molecular weight (M(r)) = 47,500). The isoelectric point (pI) of the native enzyme was 5.0. The enzyme catalyzed reversible transamination specific for D-phenylglycine or D-4-hydroxyphenylglycine in which 2-oxoglutarate was an exclusive amino group acceptor and was converted into L-glutamic acid. Neither the D- nor L-isomer of phenylalanine, tyrosine, alanine, valine, leucine, isoleucine or serine could serve as a substrate. The enzyme was most active at alkaline pH with maximum activity at pH 9-10. The temperature for maximum activity was 35-45 degrees C. The apparent K(m) values for D-phenylglycine and for 2-oxoglutarate at 35 degrees C, pH 9.5 were 1.1 and 2.4 mM, respectively. The enzyme activity was strongly inhibited by typical inhibitors of pyridoxal phosphate-dependent enzymes. Possible application of this enzyme for synthesis of enantiomerically pure D-phenylglycine was demonstrated.

Electrophoresis, Polyacrylamide Gel↗
PubMed2003

The role of various biomarkers in the evaluation of styrene genotoxicity.

We evaluated our data on the occupational exposure to styrene in lamination workers. The battery of parameters included markers of external and internal exposure and biomarkers of biological effects and susceptibility. DNA repair capacities have been determined in both exposed and control groups. Styrene workplace concentration significantly correlated with styrene concentration in blood, exhaled air and urinary mandelic acid. Haemoglobin and O(6)-styrene oxide (SO)-guanine DNA adducts were significantly higher in exposed subjects as compared to controls and correlated with exposure parameters. In styrene-exposed workers 1-SO-adenine DNA adducts were detected (2.6 per 10(9) dNp), while in controls these adducts were below the detection limit. 1-SO-adenine adduct levels were affected by both acute and cumulative exposure (P=0.001, F=86.0 and P=0.017, F=59.0, respectively) and associated with cytochrome P450 2E1 (CYP2E1) polymorphisms (R(2)=0.442). Mutant frequencies (MF) at the hypoxanthine-guanine phosphoribosyltransferase (HPRT) locus appeared to accumulate with exposure over time and were associated with glutathione S-transferase P1 (GSTP1) polymorphism. DNA repair capacity increased with the exposure, except for the group exposed to the highest styrene concentration. In this particular group, increased DNA repair capacity to remove oxidative DNA damage was found.

Adult↗
PubMed2002

GSTM1 polymorphism and styrene metabolism: insights from an acute accidental exposure.

Two workers were accidentally exposed to unusually high styrene concentrations (>1000 ppm) for about 30 min. In addition to the main styrene metabolites, mandelic acid (MA) and phenylglyoxylic acid (PGA), other minor metabolites, including specific mercapturic acids, (R,R)- and (S,R)-N-acetyl-S-(1-phenyl-2-hydroxyethyl)-L-cysteine [(R,R)-M1 and (S,R)-M1] and (R,R)- and (S,R)-N-acetyl-S-(2-phenyl-2-hydroxyethyl)-L-cysteine [(R,R)-M2 and (S,R)-M2], 4-vinylphenol-glucuronide and -sulfate, and phenylglycine, were determined by Liquid Chromatography Electrospray Tandem Mass Spectrometry (LC-ESI-MS/MS) in urine samples collected 12, 24, 36, 48, 75 and 99 h after the episode. The genotypes of microsomal epoxide hydrolase, glutathione-S-transferases M1-1 (GSTM1), T1-1 (GSTT1) and P1-1 (GSTP1) were characterized by PCR-based methods. The two subjects showed similar peak levels of MA and PGA, as well as 4-vinylphenol conjugates, whereas mercapturic acids were five times higher in the subject bearing the GSTM1pos than in the GSTM1null subject. Also, relative proportions of diasteroisomers of mercapturic acids were influenced by the GSTM1 polymorphism.

Accidents↗
PubMed2002

Finnish quality assurance programme for biological monitoring of organic solvents.

The FIOH quality assurance programme for organic solvents and their metabolites consists of analyses for 2,5-hexadione, phenol, mandelic acid, methylenedianiline, methylhippuric acid, trans,trans-muconic acid and trichloroacetic acid in urine, and creatinine and relative density for standardisation. Four times a year two levels of spiked urine or urine specimens collected from occupationally exposed workers are distributed to the participants in 22 countries. RSD and recovery were studied during 1997-2000. Average RSDs of all participants varied between 23 and 56% and were clearly dependent on the analytical method used and the concentration level of the samples. Since 1997 the target values have been determined in reference laboratories for five of the analytes. Lower RSDs (9-21%) and good recoveries were obtained for all analytes in these laboratories, indicating that good performance can be achieved even in the complex analyses performed in biological monitoring of exposure to industrial chemicals.

Environmental Monitoring↗
PubMed1997

Evaluation of genotoxic potential of styrene in furniture workers using unsaturated polyester resins.

Styrene is a widely used chemical, mostly in making synthetic rubber, resins, polyesters, plastics and insulators. Increasing attention has been focused on this compound since experiments using cytogenetic end-points have implicated styrene as a potential carcinogen and mutagen. In order to perform biological monitoring of genotoxic exposure to styrene monomer, we evaluated the urinary thioether (UT) excretion, and sister chromatid exchanges (SCEs) and micronuclei (MN) in peripheral lymphocytes from 53 furniture workers employed in small workplaces where polyester resin lamination processings were done and from 41 matched control subjects. The mean air concentration of styrene in the breathing zone of workers was 30.3 ppm. As a metabolic marker for styrene exposure, mandelic acid + phenylglyoxylic acid was measured in the urine and the mean value was 207 mg/g creatinine. The mean +/- SD value of UT excretions of workers was 4.43 +/- 3.42 mmol SH-/mol creatinine and also mean UT for controls was found to be a 2.75 +/- 1.78 mmol SH-/mol creatinine. The mean +/- SD/cell values of SCE frequency in peripheral lymphocytes from the workers and controls were 6.20 +/- 1.56 and 5.23 +/- 1.23, respectively. The mean +/- SD frequencies (%o) of MN in the exposed and control groups were 1.98 +/- 0.50 and 2.09 +/- 0.35, respectively. Significant effects of work-related exposure were detected in the UT excretion and SCEs analyzed in peripheral blood lymphocytes (p < 0.05 and p < 0.01, respectively). The MN frequency in lymphocytes from the styrene-exposed group did not differ from that in the controls (p > 0.05). Effect of smoking, age and duration of exposure on the genotoxicity parameters analyzed were also evaluated. In conclusion, although our data do not demonstrate a dose-response relationship, they do suggest that styrene exposure was evident and that this styrene exposure may contribute to the observed genotoxic damage in furniture workers.

Adult↗
PubMed2002

Electrochemical recognition of chiral species using quaternary ammonium binaphthyl salts.

The use of ephedrine-substituted quaternary ammonium binaphthyl salts as molecular receptors is demonstrated. The electrochemical oxidation of the receptor is affected by the binding of an analyte in solution. The binding site on the binaphthyl salt has been determined using computer modeling and confirmed using 1D and 2D NMR studies. It is shown that the sensitivity of the receptor is related to the size of the analyte. Axially chiral binaphthyl salts are shown to bind chiral analytes in a different manner and this is demonstrated using lactic and mandelic acid. The presence of a polar functional group on the analyte is also shown to have an effect on the guest-host interaction.

Journal Article↗
PubMed2004

Engineering p-hydroxyphenylpyruvate dioxygenase to a p-hydroxymandelate synthase and evidence for the proposed benzene oxide intermediate in homogentisate formation.

p-Hydroxyphenylpyruvate dioxygenase (HPD) plays a key role in the normal catabolism of tyrosine. An Fe2+/oxygen-dependent enzyme, it converts p-hydroxyphenylpyruvate into homogentisate and is part of the superfamily of alpha-ketoglutarate-dependent enzymes that couples oxidative decarboxylation of an alpha-ketoacid cofactor to oxidative modification of its substrate. In this case, the alpha-ketoacid is part of the substrate side chain. HPD shows strong homology to p-hydroxymandelate synthase (HMS), an enzyme that catalyzes the formation of p-hydroxymandelate from p-hydroxyphenylpyruvate, an early step in the biosynthesis of p-hydroxyphenylglycine, which is a nonproteinogenic amino acid incorporated into several biologically active secondary metabolites. Sequence alignment between the HPD and the HMS enzyme families and analysis of the Pseudomonas fluorescens HPD crystal structure highlighted four residues within each active site that may play roles in catalytic differentiation between the two products. We attempted to convert Streptomyces avermitilis HPD into an engineered S. avermitilis HMS by site-directed mutagenesis of these four residues individually and in combination. HPLC assay analysis of each His6-tagged mutant indicated that F337I successfully produced p-hydroxymandelate, along with homogentisate and an unknown compound. The structure of the latter was determined to be an oxepinone derived from the benzene-oxide intermediate long hypothesized in HPD catalysis.

4-Hydroxyphenylpyruvate Dioxygenase↗
PubMed2004

Mandelamide hydrolase from Pseudomonas putida: characterization of a new member of the amidase signature family.

A recently discovered enzyme in the mandelate pathway of Pseudomonas putida, mandelamide hydrolase (MAH), catalyzes the hydrolysis of mandelamide to mandelic acid and ammonia. Sequence analysis suggests that MAH is a member of the amidase signature family, which is widespread in nature and contains a novel Ser-cis-Ser-Lys catalytic triad. Here we report the expression in Escherichia coli, purification, and characterization of both wild-type and His(6)-tagged MAH. The recombinant enzyme was stable, exhibited a pH optimum of 7.8, and was able to hydrolyze both enantiomers of mandelamide with little enantiospecificity. The His-tagged variant showed no significant change in kinetic constants. Phenylacetamide was found to be the best substrate, with changes in chain length or replacement of the phenyl group producing greatly decreased values of k(cat)/K(m). As with another member of this family, fatty acid amide hydrolase, MAH has the uncommon ability to hydrolyze esters and amides at similar rates. MAH is even more unusual in that it will only hydrolyze esters and amides with little steric bulk. Ethyl and larger esters and N-ethyl and larger amides are not substrates, suggesting that the MAH active site is very sterically hindered. Mutation of each residue in the putative catalytic triad to alanine resulted in total loss of activity for S204A and K100A, while S180A exhibited a 1500-fold decrease in k(cat) and significant increases in K(m) values. Overall, the MAH data are similar to those of fatty acid amide hydrolase and support the suggestion that there are two distinct subgroups within the amidase signature family.

Amidohydrolases↗
PubMed1993

Structure-activity relationships in the trans-hexahydroindolo[4,3-ab]phenanthridine ("benzergoline") series. 2. Resolution, absolute configuration, and dopaminergic activity of the selective D1 agonist CY 208-243 and its implication for an "extended rotamer-based dopamine receptor model".

4,6,6a,7,8,12b-Hexahydroindolo[4,3-ab]phenanthridines ("benzergolines") was the first structural class of potent and selective dopamine D1 agonists lacking a catechol group. In order to determine the enantioselectivity of the 7-methyl derivative in the adenylate cyclase assay, its 5,5a-dihydro precursor was resolved and both enantiomers oxidized to the final products. The biological activity was found to reside entirely in the (-)-enantiomer, (-)-1 (CY 208-243). An X-ray study of its (-)-mandelic acid salt revealed a 6aR,12bR absolute configuration, which, in confirmation of the structure hypothesis, corresponds to that of the ergolines. Unexpectedly, an axial conformation of the N-methyl group was observed in the crystal structure. In contrast, subsequently analyzed crystals of the free base of (-)-1 revealed an equatorial conformation of the N-methyl group, which, we assume, represents the bioactive conformation. Based on the determined absolute configuration, (-)-1 could be oriented in a previously described "rotamer-based dopamine receptor model", which allowed the localization of a "subtype selectivity-inducing site" (aryl binding site at the D1 receptor, steric barrier at the D2 receptor), marked by the conformationally fixed "additional" phenyl group of the benzergoline molecule.

Adenylyl Cyclases↗
PubMed1976

Synthesis and dopaminergic activity of (+/-)-, (+)-, and (-)-2-dipropylamino-5-hydroxy-1,2,3,4-tetrahydronaphthalene.

In an effort to identify further the structural requirements for central dopamine receptor agonists, some monohydroxyl analogs of the known agonist 5,6-dihydroxy-2-dipropylamino-1,2,3,4-tetrahydronaphthalene were synthesized. They were examined for production of emesis in dogs and stereotyped behavior in rats. The most potent was 5-hydroxy-2-dipropylamino-1,2,3,4-tetrahydronaphthalene, which was more potent than apomorphine but less so than the dihydroxyl analog. The two enantiomers of the monohydroxyl analog were synthesized by conventional methods from an optically active intermediate, 2-benzylamino-5-methoxy-1,2,3,4-tetrahydronaphthalene. The resolution of this amine was performed with the aid of mandelic acid. Dopaminergic activity was found to be confined to the levo enantiomer. Requirements for both substitution and chirality in the tetralines were found to correspond closely to those known for the dopaminergic aporphines.

2-Naphthylamine↗
PubMed1997

Stereoselective synthesis and biodistribution of potent [11C]-labeled antagonists for positron emission tomography imaging of muscarinic receptors in the airways.

Quantitation of muscarinic receptors in the lungs in vivo with positron emission tomography (PET) is of clinical interest. For that purpose we decided to develop [11C]-labeled ligands with a high affinity (KD < 0.1 nM). Three quaternary muscarinic antagonists, racemic N-methylpiperidin-4-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate methiodide 1a (pKB = 10.39), its (R)-isomer 1b (pKB = 11.08), and (R,R)-quinuclidin-3-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate methiodide 2 (pKB = 11.28), were labeled by reacting [11C]CH3I with their tertiary amine precursors. The enantiomerically pure tertiary amine precursors were prepared by stereoselective synthesis starting from (R)-(-)-mandelic acid. In vitro binding assay of 1b and 2 demonstrated that both ligands bind with very high affinity to the muscarinic receptor subtypes M1, M2, and M3. They are more potent than the muscarinic antagonist (R)-N-methylquinuclidinyl benzilate ((R)-MQNB). Distribution studies with 1a, 1b, and 2 in control and atropine-treated male Wistar rats demonstrated significant specific binding (90-99% of total issue uptake) in tissues containing cholinoceptors (heart, intestine, lung, pancreas, spleen, stomach, submandibular gland). Because the tissue/plasma concentration ratios of 1b are most favorable, this ligand was used for further evaluation. Analysis of plasma samples showed a very rapid clearance (t1/2 = 0.3 min) of the radioligand 1b and a relatively slow appearance of a hydrophilic metabolite. At 15 min postinjection of 1b, analysis of heart, lungs, and liver showed that respectively 99%, 88%, and 8% of the tissue radioactivity corresponded with the parent compound. Ligand 1b appears to be an excellent candidate for PET studies of mAChR receptors in heart and lungs.

Animals↗
PubMed1996

Synthesis and biological profile of the enantiomers of [4-(4-amino-6,7-dimethoxyquinazolin-2-yl)-cis-octahydroquinoxalin- 1-yl]furan-2-ylmethanone (cyclazosin), a potent competitive alpha 1B- adrenoceptor antagonist.

The enantiomers of [4-(4-amino-6, 7-dimethoxyquinazolin-2-yl)-cis-octahydroquinoxalin-1-yl]-fu ran- 2-ylmethanone (cyclazosin, 1) were synthesized from the chiral furan-2-yl(cis-octahydroquinoxalin-1-yl)methanone [(+)-2 and (-)-2], which were obtained by resolution of the racemic amine with (S)-(+)- and (R)-(-)-mandelic acid. The binding profile of the enantiomers of 1 was assessed at alpha 1-, alpha 2-, D2, and 5-HT1A receptors as well as at native alpha 1A- and alpha 1B- and cloned alpha 1a-, alpha 1b-, and alpha 1d-adrenoceptor subtypes in comparison with prazosin, spiperone, and AH11110A. (+)-1 displayed a 40-90-fold selectivity for the alpha 1B(alpha 1b)-adrenoceptor relative to alpha 1A(alpha 1a) and alpha 1d subtypes. A significant enantioselectivity was observed at the alpha 1A(alpha 1a)-adrenoceptor and particularly at alpha 1d-adrenoceptors since (-)-1 was 11-14- and 47-fold, respectively, more potent than (+)-1. Furthermore the enantiomer (+)-1 displayed selectivities of 1100-, 19000-, and 12000-fold in binding to alpha 1b-adrenoceptors relative to alpha 2-adrenoceptors and 5-HT1A and D2 receptors. These results indicate that (+)-1, [(+)-cyclazosin] is the most potent and selective ligand for the alpha 1B-adrenoceptor subtype so far described and may be a valuable tool in the characterization of alpha 1-adrenoceptor subtypes.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed2000

Absolute configurations, predominant conformations and tautomeric structures of enantiomeric tert-butylphenylphosphine oxides

Enantiomeric tert-butylphenylphosphine oxides have been isolated via resolution of the racemate with mandelic acid and investigated by using vibrational circular dichroism (VCD). Vibrational absorption and circular dichroism spectra of dextrorotatory, levorotatory, and racemic mixture of tert-butylphenylphosphine oxide have been measured in CDCl(3) and CHCl(3) solutions in the 2000-900 cm(-)(1) region. Experimental spectra are compared with the ab initio predictions of absorption and VCD spectra obtained with density functional theory using B3LYP/6-31G basis set for different tautomeric structures and conformers of (S)-tert-butylphenylphosphine oxide. This comparison indicates that (-)-tert-butylphenylphosphine oxide is of the (S)-configuration and indicates only one tautomeric structure and one conformation predominant for tert-butylphenylphosphine oxide in CDCl(3) and CHCl(3) solutions.

Journal Article↗
PubMed2001

Capillary-scale polarimetry for flowing streams.

A micro-polarimeter with a 40 nL probe volume was configured so that it is compatible with capillary-scale flowing stream analysis. The optical configuration consists of two polarizing optics, a capillary, a laser source and a photodetector which is very simple to configure with low cost components. This unique polarimeter is based upon the interaction of a linearly polarized laser beam and a capillary tube, in this case one with an inner diameter of 250 microns. Side illumination of the tube results in a 360 degrees fan of scattered light, which contains a set of interference fringes that change in response to optically active solutes. Solutes that exhibit optical activity are quantifiable and are detected by analyzing the polarization state of the backscattered light. The ability of the instrument to make extremely sensitive optical activity measurements in flowing streams is shown by the determination of (R)-mandelic acid, with a detection limit of 66 x 10(-6) M (507 x 10(-12) g), and the non-optically active control, glycerol. Additionally, the detector was configured to minimize refractive index perturbations.

Microchemistry↗
PubMed2003

Chirality transfer during alkylation of chiral amides.

Chiral amides derived from O-methyl mandelic acid and achiral amines underwent enantioselective alpha-methylation on treatment with LTMP followed by addition of methyl iodide; chirality transfer from an undeprotonated chiral amide into an achiral enolate in a mixed aggregate is supposed to be responsible for the asymmetric induction.

Journal Article↗
PubMed1979

Choice of control groups in the appraisal of sympathetic nervous activity in essential hypertension.

1. Plasma noradrenaline concentrations were similar in normotensive and hypertensive outpatients, but were significantly lower in laboratory control subjects. 2. Standing plasma noradrenaline concentrations were similar in all three groups. 3. Urinary vanillyl mandelic acid, catecholamines and metanephrines were also similar in the normotensive and hypertensive groups. 4. Laboratory controls, possibly because of familiarity with the techniques of sphygmomanometry and blood sampling, may attain a 'basal' resting level of sympathetic nervous discharge more readily and rapidly than subjects who are unfamiliar with such procedures. 5. After orthostatic stimulation by standing for 2 min, the activity of the sympathetic nervous system, as determined by pulse rate and plasma noradrenaline concentrations, was similar in the three groups, despite the lower starting values in the laboratory staff. 6. The absence of differences in plasma noradrenaline or urinary catecholamine and metabolite concentrations does not support the hypothesis of excessive sympathetic nervous activity in essential hypertension.

Humans↗