Effects of a pour-on insecticidal formulation on sheep skin.
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Determination of triplet excitation energies of cyclic enones by time-resolved photoacoustic calorimetry.
Energies and lifetimes of triplet states of a series of 2-cyclohexenones have been measured in solution under ambient conditions by time-resolved photoacoustic calorimetry (PAC). The PAC triplet lifetimes are in excellent agreement with lifetimes measured by kinetic absorption spectrophotometry (KAS) using nanosecond flash techniques, indicating that the present data indeed pertain to the enone triplets previously studied using KAS. The data demonstrate that, as previously proposed, the pi pi triplet energies in these systems are indeed correlated with triplet lifetimes, and vary sensibly with the anticipated extent of conformational flexibility of the C = C bond. No evidence supporting formation of metastable trans-cyclohexenones was obtained. The data also demonstrate greater precision and, for lifetimes, greater accuracy than has hitherto been claimed for the PAC technique for study of transients with lifetimes in the 25 ns range.
Calorimetry↗
Glucose transport inhibitors protect against 1,2-cyclohexanedione-produced potassium loss from human red blood cells.
It has been suggested that the glucose transport system of human erythrocytes contains an arginine shield to prevent the leak of potassium through the transporter. To investigate this suggestion we treated human erythrocytes with the specific arginine reagent 1,2-cyclohexanedione. Under conditions which produce a covalent reaction between arginine and the reagent, a steady leak of potassium occurs. If glucose, maltose or the inhibitor phloretin are present during the reaction the extent of the leak is reduced. These findings support the view that arginines have a role in preventing potassium loss through the glucose transporter.
Arginine↗
The effects of native and modified bovine serum albumin on the permeability of frog mesenteric capillaries.
Single capillaries in the mesenteries of pithed frogs were perfused sequentially with two frog Ringer solutions. The first solution contained no protein; the second solution contained either native or chemically modified bovine serum albumin (BSA) at a concentration of 3-5 mg ml-1. During each perfusion capillary permeability was assessed from the hydraulic conductivity of the capillary wall (Lp) which was determined from measurements of fluid filtration rate at two or more different capillary pressures (Michel, Mason, Curry, Tooke & Hunter, 1974). Lp measured during perfusion with protein-free Ringer solution was on average three times greater than its value for the same vessel perfused with Ringer solution containing native BSA. This confirms the findings of Mason, Curry & Michel (1977). BSA, which had been succinylated to modify the free amino groups of its lysine residues, appeared to be as effective as native BSA in reducing Lp. After modification of its arginine side chains by exposure to 1,2-cyclohexanedione (CHD) in the presence of 0.2 M-NaOH, BSA lost its property of reducing Lp in capillaries perfused with Ringer solution. Exposure of BSA to 0.2 M-NaOH followed by dialysis against normal Ringer solution did not affect its property of reducing Lp. CHD-treated BSA at a concentration of 2.5 mg ml-1 had no effect upon the effective osmotic pressure exerted across capillary walls by Ringer perfusates containing the neutral polymer Ficoll 70 at a concentration of 40 mg ml-1. Native BSA raised the effective osmotic pressure from 7.07 +/- 1.93 cmH2O to 20.50 +/- 2.37 cmH2O (n = 7; P less than 0.001). It is concluded that the effects of BSA on permeability depend upon specific sites in the BSA molecule. It is suggested that these sites involve positively charged arginine side chains of the albumin molecule. The results are discussed in terms of the fibre-matrix hypothesis of capillary permeability and in terms of Brown's (1976) theory for the structure of albumin.
Animals↗
Albumin stimulates uptake of calcium into subcellular stores in rat cortical astrocytes.
1. When albumin from either plasma or serum is applied at low concentrations to cortical astrocytes a decrease in the level of [Ca2+]i is observed. At higher concentrations trains of calcium spikes are seen. 2. Removal of the polar lipids which are normally bound to native albumin abolishes the ability to induce spikes, but the decrease in [Ca2+]i is unaffected. The decrease is abolished by the denaturation of albumin and is not reproduced by a number of other proteins, and is therefore a specific action of albumin. We conclude that native albumin has a dual agonist action: the decrease in [Ca2+]i is induced by the albumin protein molecule, while the spikes are induced by a lipid normally bound to it. 3. The decrease is rapid (fastest tau = 12 s) and the rate is dependent on the concentration of albumin. [Ca2+]i falls from 77 nM to around 34 nM in the presence of saturating levels of albumin, and this level appears to be maintained indefinitely. 4. The decrease is due to an uptake of calcium into subcellular stores, as it is not abolished by removal of external Ca2+ or Na+ but is abolished by thapsigargin and cyclopiazonic acid, which are specific inhibitors of the endoplasmic reticulum Ca(2+)-ATPase. 5. When the state of store filling after albumin application is probed with a pulse of glutamate it can be seen that stores fill with the same time course as the decrease in [Ca2+]i. The low level of [Ca2+]i in albumin must therefore be maintained by a suppression of calcium influx rather than by a continued uptake into stores. 6. The calcium uptake potentiates the efficacy of low concentrations of calcium-releasing agonists such as glutamate and bradykinin by almost an order of magnitude. 7. A possible function for the calcium uptake caused by albumin is to potentiate the production of calcium spike trains by promoting refilling of calcium stores in the intervals between spikes. The uptake may play a role in the response of astrocytes to damage in the CNS.
Aniline Compounds↗
Alpha 1-adrenoceptor activation of a non-selective cation current in rabbit portal vein by 1,2-diacyl-sn-glycerol.
1. The transduction mechanisms involved in the activation and modulation of the noradrenaline-activated cation current (Icat) were investigated with whole-cell patch clamp techniques in rabbit portal vein smooth muscle cells. 2. Intracellular application of guanosine 5-O-(3-thiotriphosphate) (GTP gamma S, 500 microM) evoked a 'noisy' inward current at -50 mV with a similar current-voltage relationship and reversal potential to the current evoked by bath application of noradrenaline (100 microM). Guanosine 5-O-(2-thiodiphosphate) (GDP beta S, 1 mM) markedly inhibited noradrenaline-activated Icat. 3. The phospholipase C (PLC) inhibitor U73122 inhibited the amplitude of the noradrenaline-activated Icat in a concentration- and time-dependent manner and the IC50 was about 180 nM. U73122 had similar effects on the cation current evoked by GTP gamma S. 4. Intracellular application of myo-inositol 1,4,5-trisphosphate (IP3, 100 microM) from the patch pipette did not activate any membrane current in cells where intracellular calcium concentration ([Ca2+]i) was buffered to 14 nM, but subsequent addition of noradrenaline evoked Icat. 5. Bath application of the 1,2-diacyl-sn-glycerol (DAG) analogue 1-oleoyl-2-acetyl-sn-glycerol (OAG, 10 microM) activated Icat, whereas the phorbol ester phorbol 12,13-dibutyrate (PDBu, 0.1-5 microM) failed to activate Icat, in every cell examined. Icat activated by OAG after bath application of PDBu was not significantly different from OAG-activated Icat in the absence of PDBu. The DAG lipase inhibitor RHC80267 (10 microM) activated Icat in some cells, whereas the DAG kinase inhibitor R59949 (10 microM) never activated Icat. 6. Bath application of the protein kinase C inhibitor chelerythrine (1-10 microM) had no effect on either OAG-or noradrenaline-activated Icat. 7. It is concluded that noradrenaline activates Icat via a G-protein coupled to PLC and that the resulting DAG product plays a central role in the activation of cation channels via a protein kinase C-independent mechanism.
Alkaloids↗
Biophysical and pharmacological properties of the voltage-gated potassium current of human pancreatic beta-cells.
Voltage-gated potassium (Kv) currents of human pancreatic islet cells were studied by whole-cell patch clamp recording. On average, 75% of the cells tested were identified as beta-cells by single cell, post-recording RT-PCR for insulin mRNA. In most cells, the dominant Kv current was a delayed rectifier. The delayed rectifier activated at potentials above -20 mV and had a V(1/2) for activation of -5.3 mV. Onset of inactivation was slow for a major component (tau = 3.2 s at +20 mV) observed in all cells; a smaller component (tau = 0.30 s) with an amplitude of approximately 25% was seen in some cells. Recovery from inactivation had a tau of 2.5 s at -80 mV and steady-state inactivation had a V(1/2) of -39 mV. In 12% of cells (21/182) a low-threshold, transient Kv current (A-current) was present. The A-current activated at membrane potentials above -40 mV, inactivated with a time constant of 18.5 ms at -20 mV, and had a V(1/2) for steady-state inactivation of -52 mV. TEA inhibited total Kv current with an IC50 = 0.54 mm and PAC, a disubstituted cyclohexyl Kv channel inhibitor, inhibited with an IC50 = 0.57 microm. The total Kv current was insensitive to margatoxin (100 nm), agitoxin-2 (50 nm), kaliotoxin (50 nm) and ShK (50 nm). Hanatoxin (100 nm) inhibited total Kv current by 65% at +20 mV. Taken together, these data provide evidence of at least two distinct types of Kv channels in human pancreatic beta-cells and suggest that more than one type of Kv channel may be involved in the regulation of glucose-dependent insulin secretion.
Biophysical Phenomena↗
Human TRPC6 expressed in HEK 293 cells forms non-selective cation channels with limited Ca2+ permeability.
TRPC6 is thought to be a Ca(2+)-permeable cation channel activated following stimulation of G-protein-coupled membrane receptors linked to phospholipase C (PLC). TRPC6 current is also activated by exogenous application of 1-oleoyl-acetyl-sn-glycerol (OAG) or by inhibiting 1,2-diacylglycerol (DAG) lipase activity using RHC80267. In the present study, both OAG and RHC80267 increased whole-cell TRPC6 current in cells from a human embryonic kidney cell line (HEK 293) stably expressing TRPC6, but neither compound increased cytosolic free Ca(2+) concentration ([Ca(2+)](i)) when the cells were bathed in high-K(+) buffer to hold the membrane potential near 0 mV. These results suggested that TRPC6 channels have limited Ca(2+) permeability relative to monovalent cation permeability and/or that Ca(2+) influx via TRPC6 is greatly attenuated by depolarization. To evaluate Ca(2+) permeability, TRPC6 currents were examined in extracellular buffer in which Ca(2+) was varied from 0.02 to 20 mm. The results were consistent with a pore-permeation model in which Ca(2+) acts primarily as a blocking ion and contributes only a small percentage ( approximately 4%) to whole-cell currents in the presence of extracellular Na(+). Measurement of single-cell fura-2 fluorescence during perforated-patch recording of TRPC6 currents showed that OAG increased [Ca(2+)](i) 50-100 nm when the membrane potential was clamped at between -50 and -80 mV, but had little or no effect if the membrane potential was left uncontrolled. These results suggest that in cells exhibiting a high input resistance, the primary effect of activating TRPC6 will be membrane depolarization. However, in cells able to maintain a hyperpolarized potential (e.g. cells with a large inwardly rectifying or Ca(2+)-activated K(+) current), activation of TRPC6 will lead to a sustained increase in [Ca(2+)](i). Thus, the contribution of TRPC6 current to both the kinetics and magnitude of the Ca(2+) response will be cell specific and dependent upon the complement of other channel types.
Calcium↗
Effect of P-glycoprotein on the pharmacokinetics and tissue distribution of enaminone anticonvulsants: analysis by population and physiological approaches.
Multidrug resistance (MDR), mediated by P-glycoprotein (Pgp) has been identified as altering the disposition of structurally diverse compounds. Previous in vitro studies in bovine brain microvascular endothelial cells and MCF/Adr [Adriamycin (doxorubicin)-resistant human breast cancer] cells displayed that the transport of enaminone anticonvulsants was influenced by Pgp. Therefore the objectives of this study was to further evaluate the influence of Pgp on the pharmacokinetics and tissue distribution of the enaminone analogs. mdr1ab (+/+) and mdr1ab (-/-) male mice (20 +/- 5 g) were administered DM5 (methyl 4-[(4'-chlorophenyl)amino]-6-methyl-2-oxo-3-cyclohexene-1-carboxylate) or DM44 (12.5 mg/kg, i.v.). Cohorts (n = 3) were sacrificed over a 12-h period, and samples were analyzed by a validated UV-high performance liquid chromatography assay method. Population analysis was used to estimate pharmacokinetic parameters and partition coefficients were determined for tissues. The clearance (0.51 versus 0.33 l/h/kg) and V(d) (1.25 versus 0.93 l/kg) of DM5 were found to be higher (p < 0.05), however the area under the curve (26.1 versus 38.2 microg/ml. h) was lower (p < 0.05) in mdr1a/1b (-/-) versus mdr1a/1b (+/+) mice, respectively. Similar findings were observed for DM44. Tissues known to express Pgp such as the heart, liver, lung, and brain displayed 2-fold or higher tissue levels in mdr1a/1b (-/-) versus mdr1a/1b (+/+) mice. These results strongly suggest that Pgp may influence enaminone tissue distribution and pharmacokinetics and may play a significant role in the effective treatment of epilepsy with these analogs.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
The chemistry of sexual deception in an orchid-wasp pollination system.
The "sexually deceptive" orchid Chiloglottis trapeziformis attracts males of its pollinator species, the thynnine wasp Neozeleboria cryptoides, by emitting a unique volatile compound, 2-ethyl-5-propylcyclohexan-1,3-dione, which is also produced by female wasps as a male-attracting sex pheromone.
Animals↗
Cyclohexane triones, novel membrane-active antibacterial agents.
The cyclohexane triones are a novel group of synthetic antibacterial agents that are active against gram-positive bacteria, Haemophilus influenzae, and Mycobacterium smegmatis. In general, these compounds behaved in a manner similar to that of hexachlorophene, inhibiting the transport of low-molecular-weight hydrophilic substances into bacteria. Unlike cationic detergents, such as chlorhexidine, they did not cause disruption of the bacterial cytoplasmic membrane over a short time period. The most potent antibacterial cyclohexane trione studied had a reduced ability to inhibit solute transport in comparison with certain less active analogs. Cyclohexane triones may express more than a single type of antibacterial effect.
Anti-Bacterial Agents↗
Purification and characterization of monovalent cation-activated levodione reductase from Corynebacterium aquaticum M-13.
(6R)-2,2,6-Trimethyl-1,4-cyclohexanedione (levodione) reductase was isolated from a cell extract of the soil isolate Corynebacterium aquaticum M-13. This enzyme catalyzed regio- and stereoselective reduction of levodione to (4R,6R)-4-hydroxy-2,2, 6-trimethylcyclohexanone (actinol). The relative molecular mass of the enzyme was estimated to be 142,000 Da by high-performance gel permeation chromatography and 36,000 Da by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The enzyme required NAD(+) or NADH as a cofactor, and it catalyzed reversible oxidoreduction between actinol and levodione. The enzyme was highly activated by monovalent cations, such as K(+), Na(+), and NH(4)(+). The NH(2)-terminal and partial amino acid sequences of the enzyme showed that it belongs to the short-chain alcohol dehydrogenase/reductase family. This is the first report of levodione reductase.
Amino Acid Sequence↗
Production of a doubly chiral compound, (4R,6R)-4-hydroxy-2,2,6-trimethylcyclohexanone, by two-step enzymatic asymmetric reduction.
A practical enzymatic synthesis of a doubly chiral key compound, (4R,6R)-4-hydroxy-2,2,6-trimethylcyclohexanone, starting from the readily available 2,6,6-trimethyl-2-cyclohexen-1,4-dione is described. Chirality is first introduced at the C-6 position by a stereoselective enzymatic hydrogenation of the double bond using old yellow enzyme 2 of Saccharomyces cerevisiae, expressed in Escherichia coli, as a biocatalyst. Thereafter, the carbonyl group at the C-4 position is reduced selectively and stereospecifically by levodione reductase of Corynebacterium aquaticum M-13, expressed in E. coli, to the corresponding alcohol. Commercially available glucose dehydrogenase was also used for cofactor regeneration in both steps. Using this two-step enzymatic asymmetric reduction system, 9.5 mg of (4R,6R)-4-hydroxy-2,2,6-trimethylcyclohexanone/ml was produced almost stoichiometrically, with 94% enantiomeric excess in the presence of glucose, NAD(+), and glucose dehydrogenase. To our knowledge, this is the first report of the application of S. cerevisiae old yellow enzyme for the production of a useful compound.
Cyclohexanones↗
Novel haloperoxidase from the agaric basidiomycete Agrocybe aegerita oxidizes aryl alcohols and aldehydes.
Agrocybe aegerita, a bark mulch- and wood-colonizing basidiomycete, was found to produce a peroxidase (AaP) that oxidizes aryl alcohols, such as veratryl and benzyl alcohols, into the corresponding aldehydes and then into benzoic acids. The enzyme also catalyzed the oxidation of typical peroxidase substrates, such as 2,6-dimethoxyphenol (DMP) or 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonate) (ABTS). A. aegerita peroxidase production depended on the concentration of organic nitrogen in the medium, and highest enzyme levels were detected in the presence of soybean meal. Two fractions of the enzyme, AaP I and AaP II, which had identical molecular masses (46 kDa) and isoelectric points of 4.6 to 5.4 and 4.9 to 5.6, respectively (corresponding to six different isoforms), were identified after several steps of purification, including anion- and cation-exchange chromatography. The optimum pH for the oxidation of aryl alcohols was found to be around 7, and the enzyme required relatively high concentrations of H(2)O(2) (2 mM) for optimum activity. The apparent K(m) values for ABTS, DMP, benzyl alcohol, veratryl alcohol, and H(2)O(2) were 37, 298, 1,001, 2,367 and 1,313 microM, respectively. The N-terminal amino acid sequences of the main AaP II spots blotted after two-dimensional gel electrophoresis were almost identical and exhibited almost no homology to the sequences of other peroxidases from basidiomycetes, but they shared the first three amino acids, as well as two additional amino acids, with the heme chloroperoxidase (CPO) from the ascomycete Caldariomyces fumago. This finding is consistent with the fact that AaP halogenates monochlorodimedone, the specific substrate of CPO. The existence of haloperoxidases in basidiomycetous fungi may be of general significance for the natural formation of chlorinated organic compounds in forest soils.
Agaricales↗
Transcriptome analysis of Paracoccidioides brasiliensis cells undergoing mycelium-to-yeast transition.
Paracoccidioides brasiliensis is a thermodimorphic fungus associated with paracoccidioidomycosis (PCM), a systemic mycosis prevalent in South America. In humans, infection starts by inhalation of fungal propagules, which reach the pulmonary epithelium and transform into the yeast parasitic form. Thus, the mycelium-to-yeast transition is of particular interest because conversion to yeast is essential for infection. We have used a P. brasiliensis biochip carrying sequences of 4,692 genes from this fungus to monitor gene expression at several time points of the mycelium-to-yeast morphological shift (from 5 to 120 h). The results revealed a total of 2,583 genes that displayed statistically significant modulation in at least one experimental time point. Among the identified gene homologues, some encoded enzymes involved in amino acid catabolism, signal transduction, protein synthesis, cell wall metabolism, genome structure, oxidative stress response, growth control, and development. The expression pattern of 20 genes was independently verified by real-time reverse transcription-PCR, revealing a high degree of correlation between the data obtained with the two methodologies. One gene, encoding 4-hydroxyl-phenyl pyruvate dioxygenase (4-HPPD), was highly overexpressed during the mycelium-to-yeast differentiation, and the use of NTBC [2-(2-nitro-4-trifluoromethylbenzoyl)-cyclohexane-1,3-dione], a specific inhibitor of 4-HPPD activity, as well as that of NTBC derivatives, was able to inhibit growth and differentiation of the pathogenic yeast phase of the fungus in vitro. These data set the stage for further studies involving NTBC and its derivatives as new chemotherapeutic agents against PCM and confirm the potential of array-based approaches to identify new targets for the development of alternative treatments against pathogenic microorganisms.
4-Hydroxyphenylpyruvate Dioxygenase↗
Sequence and properties of pentaerythritol tetranitrate reductase from Enterobacter cloacae PB2.
Pentaerythritol tetranitrate reductase, which reductively liberates nitrite from nitrate esters, is related to old yellow enzyme. Pentaerythritol tetranitrate reductase follows a ping-pong mechanism with competitive substrate inhibition by NADPH, is strongly inhibited by steroids, and is capable of reducing the unsaturated bond of 2-cyclohexen-1-one.
Amino Acid Sequence↗
Cloning and sequence analysis of two Pseudomonas flavoprotein xenobiotic reductases.
The genes encoding flavin mononucleotide-containing oxidoreductases, designated xenobiotic reductases, from Pseudomonas putida II-B and P. fluorescens I-C that removed nitrite from nitroglycerin (NG) by cleavage of the nitroester bond were cloned, sequenced, and characterized. The P. putida gene, xenA, encodes a 39,702-Da monomeric, NAD(P)H-dependent flavoprotein that removes either the terminal or central nitro groups from NG and that reduces 2-cyclohexen-1-one but did not readily reduce 2,4,6-trinitrotoluene (TNT). The P. fluorescens gene, xenB, encodes a 37,441-Da monomeric, NAD(P)H-dependent flavoprotein that exhibits fivefold regioselectivity for removal of the central nitro group from NG and that transforms TNT but did not readily react with 2-cyclohexen-1-one. Heterologous expression of xenA and xenB was demonstrated in Escherichia coli DH5alpha. The transcription initiation sites of both xenA and xenB were identified by primer extension analysis. BLAST analyses conducted with the P. putida xenA and the P. fluorescens xenB sequences demonstrated that these genes are similar to several other bacterial genes that encode broad-specificity flavoprotein reductases. The prokaryotic flavoprotein reductases described herein likely shared a common ancestor with old yellow enzyme of yeast, a broad-specificity enzyme which may serve a detoxification role in antioxidant defense systems.
Amino Acid Sequence↗
Peripheral neuropathy as the presenting feature of tyrosinaemia type I and effectively treated with an inhibitor of 4-hydroxyphenylpyruvate dioxygenase.
A 21 month old girl presented with a short history of frequent falls and a right sided foot drop. She went on to suffer recurrent episodes of distal weakness in her arms and legs with hyporeflexia. Electrophysiological studies were consistent with inflammatory demyelinating polyradiculoneuropathy (IDP) and treatment with corticosteroids appeared to lead to an improvement. However, the development of hypertension, evidence of tubulopathy, and hepatomegaly led to re-evaluation. A diagnosis of type I tyrosinaemia was made, based on increased urinary excretion of succinylacetone and decreased activity of fumarylacetoacetase in her cultured skin fibroblasts. A low tyrosine diet did not prevent life-threatening exacerbations of neuropathy but intravenous haemarginate appeared to aid her recovery from one exacerbation. An immediate improvement in strength was seen after starting treatment with 2-(2-nitro-4-trifluoro-methyl-benzoyl)-1,3-cyclohexanedione (NTBC), an inhibitor of 4-hydroxy-phenylpyruvate dioxygenase. A liver transplant was performed but the patient died of immediate postoperative complications. Tyrosinaemia needs to be considered in a child with recurrent peripheral neuropathy because (i) the signs of liver disease and renal tubular dysfunction may be subtle; (ii) acute exacerbations may be life threatening; (iii) specific forms of treatment are available.
4-Hydroxyphenylpyruvate Dioxygenase↗