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PubMed1991

Vacuolar Release of 1-(Malonylamino)cyclopropane-1-Carboxylic Acid, the Conjugated Form of the Ethylene Precursor.

The mechanisms underlying the vacuolar retention or release of 1-(malonylamino)cyclopropane-1-carboxylic acid (MACC), the conjugated form of the ethylene precursor, has been studied in grape (Vitis vinifera) cells grown in vitro using the technique of compartmental analysis of radioisotope elution. Following its accumulation in the vacuole, M[2,3-(14)C]ACC could be released from cells when the vacuolar pH was artificially lowered by external buffers from its initial value of 6.2 to below the critical pH of 5.5. Successive release and retention of vacuolar MACC could be achieved by switching the vacuolar pH from values lower and higher than 5.5. The rate constant of efflux was highly correlated with the vacuolar pH. In plant tissues having low vacuolar pH under natural conditions, e.g. apple fruits (pH 4.2) and mung bean hypocotyls (pH 5.3), an efflux of M[2,3-(14)C]ACC also occurred. Its rate constant closely corresponded to the theorical values derived from the correlation established for grape cells. Evidence is presented that the efflux proceeded by passive lipophilic membrane diffusion only when MACC was in the protonated form. In contrast to other organic anions like malic acid, the mono and diionic species could not permeate the tonoplast, thus indicating the strict dependence of MACC retention upon the ionic status of the molecule and the absence of carrier-mediated efflux.

Journal Article↗
PubMed1985

Design and synthesis of new transition-state analogue inhibitors of aspartate transcarbamylase.

Six transition-state or bisubstrate analogue inhibitors (6-11) have been designed, synthesized, and tested against aspartate transcarbamoylase (ATCase). Several of these inhibitors, 7-9, were designed as analogues of N-(phosphonoacetyl)-L-aspartate (PALA, 5a) and incorporated a tetrahedral sulfur group (-S-, -SO-, -SO2-) alpha to a phosphonic acid moiety. Synthesis of 7-9 was accomplished with a new reagent, diethyl (mercaptomethyl)phosphonate (19). Thiol addition of 19 to diethyl itaconate or other olefins proves a new general synthetic route to (thiomethyl)-phosphonate analogues of acyl phosphates or diphosphate anhydrides. Analysis of the observed inhibition kinetics with ATCase and structural modeling studies indicate that increased steric size of the sulfur moieties in the sulfide 7, sulfoxide 8, sulfone 9, and sulfonamide 10 may cause these compounds to be less potent inhibitors of Escherichia coli ATCase than N-(phosphonoacetyl)-L-aspartate (PALA, 5a). The pKa of the carbonyl groups (or S-analogue thereof) may be a key factor in determining the affinity of ATCase for inhibitor. The distance from the alpha-carbon to the phosphorus atom was judged to be a less important factor in determining the tightness of inhibitor binding since no significant change in the inhibition constant (Ki) occurred upon elimination of the alpha-methylene group in sulfide 7 to give sulfide 11. The ester analogue of PALA (5a), O-(phosphonoacetyl)-L-malic acid (6), exhibited a Ki of 2 X 10(-6) M.

Antimetabolites, Antineoplastic↗
PubMed2007

Quantitative trait loci and candidate gene mapping of aluminum tolerance in diploid alfalfa.

Aluminum (Al) toxicity in acid soils is a major limitation to the production of alfalfa (Medicago sativa subsp. sativa L.) in the USA. Developing Al-tolerant alfalfa cultivars is one approach to overcome this constraint. Accessions of wild diploid alfalfa (M. sativa subsp. coerulea) have been found to be a source of useful genes for Al tolerance. Previously, two genomic regions associated with Al tolerance were identified in this diploid species using restriction fragment length polymorphism (RFLP) markers and single marker analysis. This study was conducted to identify additional Al-tolerance quantitative trait loci (QTLs); to identify simple sequence repeat (SSR) markers that flank the previously identified QTLs; to map candidate genes associated with Al tolerance from other plant species; and to test for co-localization with mapped QTLs. A genetic linkage map was constructed using EST-SSR markers in a population of 130 BC(1)F(1) plants derived from the cross between Al-sensitive and Al-tolerant genotypes. Three putative QTLs on linkage groups LG I, LG II and LG III, explaining 38, 16 and 27% of the phenotypic variation, respectively, were identified. Six candidate gene markers designed from Medicago truncatula ESTs that showed homology to known Al-tolerance genes identified in other plant species were placed on the QTL map. A marker designed from a candidate gene involved in malic acid release mapped near a marginally significant QTL (LOD 2.83) on LG I. The SSR markers flanking these QTLs will be useful for transferring them to cultivated alfalfa via marker-assisted selection and for pyramiding Al tolerance QTLs.

Aluminum↗
PubMed2004

Perturbations of malate accumulation and the endogenous rhythms of gas exchange in the Crassulacean acid metabolism plant Kalanchoë daigremontiana: testing the tonoplast-as-oscillator model.

In continuous light, leaves of the Crassulacean acid metabolism (CAM) plant Kalanchoë daigremontiana Hamet et Perrier exhibit a circadian rhythm of CO2 uptake, stomatal conductance and leaf-internal CO2 pressure. According to a current quantitative model of CAM, the pacemaking mechanism involves periodic turgor-related tension and relaxation of the tonoplast, which determines the direction of the net flux of malate between the vacuole and the cytoplasm. Cytoplasmic malate, in turn, through its inhibitory effect on phospho enolpyruvate carboxylase, controls the rate of CO2 uptake. According to this mechanism, when the accumulation of malate is disrupted by removing CO2 from the ambient air, the induction of a phase delay with respect to an unperturbed control plant is expected. First, using the mathematical model, such phase delays were observed in numerical simulations of three scenarios of CO2 removal: (i) starting at a trough of CO2 uptake, lasting for about half a cycle (ca. 12 h in vivo); (ii) with the identical starting phase, but lasting for 1.5 cycles (ca. 36 h); and (iii) starting while CO2 increases, lasting for half a cycle again. Applying the same protocols to leaves of K. daigremontiana in vivo did not induce the predicted phase shifts, i.e. after the end of the CO2 removal the perturbed rhythm adopted nearly the same phase as that of the control plant. Second, when leaves were exposed to a nitrogen atmosphere for three nights prior to onset of continuous light to prevent malate accumulation, a small, 4-h phase advance was observed instead of a delay, again contrary to the model-based expectations. Hence, vacuolar malic acid accumulation is ruled out as the central pacemaking process. This observation is in line with our earlier suggestion [T.P. Wyka, U. Lüttge (2003) J Exp Bot 54:1471-1479] that in extended continuous light, CO2 uptake switches gradually from a CAM-like to a C3-like mechanism, with oscillations of the two CO2 uptake systems being tightly coordinated. It appears that the circadian rhythm of gas exchange in this CAM plant emerges from one or several devices that are capable of generating temporal information in a robust manner, i.e. they are protected from even severe metabolic perturbations.

Carbon Dioxide↗
PubMed1983

Relationships between Photosynthetically Active Radiation, Nocturnal Acid Accumulation, and CO(2) Uptake for a Crassulacean Acid Metabolism Plant, Opuntia ficus-indica.

The influences of photosynthetically active radiation (PAR) and water status on nocturnal Crassulacean acid metabolism (CAM) were quantitatively examined for a widely cultivated cactus, Opuntia ficus-indica (L.) Miller. When the total daily PAR was maintained at 10 moles photons per square meter per day but the instantaneous PAR level varied, the rate of nocturnal H(+) accumulation (tissue acidification) became 90% saturated near 700 micromoles per square meter per second, a PAR level typical for similar light saturation of C(3) photosynthesis. The total nocturnal H(+) accumulation and CO(2) uptake reached 90% of maximum for a total daily PAR of about 22 moles per square meter per day. Light compensation occurred near 0 moles per square meter per day for nocturnal H(+) accumulation and 4 moles per square meter per day for CO(2) uptake. Above a total daily PAR of 36 moles per square meter per day or for an instantaneous PAR of 1150 micromoles per square meter per second for more than 6 hours, the nocturnal H(+) accumulation actually decreased. This inhibition, which occurred at PAR levels just above those occurring in the field, was accompanied by a substantial decrease in chlorophyll content over a 1-week period.A minimum ratio of H(+) accumulated to CO(2) taken up of 2.5 averaged over the night occurred for a total daily PAR of 31 moles per square meter per day under wet conditions. About 2 to 6 hours into the night under such conditions, a minimum H(+)-to-CO(2) ratio of 2.0 was observed. Under progressively drier conditions, both nocturnal H(+) accumulation and CO(2) uptake decreased, but the H(+)-to-CO(2) ratio increased. A ratio of two H(+) per CO(2) is consistent with the H(+) production accompanying the conversion of starch to malic acid, and it apparently occurs for O. ficus-indica when CAM CO(2) uptake is strongly favored over respiratory activity.

Journal Article↗
PubMed1996

In vitro properties of a chitosan-bonded self-hardening paste with hydroxyapatite granules.

A new self-hardening paste was made by using a combination of chitosan, hydroxyapatite (HA) granules, ZnO, and CaO. The sol was made by dissolving 0.1 g of chitosan in a solution of 0.1 g malic acid and 2.0 mL physiological saline solution. Mixed with 0.03 g of CaO and 0.04 g of ZnO powders was 2.77 g (55 wt %) of HA granules which had a homogeneous pore distribution and a porosity of 35-48%. The size of the granules was set for 0.1-0.3 mm. Kneading and setting of the paste generated a little amount of heat (32.8 degrees C) as compared with the heat produced by polymethyl-methacrylate (PMMA) bone cement (114.5 degrees C). The pH value of chitosan-HA-hardened composite after setting was nearly equal to that of human plasma (pH 7.4), while that of PMMA bone cement maintained an acid pH of 4.7. Hydroxyapatite granules less than 0.1 mm, 0.1-0.3 mm, or 0.3-0.6 mm were set using chitosan sol. The size of the granules did not influence the compressive strength of the set chitosan-HA-hardened composite. The greatest compressive strength of chitosan-HA-hardened composite was obtained by using 55 wt % of HA granules. The strength of the chitosan-HA-hardened composite was comparable to that of the cancellous bone derived from tibial eminentia, but was considerably lower than that of the PMMA bone cement.

Bone Cements↗
PubMed1999

Total Synthesis of (+)-Gelsedine.

A novel iodide-promoted, allene-terminated cyclization of an N-acyliminium ion, a stereoselective Heck spirocyclization, and a chemoselective demethylation at the nitrogen atom of an oxindole are the key transformations in the first total synthesis of the indole alkaloid (+)-gelsedine (1). This dextrorotatory form of natural gelsedine was formed as a single enantiomer in 21 steps from (S)-malic acid.

Journal Article↗
PubMed2001

Enantiospecific synthesis of the (9S,18R)-diastereomer of the leukocyte adhesion inhibitor cyclamenol A.

Cyclamenol A is one of the very few non-carbohydrate and non-peptide natural products that inhibit leukocyte adhesion to endothelial cells. We report on the first enantioselective total synthesis of the (9S, 18R)-diastereomer of this macrocyclic polyene lactam. Key elements of the synthesis are i) the synthesis of the required chiral building blocks by employing readily accessible building blocks from the chiral pool, that is, (S)-malic acid and (R)-hydroxyisobutyric acid, ii) assembly of a linear polyene precursor by means of Wittig and Horner olefination reactions as key C-C bond-forming transformations, iii) ring closure by means of a vanadium-mediated pinacolisation reaction and iv) conversion of the generated cis-diol into a (Z)-olefin to complete the entire polyene system of the natural product. Attempts to close the macrocyclic ring by a macrolactamisation, a double Stille coupling or direct olefination in a McMurry reaction failed. Crucial to the successful completion of the synthesis was the correct orchestration of the final steps. It was necessary to first deprotect the intermediate formed after macrocycle formation and to generate the sensitive heptaene system in the last step by means of a Corey-Hopkins sequence.

Biological Factors↗
PubMedDate not supplied

Relative bioavailability of almitrine bismesylate in humans.

Bioavailability and bioequivalency studies of almitrine bismesylate from U.S. manufactured film coated, waxed, 50 mg tablets were compared in 34 normal healthy volunteers to 50 mg European film coated, waxed and unwaxed, tablets and a 0.5 per cent (w/v) oral reference solution of almitrine bismesylate in d,l malic acid. The U.S. manufactured formulations were 85.88 and 87.85 per cent of the calculated mean area under the individual concentration-time curve for almitrine bismesylate reference solution compared to 88.40 and 88.86 per cent for the waxed and unwaxed film coated European tablets, respectively. The mean peak plasma concentrations for the U.S. formulations were 176.3 ng ml-1 and 180.1 ng ml-1 compared to 196.3 and 200.1 ng ml-1 for the waxed and unwaxed European formulations, respectively. Mean time to peak plasma concentrations for the two U.S. formulations and the waxed and unwaxed European formulations were 3.22, 3.33, 3.06, and 3.26 h, respectively. In addition, the oral reference solution yielded a mean peak plasma concentration of 222.8 ng ml-1 and a mean time to peak plasma concentration of 2.68 h. Analysis of variance and multiple range comparisons (p less than 0.05) indicated that the tablet formulations were bioequivalent. The results of this study show that the U.S. formulated almitrine bismesylate tablets exceed 85 per cent relative bioavailability with respect to the oral reference solution and are bioequivalent compared to the marketed standard European tablet formulations.

Adult↗
PubMed2006

Apoptolidinone A: synthesis of the apoptolidin A aglycone.

An efficient stereocontrolled synthesis of apoptolidinone A, the aglycone of apoptolidin A is described. The synthetic strategy relies on a cross coupling between C11/C12 of a northern half (C1-C11) and a southern part (C12-C28) followed by a ring-size selective macrolactonization. Key steps for the introduction of the southern half stereocenters are a stereoselective aldol reaction, a substrate controlled dihydroxylation and a chelation-controlled Grignard/aldehyde addition. The conjugated triene of the northern half was built up successively by E-selective Wittig reactions. L-Malic acid was chosen as the chiral pool source for the C8/C9 stereocenters. The final cleavage of the silyl ethers and the conversion of the C21 methyl ketal into the hemiketal was achieved by HF.pyridine.

Hydroxylation↗
PubMed1993

Preparative and analytical separation of the zopiclone enantiomers and determination of their affinity to the benzodiazepine receptor binding site.

We report the preparative separation of rac-zopiclone using malic acid as the resolving agent. Furthermore, two different methods for the analytical determination of zopiclone enantiomers by HPLC on chiral stationary phases are described. The benzodiazepine receptor binding of the isolated enantiomers was investigated. Half-maximal inhibitory concentrations of (+)- and (-)-zopiclone were 21 or 1,130 nmol/liter, respectively, indicating a more than 50 times higher affinity of the (+)-enantiomer toward the receptor.

Animals↗
PubMed2003

Oxidative stress is generated via the mitochondrial respiratory chain during plant cell apoptosis.

BACKGROUND: We present evidence that in plant cells DNA damage induced by the topoisomerase trapping drug camptothecin induces oxidative stress via the mitochondrial respiratory chain. METHODS: Flow cytometry was used to analyse mitochondrial respiratory chain activity by simultaneous measurement of mitochondrial generation of reactive oxygen intermediates (ROI) and mitochondrial membrane potential (DeltaPsim), in live functioning sugarbeet protoplasts. The mitochondrial respiratory chain function was assessed by the addition of substrate and inhibitors to the digitonin-permeabilised protoplasts. Mitochondrial activity was also measured in protoplasts at different stages of induced apoptosis by camptothecin. RESULTS: The addition of camptothecin to sugarbeet protoplasts resulted in increased mitochondrial generation of ROI, occurring concurrently with the hyperpolarisation of the mitochondrial inner membrane. Subsequently, there was a decrease in mitochondrial-generated ROI, in association with a decrease in DeltaPsim. These camptothecin-treated digitonin-permeabilised protoplasts could be re-energised and ROI decreased by the addition of malic acid in the early stages of apoptosis induction, but not in the latter stages. There was a depolarisation of the mitochondrial inner membrane in the final stages of apoptosis. CONCLUSIONS: These results are consistent with impaired adenine nucleotide exchange across the mitochondrial membrane, suggesting that similar mechanisms regulate plant apoptosis as those described for mammalian apoptosis.

Apoptosis↗
PubMed1998

Determination of titanocene, a new drug with anticancer potential, and its metabolism in solution by capillary electrophoresis.

Titanocene dichloride is one of the most promising cancerostatica of the future: nevertheless, its high activity against several tumor cells was discovered 20 years ago. Detailed knowledge of the mechanism of hydrolysis of titanocene dichloride and its stability in the infusion liquid is a prerequisite for clinical tests and for a successful application for permission as medication. Capillary electrophoresis (CE) was used to observe the hydrolysis behavior of titanocene dichloride in aqueous solutions. The hydrolysis products were separated in a 20 mM phosphate buffer, pH 6, and in a 20 mM malic acid buffer, pH 3. Up to five hydrolysis products were obtained. A significant influence of the sample preparation (pH, isoionic additives) on the hydrolysis rate was observed. The hydrolysis products were characterized by the UV scan and the element-selective particle-induced X-ray emission (PIXE) detection technique. The results obtained correspond with the hydrolysis mechanism described in the literature. The determination of free titanocene dichloride in human plasma failed due to the high affinity of the plasma proteins for this compound.

Antineoplastic Agents↗
PubMed1990

Purification and properties of a malolactic enzyme from Leuconostoc oenos ATCC 23278.

The malolactic enzyme of Leuconostoc oenos ATCC 23278 was purified 136fold. The molecular weight was estimated at 132,000 when determined by gel filtration. The enzyme contained two identical subunits (Mw = 66,000 using sodium dodecyl sulfate gel electrophoresis). The malolactic enzyme catalyzes the NAD(+)- and Mn(+)-dependent reaction L-malate----L-lactate + CO2. The apparent Km values for malic acid, NAD+, and Mn2+ were 17 mM, 0.044 mM, and 0.017 mM, respectively. The optimal pH and the optimal temperature for activity were 5.0, and 37 degrees C, respectively and the isoelectric point was pH 4.30. L-lactate and ethanol were non-competitive inhibitors, whereas succinate, citrate, and D-tartrate showed competitive type inhibitions.

Chromatography, Gel↗
PubMed2005

Low-molecular-weight poly(alpha-methyl beta,L-malate) of microbial origin: synthesis and crystallization.

Low-molecular-weight poly(alpha-methyl beta,L-malate) made of approximately 25-30 units was prepared from microbial poly(beta,L-malic acid) by treatment with diazomethane. The thermal characterization of the polymalate methyl ester was carried out and its crystalline structure was preliminary examined. Its ability to crystallize both from solution and from the melt was comparatively evaluated.

Animals↗
PubMed1998

Effects of glutathione depletion on oxidant-induced endothelial cell injury.

Ischemia-reperfusion produces edema in vivo by disrupting endothelial cell junctional integrity. A cultured rat pulmonary artery endothelial cell (RPAEC) model was used to analyze the effects of oxidants and ischemic plasma in vitro. RPAEC cultures were treated with ischemic human plasma from transverse rectus abdominis musculocutaneous (TRAM) flaps following mastectomy or with an equal quantity of nonischemic plasma taken peripherally. Endothelial cells treated with ischemic plasma rounded and formed gaps within 5 min, then ruffled and blebbed after 10 min. Cultures treated with human nonischemic plasma had no gross morphological changes. Additionally, cultures treated with human ischemic plasma demonstrated an increase in diffusion rate of 125I-albumin across monolayers while monolayers treated with human nonischemic plasma had no increase in diffusion rate. RPAEC monolayers were treated with malic acid diethyl ester (DEM) or L-buthionine-[S, R]-sulfoximine (BSO) to decrease cellular stores of glutathione before exposure to oxidant stress. Cultures depleted of cellular glutathione stores were significantly (P < 0.05) more susceptible to 50 microM H2O2 than controls, as determined by an increase in diffusion rate of 125I-albumin across monolayers. To determine if ischemic plasma effects were mediated by oxidants, cultures were depleted of glutathione by DEM or BSO pretreatment before exposure to plasma from the ischemic hind limbs of Sprague-Dawley rats. Glutathione-depleted RPAEC monolayers were significantly (P < 0.05) and substantially (2-3 X) more susceptible to the effects of ischemic plasma than were cultures with normal glutathione levels. Glutathione depletion had no effect on cultures treated with an equal amount of nonischemic plasma from sham-operated rats. These data strongly suggest that ischemic plasma in the absence of any cellular component are able to induce an oxidant injury in endothelial cells and thereby compromise junctional integrity.

Animals↗
PubMed1989

Almitrine bismesylate disposition in the human digestive tract.

The absorption of almitrine from the upper gastrointestinal tract has been evaluated in 6 healthy volunteers by an intubation technique. Almitrine bismesylate dissolved in malic acid was introduced into the stomach after homogenization with a meal containing the marker 14C-polyethylene glycol (PEG) 4000. Unlabeled PEG 4000 was infused into the second part of duodenum throughout the experiment. Samples of the luminal content were collected every 15 min for four hours from the stomach and at the ligament of Treitz. Blood was also collected. Almitrine was neither absorbed from nor metabolized in the stomach. About 37% of the quantity of drug emptied from the stomach was absorbed from the duodenum. Almitrine was detected in plasma 50 min after ingestion of the meal and its plasma concentration-time profile reflected the cumulative gastric emptying rate. The metabolite tetrahydroxy almitrine was found in intestinal samples as soon as unchanged drug was detected in plasma. The intraluminal rate of formation of the metabolite increased with time. The results suggest hepatic metabolism of almitrine followed by rapid excretion of the metabolite in the bile.

Adult↗