Inhibition of the biosynthesis of isoprenoid compounds by phenolic acids in the rat brain

The incorporation of [2-14C]mevalonate into nonsaponifiable lipids by rat brain homogenates is inhibited by phenolic acids derived from tyrosine. The phenyl acids derived from phenylalanine are inhibitory only at very high concentrations compared with phenolic acids. The brain is more sensitive to inhibition by the phenolic acids than the liver. These studies indicate a possible role for phenolic acids in the impairment of cerebral sterol metabolism in phenylketonuria.

The metabolism of phenolic acids in the rat

Some of the enzyme systems in the formation of p-hydroxybenzoate from tyrosine have been studied in the rat liver in vitro. The conversion of p-hydroxycinnamate into p-hydroxybenzoate, which was found in rat liver mitochondria showed a number of differences when compared with the b-oxidation of fatty acids. Studies with p-hydroxy[U-14C]cinnamate indicated that 14CO2 was released during the formation of p-hydroxybenzoate. The formation of p-hydroxycinnamate from tyrosine of p-hydroxyphenyl-lactate could not be demonstrated in vitro. The interconversion of p-hydroxycinnamate and p-hydroxyphenylpropionate was demonstrated in rat liver mitochondria.

Effect of phenyl and phenolic acids on mevalonate-5-Phosphate decarboxylase if the brain

Phenyl and phenolic acids are known to inhibit metabolism of mevalonate in rat brain. The site of inhibition has been found to be mevalonate-5-pyrophosphate decarboxylase. Phenolic acids also inhibited mevalonate-5-phosphate kinase on preincubation. The kinetics showed that p-coumaric acid and isoferulic acid were competing with substrates, mevalonate-5-phosphate or mevalonate-5-pyre phosphate, whereas others showed an uncompetitive type of inhibition. Chlorophenoxyisobutyrate, a hypocholesterolaemic drug, had no effect on these enzymes. An improved method for the synthesis of mevalonate-5-phosphate and mevalonate-5-pyrophosphate, labeled at carbon-1, is described.

Inhibition of rat liver mevalonate pyrophosphate decarboxylase and mevalonate phosphate kinase by phenyl and phenolic compounds.

1. Mevalonate pyrophosphate decarboxylase of rat liver is inhibited by various phenyl and phenolic acids. 2. Some of the phenyl and phenolic acids also inhibited mevalonate phosphate kinase. 3. Compounds with the phenyl-vinyl structure were more effective. 4. Kinetic studies showed that some of the phenolic acids compete with the substrates, mevalonate 5-phosphate and mevalonate 5-pyrophosphate, whereas others inhibit umcompetitively. 5. Dihydroxyphenyl and trihydroxyphenyl compounds and p-chlorophenoxyisobutyrate, a hypocholesterolaemic drug, had no effect on these enzymes. 6. Of the three mevalonate-metabolizing enzymes, mevalonate pyrophosphate decarboxylase has the lowest specific activity and is probably the rate-determining step in this part of the pathway.

In praise of H2O2, the versatile ROS, and its vanadium complexes

Hydrogenperoxide (H2O2) is generated in mitochondria in aerobic cells as a minor product of electron transport, is inhibited selectively by phenolic acids (in animals) or salicylhydroxamate (in plants) and is regulated by hormones and environmental conditions. Failure to detect this activity is due to presence of H2O2-consuming reactions or inhibitors present in the reaction mixture. H2O2 has a role in metabolic regulation and signal transduction reactions. A number of enzymes and cellular activities are modified, mostly by oxidizing the protein-thiol groups, on adding H2O2 in mM concentrations. On complexing with vanadate, also occurring in traces, H2O2 forms diperoxovanadate (DPV), stable at physiological pH and resistant to degradation by catalase. DPV was found to substitute for H2O2 at concentrations orders of magnitude lower, and in presence of catalase, as a substrate for user reaction, horseradish peroxidase (HRP), and in inactivating glyceraldehyde-3-phosphate dehydrogenase. superoxide dismutase (SOD)-sensitive oxidation of NADH was found to operate as peroxovanadate cycle using traces of DPV and decameric vanadate (V-10) and reduces O-2 to peroxide (DPV in presence of free vanadate). This offers a model for respiratory burst. Diperoxovanadate reproduces several actions of H2O2 at low concentrations: enhances protein tyrosine phosphorylation, activates phospholipase D, produces smooth muscle contraction, and accelerates stress induced premature senescence (SIPS) and rounding in fibroblasts. Peroxovanadates can be useful tools in the studies on H2O2 in cellular activities and regulation.

Inhibition of the biosynthesis of sterols by phenyl and phenolic compounds in rat liver

The presence of mitochondria increased the incorporation of [2-14C]mevalonate into sterols in a cell-free system from rat liver. Various phenyl and phenolic compounds inhibited the incorporation of mevalonate when added in vitro. p-Hydroxycinnamate, a metabolite of tyrosine, was the most powerful inhibitor among the compounds tested. Catechol, resorcinol and quinol were inhibitory at high concentrations. Organic acids lacking an aromatic ring were not inhibitory. Two hypocholesterolaemic drugs, Clofibrate (α-p-chlorophenoxyisobutyrate) and Clofenapate [α,4-(p-chlorophenyl)phenoxyisobutyrate], which are known to affect some step before the formation of mevalonate in the biosynthesis of cholesterol in vivo, showed inhibition at a step beyond the formation of mevalonate in vitro. The presence of the aromatic ring and the carboxyl group in a molecule appears to be necessary for the inhibition.

Phenylboronic acids in crystal engineering: Utility of the energetically unfavorable syn,syn-conformation in co-crystal design

Phenylboronic acids can exist, in principle, in three different conformers (syn,syn; syn,anti and anti,anti) with distinct energy profiles. In their native state, these compounds prefer the energetically favored syn, anti-conformation. In molecular complexes, however, the functionality exhibits conformational diversity. In this paper we report a series of co-crystals, with N-donor compounds, prepared by a design strategy involving the synthons based on the syn, syn-conformation of the boronic acid functionality. For this purpose, we employed compounds with the 1,2-diazo fragment (alprazolam, 1H-tetrazole, acetazolamide and benzotriazole), 1,10-phenanthroline and 2,2'-bipyridine for the co-crystallization experiments. However, our study shows that the mere presence of the 1,2-diazo fragment in the coformer does not guarantee the successful formation of co-crystals with a syn, syn-conformation of the boronic acid. [GRAPHICS] The -B(OH)(2) fragment makes unsymmetrical O-H center dot center dot center dot N heterosynthons with alprazolam (ALP) and 1,10-phenanthroline (PHEN). In the co-crystals of phenylboronic acids with 1H-tetrazole (TETR) and 2,2'-bipyridine (BPY), the symmetrical boronic acid dimer is the major synthon. In the BPY complex, boronic acid forms linear chains and the pyridine compound interacts with the lateral OH of boronic acid dimers that acts as a connector, thus forming a ladder structure. In the TETR complex, each heterocycle interacts with three boronic acids. While two boronic acids interact using the phenolic group, the third molecule generates O-H center dot center dot center dot N hydrogen bonds using the extra OH group, of -B(OH)(2) fragment, left after the dimer formation. Thus, although molecules were selected retrosynthetically with the 1,2-diazo fragment or with nearby hetero-atoms to induce co-crystal formation using the syn,syn-orientation of the -B(OH)(2) functionality, co-crystal formation is in fact selective and is probably driven by energy factors. Acetazolamide (ACET) contains self-complementary functional groups and hence creates stable homosynthons. Phenylboronic acids being weak competitors fail to perturb the homosynthons and hence the components crystallize separately. Therefore, besides the availability of possible hydrogen bond acceptors in the required position and orientation, the ability of the phenyl-boronic acid to perturb the existing interactions is also a prerequisite to form co-crystals. This is illustrated in the table below. In the case of ALP, PHEN and BPY, the native structures are stabilized by weak interactions and may be influenced by the boronic acid fragment. Thus phenylboronic acids can attain co-crystals with those compounds, wherein the cyclic O-H center dot center dot center dot N hydrogen bonds are stronger than the individual homo-interactions. This can lower the lattice energy of the molecular complex as compared with the individual crystals. [GRAPHICS] Phenylboronic acids show some selectivity in the formation of co-crystals with N-heterocycles. The differences in solubility of the components fall short to provide a possible reason for the selective formation of co-crystals only with certain compounds. These compounds, being weak acids, do not follow the Delta pK(a) analysis and hence fail to provide any conclusive observation. Theoretical results show that of the three conformers possible, the syn,anti conformer is the most stable. The relative stabilities of the three conformers syn,anti,syn,syn and anti,anti are 0.0, 2.18 and 3.14 kcal/mol, respectively. The theoretical calculations corroborate the fact that only energetically favorable synthons can induce the formation of heterosynthons, as in ALP and PHEN complexes. From a theoretical and structural analysis it is seen that phenylboronic acids will form interactions with those molecules wherein the heterocyclic and acidic fragments can interrupt the homosynthons. However, the energy profile is shallow and can be perturbed easily by the presence of competing functional groups (such as OH and COOH) in the vicinity. [GRAPHICS] .

X-ray studies on crystalline complexes involving amino acids and peptides. XXXIII. Crystal structures of L- and DL-arginine complexed with oxalic acid and a comparative study of amino acid oxalic acid complexes

The DL- and L-arginine complexes of oxalic acid are made up of zwitterionic positively charged amino acid molecules and semi-oxalate ions. The dissimilar molecules aggregate into separate alternating layers in the former. The basic unit in the arginine layer is a centrosymmetric dimer, while the semi-oxalate ions form hydrogen-bonded strings in their layer. In the L-arginine complex each semi-oxalate ion is surrounded by arginine molecules and the complex can be described as an inclusion compound. The oxalic acid complexes of basic amino acids exhibit a variety of ionization states and stoichiometry. They illustrate the effect of aggregation and chirality on ionization state and stoichiometry, and that of molecular properties on aggregation. The semi-oxalate/oxalate ions tend to be planar, but large departures from planarity are possible. The amino acid aggregation in the different oxalic acid complexes do not resemble one another significantly, but the aggregation of a particular amino acid in its oxalic acid complex tends to have similarities with its aggregation in other structures. Also, semi-oxalate ions aggregate into similar strings in four of the six oxalic acid complexes. Thus, the intrinsic aggregation propensities of individual molecules tend to be retained in the complexes.

Measurement of Partition Coefficients of Substituted Benzoic Acids between Two Immiscible Solvents by Hyper-Rayleigh Scattering

We demonstrate that the hyper-Rayleigh scattering technique can be employed to measure the partition coefficient (k(p)) of a solute in a mixture of two immiscible solvents. Specifically, partition coefficients of six substituted benzoic acids in water/toluene (1:1 v/v) and water/chloroform (1:1 v/v) systems have been measured. Our values compare well with the k(p) values measured earlier by other techniques, The advantages offered by this technique are also discussed.

A soluble preparation from developing groundnut seeds (Arachis hypogaea) catalyzes de novo synthesis of long chain fatty acids

A 100,000 x g supernatant fraction prepared from developing groundnut seeds (30-35 days after flowering) catalyzed the synthesis of fatty acids from [l-14C]acetate at a rate of 120nmoles of acetate incorporated per hr per gram fresh weight of tissue. 90% of this incorporated label was associated with fatty acids. The major fatty acids formed were stearic- (77%) and palmitic acids (14%) with 4% of oleic acid. The fatty acid synthetase activity was stable when stored at 0-4 degrees C for at least fifteen days. It is concluded from these results that acetyl-coA carboxylase and all the enzymes of fatty acid synthetase from developing groundnut seeds are soluble.

Prop-2-ynyl as a protective group for carboxylic acids: A mild method for the highly selective deprotection of prop-2-ynyl esters using tetrathiomolybdate

It is shown that prop-2-ynyl esters are useful protecting groups for carboxylic acids and that they are selectively deprotected in the presence of other esters on treatment with tetrathiomolybdate under mild conditions.

Frictional response of fatty acids on steel

Self-assembled monolayers of fatty acids were formed on stainless steel by room-temperature solution deposition. The acids are covalently bound to the Surface as carboxylate in a bidentate manner. To explore the effect Of Saturation in the carbon backbone on friction in sliding tribology, we Study the response of saturated stearic acid (SA) and unsaturated linoleic acid (LA) as self-assembled monolayers using lateral force microscopy and nanotribometry and when the molecules are dispersed in hexadecane, using pin-on-disc tribometry. Over a very wide range (10 MPa-2.5 GPa) of contact pressures it is consistently demonstrated that the unsaturated linoleic acid molecules yield friction which is significantly lower than that of the saturated stearic acid. it is argued, using density functional theory predictions and XPS of slid track, that when the molecular backbone of unsaturated fatty acids are tilted and pressed strongly by a probe, in tribological contact, the high charge density of the double bond region of the backbone allows coupling with the steel Substrate. The interaction yields a low friction carboxylate soap film on the substrate. The saturated fatty acid does not show this effect.

Effect of Dietary Unsaturated Oils on the Biosynthesis of Cholesterol, and on Biliary and Fecal Excretion of Cholesterol and Bile Acids in Rats1

The aim of the present work was to investigate whether the hypocholesterolemic effect of polyunsaturated oils is due to inhibition of cholesterol synthesis or increased excretion of cholesterol and bile acids through the bile and feces of animals. Separate groups of rats were fed diets containing 10% safflower oil, coconut oil or hydrogenated vegetable oils for 30 days, after which the hepatic cholesterol and bile acid synthesis and their excretion through the bile and feces were studied. As compared to the rats in the other two groups, those given the diet containing 10% safflower oil showed markedly increased rates of bile flow and excreted through their bile and feces markedly higher amounts of cholesterol and bile acids. At the same time incorporation of [1-14C] acetate and [2-14C] mevalonate into the liver cholesterol and conversion of [4-14C] cholesterol into 14C-bile acids were also higher in the same rats. In the light of these observations it has been discussed that in the animals given polyunsaturated oils, biliary and fecal loss of cholesterol and bile acids far outweighs the activation of cholesterol synthesis and thereby effectively lowers the serum cholesterol levels.

x-ray studies on crystalline complexes involving amino-acids and peptides .10. head-to-tail sequences in the crystal-structure of l-lysine acetate

l-Lysine acetate crystallises in the monoclinic space group P21 with a = 5.411 (1), b = 7.562(1), c= l2.635(2) Å and β = 91.7(1). The crystal structure was solved by direct methods and refined to an R value of 0.049 using the full matrix least squares method. The conformation and the aggregation of lysine molecules in the structure are similar to those found in the crystal structure of l-lysine l-aspartate. A conspicuous similarity between the crystal structures of l-arginine acetate and l-lysine acetate is that in both cases the strongly basic side chain, although having the largest pK value, interacts with the weakly acidic acetate group leaving the α-amino and the α-carboxylate groups to take part in head-to-tail sequences. These structures thus indicate that electrostatic effects are strongly modulated by other factors so as to give rise to head-to-tail sequences which have earlier been shown to be an almost universal feature of amino acid aggregation in the solid state.

Studies in metal-ammonia reduction-5: Reduction and reductive methylation of some naphthoic acids

Birch reductio and reductive methylations of some substituted naphtholic acids have been examined. The factors influencing the mechanism of reduction process have been discussed. Some of the reduced naphthoic acids are useful synthons for synthesis.