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PubMed1985

Inhibition of chlorophyll synthesis in Hordeum vulgare by 3-amino 2,3-dihydrobenzoic acid (gabaculin).

Gabaculin (3-amino 2,3-dihydrobenzoic acid) is shown to be a very potent inhibitor of chlorophyll formation in Hordeum vulgare. Exposure of leaf segments to 30 microM gabaculin results in an 80% inhibition of chlorophyll synthesis, and this is paralleled by a decrease in carotenoid. Dual-inhibitor studies with dioxoheptanoic acid, which is an inhibitor of delta-amino-laevulinic acid dehydratase, show that gabaculin inhibits an earlier step than dioxoheptanoic acid and affects delta-amino-laevulinic acid synthesis rather than its subsequent metabolism.

Aminolevulinic Acid↗
PubMed1979

Dopamine-dependent hyperactivity in the rat following manipulation of GABA mechanisms in the region of the nucleus accumbens.

The effect of manipulation of GABA mechanisms in the region of the nucleus accumbens on dopamine-dependent locomotor hyperactivity in the rat has been studied. Two models of hyperactivity were used: (1) the injection of dopamine into the region of the nucleus accumbens in nialamide-pretreated animals and (2) the systemic administration of d-amphetamine. Both GABA and the GABA agonist 3-aminopropane sulphonic acid (3-APS) depressed hyperactivity in a dose-related manner. High concentrations of GABA (greater than 100 micrograms) were required to produce a significant effect and the response was short-lived possibly reflecting the efficient GABA inactivating mechanisms. 3-APS proved to be approximately 10 times more potent as compared to GABA in the dopamine-accumbens hyperactivity model. Conversely GABA receptor antagonism with low doses of either picrotoxin or bicuculline enhanced the mild locomotor response induced by a low dose of dopamine injected into the nucleus accumbens. However such results were difficult to evaluate fairly as higher doses of the GABA antagonists resulted in varying degrees of generalized seizures. Blockade of GABA uptake systems with cis-1, 3-aminocyclohexane carboxylic acid (ACHC), nipecotic acid or beta-alanine within the region of the nucleus accumbens produced dose-related depression of dopamine-dependent hyperactivity in both models. GABA uptake blockade (nipecotic acid) significantly enhanced the GABA-mediated depression of hyperactivity induced by bilateral injection of dopamine into the nucleus accumbens. The results demonstrate an inhibitory action of GABA and drugs facilitating GABA-ergic transmission on dopamine-dependent hyperactivity in the rat. Although open to criticisms of not being able to distinguish between true GABA effects and the results of non-specific neuronal depression the hyperactivity model underlines the potency of the GABA uptake blocking compounds and their possible potential for future clinical use.

Amino Acids↗
PubMed1983

Synthesis and separation of tritium-labeled intermediates of the shikimate pathway.

[5-3H]Shikimate (sp radioact 2000 Ci/mol) has been synthesized by reduction of the methyl ester of 5-dehydroshikimate with NaB3H4 and subsequent hydrolysis of the ester group (M. M. Leduc, P. M. Dansette, and R. G. Azerad (1970) Eur. J. Biochem. 15, 428-435). The [5-3H]shikimate has been converted enzymatically to [5-3H]chorismate and [5-3H]prephenate of similar high specific radioactivity by using a cell-free extract of Aerobacter aerogenes 62-1. In addition, a chromatographic procedure, which utilizes polyethyleneimine-cellulose thin-layer chromatograms, has been developed for the separation of intermediates along the shikimate pathway between shikimate and hydroxyphenylpyruvate or phenylpyruvate. Since the method allows quantitative measurement of tritium-labeled intermediates, it provides the basis for sensitive radioassays of the individual enzymes and allows study of the reaction flux along the overall pathway. The same intermediates can be separated on a large scale by use of a column of DEAE-Sephacel.

Chorismic Acid↗
PubMed1991

Separation and partial characterization of enzymes catalyzing delta-aminolevulinic acid formation in Synechocystis sp. PCC 6803.

Formation of the universal tetrapyrrole precursor, delta-aminolevulinic acid (ALA), from glutamate via the five-carbon pathway requires three enzymes: glutamyl-tRNA synthetase, glutamyl-tRNA reductase, and glutamate-1-semialdehyde (GSA) aminotransferase. All three enzymes were separated from extracts of the unicellular cyanobacterium Synechocystis sp. PCC 6803, and two of them, glutamyl-tRNA synthetase and GSA aminotransferase, were partially characterized. After an initial high speed centrifugation and differentiatial ammonium sulfate fractionation of cell extract, the enzymes were separated by successive affinity chromatography on Reactive Blue 2-Sepharose and 2',5'-ADP-agarose. All three enzyme fractions were required to reconstitute ALA formation from glutamate. The apparent native molecular masses of glutamyl-tRNA synthetase and GSA aminotransferase were determined by gel filtration chromatography to be 63 and 98 kDa, respectively. Neither glutamyl-tRNA synthetase nor GSA aminotransferase activity was affected by hemin concentrations up to 10 and 30 microM, respectively, and neither activity was affected by protochlorophyllide concentrations up to 2 microM. GSA aminotransferase was inhibited 50% by 0.5 microM gabaculine. The gabaculine inhibition was reversible for up to 1 h after its addition, if the gabaculine was removed by gel filtration before the enzyme was incubated with substrate. However, irreversible inactivation was obtained by preincubating the enzyme at 30 degrees C either for several hours with gabaculine alone or for a few minutes with both gabaculine and GSA. Neither pyridoxal phosphate nor pyridoxamine phosphate significantly affected the activity of GSA aminotransferase at physiologically relevant concentrations, and neither of these compounds reactivated the gabaculine-inactivated enzyme. It was noted that the presence of pyridoxamine phosphate in the ALA assay mixture produced a false positive color reaction even in the absence of enzyme.

Aldehyde Oxidoreductases↗
PubMed1985

Abscisic acid increases lipid bilayer permeability to cations as studied by phosphorus-31 NMR.

Using a 31P-NMR lanthanide shift technique, abscisic acid is shown to enhance the permeability to praeseodymium of lipid bilayers composed of 80 mol% phosphatidylcholine and 20 mol% phosphatidylethanolamine. Praeseodymium permeability is immeasurably slow in the absence of the hormone whether or not phosphatidylethanolamine is present in the bilayers. Only in the presence of abscisic acid is praeseodymium permeability observed, the effect being significantly greater when phosphatidylethanolamine is present. These results substantiate prior reports from nonelectrolyte permeability studies that abscisic acid interacts with phosphatidylethanolamine in lipid bilayers.

Abscisic Acid↗
PubMed1985

Modulation of DNA binding of glucocorticoid receptor by aurintricarboxylic acid.

Effects of aurintricarboxylic acid (ATA) were examined on the DNA binding properties of rat liver glucocorticoid-receptor complex. The DNA-cellulose binding capacity of the glucocorticoid-receptor complex was completely abolished by a pretreatment of receptor preparation with 0.1-0.5 mM ATA at 4 degrees C. The half-maximal inhibition (i.d.50) in the DNA binding of [3H]triamcinolone acetonide-receptor complex [( 3H]TARc) was observed at 130- and 40 microM ATA depending upon whether the inhibitor was added prior to or following the receptor activation. The entire DNA-cellulose bound [3H]TARc could be extracted in a concentration-dependent manner by incubation with 2-100 microns ATA. The [3H]TARc remained intact under the above conditions, the receptor in both control and ATA-treated preparations sedimented in the same region in salt-containing 5-20% sucrose gradients. The action of ATA appeared to be on the receptor and not on DNA-cellulose. The DNA-binding capacity of ATA-treated receptor preparations could be recovered upon exhaustive dialysis. The treatment with ATA did not appear to change the ionic behavior of heat activated GRc; the receptor in both control and the ATA-treated preparations showed similar elution profiles. Therefore, ATA appears to alter the binding to and dissociation of glucocorticoid-receptor complex from DNA. The use of ATA should offer a good chemical probe for analysis of the DNA binding domain(s) of the glucocorticoid receptor.

Animals↗
PubMed1988

GABA transaminase inhibitors enhance the release of endogenous GABA but decrease the release of beta-alanine evoked by electrical stimulation of slices of the rat medulla oblongata.

Slices of the rat medulla oblongata were superfused and electrically stimulated. The amount of endogenous GABA, beta-alanine and glutamate release from the slices was determined by high performance liquid chromatography with fluorometric detection. Inhibitors of GABA-transaminase (GABA-T), aminooxyacetic acid (10(-5) M), gamma-acetylenic GABA (10(-4) and 10(-3) M) and gabaculine (10(-5) M), enhanced the stimulus-evoked release of GABA and reduced that of beta-alanine, while no change was observed in the release of glutamate. These changes in amino acid release from the slices were accompanied by an increase in the content of GABA and a decrease in that of beta-alanine. The stimulus-evoked release of these amino acids was abolished by Ca2+-deprivation, in either the presence or absence of GABA-T inhibitors. These results suggest a modulatory role of GABA-T for synaptically releasable GABA and involvement of this enzyme in the synthesis of releasable beta-alanine.

4-Aminobutyrate Transaminase↗
PubMed1988

Formation of 5-aminolevulinate via glutamate-1-semialdehyde and 4,5-dioxovalerate with participation of an RNA component in Scenedesmus obliquus mutant C-2A'.

In the yellow mutant C-2A' of the unicellular green alga Scenedesmus obliquus the participation of an RNA species in the conversion of glutamate to 5-aminolevulinate is clearly demonstrated by the fact that RNAase treatment of a soluble enzyme preparation drastically decreases the formation of 5-aminolevulinate. The involvement of 4,5-dioxovalerate in the C5 pathway is demonstrated by the decrease of label in enzymatically formed 5-aminolevulinate from [14C]glutamate by providing an increased unlabelled pool of 4,5-dioxovalerate. Evidence supporting the role of glutamate-1-semialdehyde as an additional intermediate in the reaction sequence is also presented. We propose a new reaction scheme, consistent with the results reported here, for the formation of 5-aminolevulinate via the C5 pathway.

Aminolevulinic Acid↗
PubMed1988

The effect of antifibrinolytic agents on wound healing.

The effect on the tensile strength of healing wounds of 2 of the most commonly used antifibrinolytic substances, tranexamic acid and epsilon-aminocaproic acid, has been studied in white rats. 2 symmetrical linear lines were made on the dorsal skin, in 1 of which was injected 1 ml of the test solution. The incisions were closed with interrupted sutures, and after 7 days the animal was sacrificed, the wound excised and its tensile strength determined. The results showed tranexamic acid (1 ml of a solution containing 100 mg/ml) to have a positive effect on wound healing, whereas epsilon-aminocaproic acid (1 ml of a solution containing 400 mg/ml) had a negative effect. When both agents were compared in the same animal, wounds in tissue injected with tranexamic acid had a higher tensile strength than those made in tissue pre-treated with epsilon-aminocaproic acid. Even compared at the same ionic strength, similar results were obtained. It is clear from this investigation that, unlike epsilon-aminocaproic acid, tranexamic acid has a positive effect on wound healing, and that this effect is not due to the antifibrinolytic properties, as both are powerful fibrinolytic inhibitors.

Aminocaproates↗
PubMed1994

Inhibition of thermolysin and neutral endopeptidase 24.11 by a novel glutaramide derivative: X-ray structure determination of the thermolysin-inhibitor complex.

Determination of the X-ray structure of thermolysin-inhibitor complexes has proven useful in aiding our understanding of the mode of binding of inhibitors of related, physiologically important, mammalian zinc peptidases including neutral endopeptidase EC 3.4.24.11 and angiotensin-converting enzyme. Here we describe the mode of binding to crystalline thermolysin of N-[1-(2(R,S)-carboxy-4-phenylbutyl)-cyclopentylcarbonyl]-(S) -tryptophan (CCT). CCT is an analogue of both candoxatrilat, a potent inhibitor of neutral endopeptidase 24.11, and of the 5-indanyl ester prodrug candoxatril, which is under clinical evaluation as a potential therapy for congestive heart failure. CCT differs from the previously studied N-carboxyalkyl dipeptide CLT [N-(S)-(1-carboxy-3-phenylpropyl)-(S)-leucyl-(S)-tryptophan] in several important respects. It has a highly constrained gem-cyclopentyl P1' substituent and lacks the characteristic imino nitrogen substituent of CLT. The structure determination shows that, notwithstanding the conformational influence of the gem-cyclopentyl substituent, CCT binds within the active site of thermolysin in a similar manner to CLT. Although the characteristic hydrogen bond between the imino nitrogen of CLT and thermolysin is absent in CCT, the affinities of the two inhibitors for the enzyme are virtually identical. These results illustrate the importance of considering not only those hydrogen bonds that are formed in an enzyme-ligand complex but also the other hydrogen bonds that may be lost due to desolvation of the enzyme and ligand on formation of the complex. In addition, the overall conformational demands placed upon a ligand in order to achieve receptor interaction may be critically important.

Amino Acid Sequence↗
PubMed1984

The conformation of abscisic acid by n.m.r. and a revision of the proposed mechanism for cyclization during its biosynthesis.

The n.m.r. spectrum of abscisic acid (ABA) formed from [1,2-13C2]acetate by the fungus Cercospora rosicola shows 13C-13C coupling between C-6' (41.7 p.p.m.; 36 Hz) and the downfield 6'-methyl group (6'-Me) (24.3 p.p.m, 36 Hz). This 6'-Me, therefore, is derived from C-3' of mevalonate [Bennett, Norman & Maier (1981) Phytochemistry 20, 2343-2344]. An i.n.e.p.t. (insensitive nuclei enhanced by polarization transfer) pulse sequence demonstrated that the downfield 13C signal is produced by the 6'-Me that gives rise to the upfield 1H 6'-Me signal (23.1 d). The absolute configuration of this, the equatorial 6'-Me group, was determined as 6'-pro-R by decoupling and n.O.e. (nuclear-Overhauser-enhancement) experiments at 300 MHz using ABA, ABA in which the axial 6'-pro-S 5'-hydrogen atom had been exchanged with 2H in NaO2H and the 1',4'-cis- and 1',4'-trans-diols formed from these samples. The configuration at C-1' and at C-6' are now compatible with a chair-folded intermediate during cyclization, as proposed for beta- and epsilon-rings of carotenoids. ABA in solution exists, as in the crystalline form, with the ring in a pseudo-chair conformation. The side chain is axial and the C-3 Me and the C-5 hydrogen atoms are predominantly cis(Z).

Abscisic Acid↗
PubMed1988

Haem synthesis during cytochrome P-450 induction in higher plants. 5-Aminolaevulinic acid synthesis through a five-carbon pathway in Helianthus tuberosus tuber tissues aged in the dark.

Chlorophyll and haem synthesis in illuminated Jerusalem artichoke tuber tissues were very efficiently inhibited by gabaculine (3-amino-2,3-dihydrobenzoic acid). This inhibition seems to be due specifically to a blockade of the pathway for 5-aminolaevulinate biosynthesis which used glutamate as a substrate (the so-called C5 pathway) since we could not detect any inhibition of protein synthesis in the treated tissues and there was no effect of gabaculine on the glycine-dependent yeast 5-aminolaevulinate synthase used as a model. In dark-aged artichoke tissues, gabaculine also effectively blocked cytochrome P-450 induction, peroxidase activity and 5-aminolaevulinic acid synthesis, thus suggesting the involvement of a C5 pathway in cytoplasmic and microsomal haemoprotein synthesis in this higher plant. Allylglycine and (2-amino-ethyloxyvinyl)glycine, two olefinic glycine analogues which are potential suicide inhibitors of pyridoxal phosphate enzymes, were also demonstrated to be effective blockers of chlorophyll synthesis in artichoke tuber and Euglena cells exposed to light.

Allylglycine↗
PubMed1988

The effect of gabaculine on tetrapyrrole biosynthesis and heterotrophic growth in Cyanidium caldarium.

Pigment synthesis in four strains of the unicellular red alga Cyanidium caldarium with different pigment-synthesizing patterns was inhibited in the presence of gabaculine (3-amino-2,3-dihydrobenzoic acid). Parallel inhibition of light-induced chlorophyll and phycocyanin synthesis was observed in strain III-D-2, which only synthesizes pigments in the light. Similar parallel inhibition was observed in the dark in mutant CPD, which is able to synthesize chlorophyll and phycocyanin in the absence of light. Inhibition of pigment synthesis in all strains was overcome by addition of 5-aminolaevulinic acid. Inhibition of phycocyanin synthesis in mutant GGB (unable to synthesize chlorophyll) and inhibition of chlorophyll synthesis in mutant III-C (unable to synthesize phycocyanin) were also observed. Gabaculine also inhibited the heterotrophic growth of C. caldarium in the dark. However, inhibition was overcome after an extended lag period, following which cell growth proceeded at a similar rate to that of control cells not exposed to gabaculine. Heterotrophic growth in cells pre-exposed to gabaculine was not inhibited by subsequent exposure. Possible mechanisms for this adaptation are discussed.

Aminolevulinic Acid↗
PubMed1998

Hepatic zonation of the catabolism of arginine and ornithine in the perfused rat liver.

The metabolism of 14C-labelled arginine and ornithine was studied in the isolated, nonrecirculating, perfused rat liver. The catabolism of these amino acids required ornithine aminotransferase since treatment of rats with gabaculine, an inhibitor of this enzyme, decreased substantially the production of 14CO2 from the 14C-labelled amino acids. In the liver, ornithine aminotransferase is restricted to a small population of hepatocytes proximal to the terminal hepatic vein [Kuo, F.C., Hwu, W.L., Valle, D. and Darnell Jr., J.E. (1991) Proc. Natl. Acad. Sci. U.S.A. 88, 9468-9472], i.e. the perivenous subpopulation of hepatocytes. Catabolism of arginine requires arginase to convert arginine to ornithine which can then be catabolized through ornithine aminotransferase. The presence of arginase activity in the perivenous hepatocytes was demonstrated by experiments in which livers were perfused with [14C]arginine in both antegrade and retrograde directions. Identical rates of 14CO2 production were obtained in these experiments, a result which could only occur if the process of arginine catabolism through ornithine aminotransferase can be carried out in its entirety in the perivenous cells.

Animals↗