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PubMed1980

[Diaplacental inhibition of fetal blood coagulation in pregnant sheep (author's transl)].

We investigated the effect of the synthetic low-molecular thrombin inhibitor 4-amidinophenyl-pyruvic acid (APPA) on the maternal and fetal coagulation at 10 far advanced in pregnancy sheep. APPA inhibits as well the maternal as by diaplacental passage the fetal hemostasis in dependence on the dosage till the incoagulability. The effect in the fetal organism occurs after a delay of some minutes and wars of a bit earlier.

Animals↗
PubMed1975

Synthesis of isosteres of p-amidinophenylpyruvic acid. Inhibitors of trypsin thrombin, and pancreatic kallikrein.

A series of amino acids, amidino acids, and amidino esters was synthesized and the compounds were evaluated for their inhibitory activity against bovine trypsin, bovine thrombin, and porcine pancreatic kallikrein and as anticoagulants. Among these compounds, ethyl 4-amidino-2-iodophenoxyacetate was found to be the most effective inhibitor of the enzymes in question, with a potency (Ki = 3.16 x 10-6 M vs. trypsin; Ki = 4.8 x 10-5 M vs. thrombin) similar to that of p-amidinophenylpyruvic acid (Ki = 6.0 x 10-6 M vs. trypsin; Ki = 2.0 x 10-5 M vs. thrombin). Ethyl 4-amidino-2-iodophenoxyacetate was also found to be the most effective in blocking the clotting activity of plasma, as indicated by significant prolongation of the partial thromboplastin time. This paper reports the synthetic methods, the enzyme inhibitory activity, and the structure-activity relationships observed.

Amidines↗
PubMed1982

Pharmacology of benzamidine-type thrombin inhibitors.

Findings on the pharmacology of derivatives of benzamidine characterized as potent competitive inhibitors of the clotting enzyme thrombin were presented including data on their toxicity. Bis-benzamidines and amidinophenylalanine amides were shown to exert pharmacodynamic effects in intact animals and isolated preparations (hypotension; influence on smooth muscle reactions to serotonin and histamine). Studies with 14C-4-amidinophenylpyruvic acid and 3H-N alpha-tosyl-(3-amidino)-phenylalanine piperidide on the pharmacokinetics in rabbits showed that benzamidine derivatives are suited, in principle, for use as anticoagulants in vivo. Pharmacokinetic properties of individual thrombin inhibitors have to be taken into account in order to reach and maintain adequate plasma levels. The antithrombotic effect of benzamidine-type thrombin inhibitors in animals experiments is directly related to their antithrombin activity.

Amidines↗
PubMed2002

Design, synthesis, and evaluation of postulated transient intermediate and substrate analogues as inhibitors of 4-hydroxyphenylpyruvate dioxygenase.

An epoxybenzoquinone, 4-hydroxyphenoxypropionic acid, and 2-hydroxy-3-phenyl-3-butenoic acid derivatives have been designed, synthesized, and evaluated for in vitro inhibition activity against 4-hydroxyphenylpyruvate dioxygenase (4-HPPD) from pig liver by the spectrophotometric enol-borate method. The biological data demonstrated that neither epoxybenzoquinone ester nor 2-hydroxy-3-phenyl-3-butenoic acid is an inhibitor of 4-HPPD. The most potent 4-HPPD inhibitor tested was 3-hydroxy-4-phenyl-2(5H)-furanone with an IC(50) value of 0.5 microM, which may serve as a lead compound for further design of more potent 4-HPPD inhibitors.

4-Hydroxyphenylpyruvate Dioxygenase↗
PubMed1989

Biochemical and developmental features of experimental phenylketonuria induced by L-ethionine in suckling rats.

Suckling rats were injected subcutaneously with doses of L-ethionine (0.1 mumole/g body wt) at intervals of 12 hr. In the latter group, phenylalanine hydroxylase was effectively inhibited in vivo resulting in hyperphenylalaninemia and phenylketonuria. Due to the well-known sex-specific differences in L-ethionine metabolism female rats were much more affected by chronic administration of L-ethionine. The underlying mechanism of enzyme inhibition by ethionine could be disturbed protein synthesis and impaired protein phosphorylation, which was suggested by pronounced decreases in ATP content in liver. In the high dosage group depletions mainly of the branched-chain amino acids and lysine occurred in serum and brain, whereas the concentrations of methionine and tryptophan were increased. Tyrosine tended to be decreased in the course of hyperphenylalaninemia. Hyperphenylalaninemia and other resulting amino acid imbalances obviously impaired brain development during the early postnatal period. Concomitantly with reductions in protein concentrations, the activity of cathepsin D, a major intralysosomal acid proteinase, was increased in brain, suggesting also higher protein catabolism in brain. Side effects of this treatment, however, were higher mortality, loss of body weight, and a general impression of delayed development, resembling a state of undernutrition to some extent. These obvious side effects of ethionine limit the usefulness of ethionine as a suitable model for classic phenylketonuria in suckling rats.

Adenosine Triphosphate↗
PubMed1978

Acid proteinase of hypothalamus. Purification, some properties, and action on somatostatin and substance P.

In a continuing study of the physiological role of protein breakdown in the hypothalamus, acid proteinase from bovine hypothalamus was purified about 1000-fold. The molecular weight of the enzyme was approximately 50,000. Masimal activity against hemoglobin was obtained at pH 3.2-3.5; serum albumin was split much more slowly. Hypothalamus acid proteinase was partially inhibited by beta-phenyl pyruvate, or benzethonium Cl, and was completely inhibited by low concentrations of pepstatin. This proteinase splits somatostatin, substance P, and analogs of substance P. The probable sites of enzyme action on these peptides were determined by the end group dansyl technique. The enzyme, most likely cathepsin D, may play an important role in the formation and breakdown of peptide hormones in the hypothalamus.

Animals↗
PubMed1996

Characterization of two new matrices for matrix-assisted laser desorption/ionization mass spectrometry.

Three structurally related compounds, 4-hydroxy-33-methoxyphenylpyruvic acid (HMPPA), indole-3 pyruvic acid (IPA), and indole-3-glyoxylic acid have been evaluated as matrix-assisted laser desorption/ionization (MALDI) matrices. HMPPA and IPA were found to be effective matrices for MALDI-MS analysis of proteins and peptides and have been characterized in this work. HMPPA was found to be a particularly good matrix for the analysis of proteins and peptides because of its tolerance towards impurities and the resulting sensitivity in MALDI-MS experiments. Analysis of model proteins and peptides, including those in biological fluid, are demonstrated.

Glyoxylates↗
PubMed2005

Phenylacetate catabolism in Rhodococcus sp. strain RHA1: a central pathway for degradation of aromatic compounds.

In gram-negative bacteria, a pathway for aerobic degradation of phenylacetic acid (PAA) that proceeds via phenylacetyl-coenzyme A (CoA) and hydrolytic ring fission plays a central role in the degradation of a range of aromatic compounds. In contrast, the PAA pathway and its role are not well characterized in gram-positive bacteria. A cluster including 13 paa genes encoding enzymes orthologous to those of gram-negative bacteria was identified on the chromosome of Rhodococcus sp. strain RHA1. These genes were transcribed during growth on PAA, with 11 of the genes apparently in an operon yielding a single transcript. Quantitative proteomic analyses revealed that at least 146 proteins were more than twice as abundant in PAA-grown cells of RHA1 than in pyruvate-grown cells. Of these proteins, 29 were identified, including 8 encoded by the paa genes. Knockout mutagenesis indicated that paaN, encoding a putative ring-opening enzyme, was essential for growth on PAA. However, paaF, encoding phenylacetyl-CoA ligase, and paaR, encoding a putative regulator, were not essential. paaN was also essential for growth of RHA1 on phenylacetaldehyde, phenylpyruvate, 4-phenylbutyrate, 2-phenylethanol, 2-phenylethylamine, and l-phenylalanine. In contrast, growth on 3-hydroxyphenylacetate, ethylbenzene, and styrene was unaffected. These results suggest that the range of substrates degraded via the PAA pathway in RHA1 is somewhat limited relative to the range in previously characterized gram-negative bacteria.

Acetaldehyde↗
PubMed1982

Inhibition of 4-hydroxyphenylpyruvate dioxygenase from Pseudomonas sp. strain P.J. 874 the enol tautomer of the substrate.

Progressive inactivation of purified 4-hydroxyphenylpyruvate dioxygenase (4-hydroxyphenylpyruvate:oxygen oxidoreductase (hydroxylating, decarboxylating), EC 1.13.11.27) from Pseudomonas sp. strain P.J. 874 by enol-4-hydroxyphenylpyruvate was initially pseudo-first-order with respect to the remaining enzymic activity, as measured with an enol-borat assay at pH 7.5 and 37 degrees C. No inhibitory product was detected. Saturation kinetics suggests formation of a reversible complex prior to an inactivation event at the active site of the enzyme. The initial concentration of enol-4-hydroxyphenylpyruvate, which gave half-maximum inactivation, varied linearly with the assay concentration of ascorbate from 30 microM at zero (extrapolated value) to 0.8 mM at 20 mM ascorbate. The limiting rate constant for the inactivation increased linearly from 0.01 to 0.02 s-1 in this interval. Inhibition by ascorbate present during preincubations was partially relieved by enol-4-hydroxyphenylpyruvate. Inhibition by 1,2-dihydroxybenzene-3,5-disulfonic acid present during preincubations was prevented by ascorbate but not reversed by enol-4-hydroxyphenylpyruvate. The reductively-activated enzyme used keto-4-hydroxyphenylpyruvate as substrate for formation of 14CO2 and homogentisate. enol-4-Hydroxyphenylpyruvate was a noncompetitive inhibitor vs. keto-4-hydroxyphenylpyruvate with an intercept inhibition constant of about 40 microM when a 14CO2 assay was used. It is suggested that interaction of enol-4-hydroxyphenylpyruvate with enzyme-bound Fe3+, formed by autooxidation, caused the substrate inhibition of 4-hydroxyphenylpyruvate dioxygenase, long known to be relieved by a variety of reductants. The possible role for the inhibition mechanism in the regulation of tyrosine catabolism in vivo is discussed.

4-Hydroxyphenylpyruvate Dioxygenase↗
PubMed1999

Modelling of factor Xa-inhibitor complexes: a computational flexible docking approach.

In order to understand the structural basis of Factor Xa (FXa) specificity, structural complexes of FXa with its synthetic inhibitors are determined using a computational docking approach. The AutoDock suite of programs is used to determine the binding modes of the synthetic inhibitors such as 3- and 4-amidinobenzylphenyl ether (ABP), amidinophenyl pyruvic acid (APPA), diamidinobenzofuranyl ethene (DABE), and DX-9065a 2-(5'-amidino-2'-benzofuranyl)-3-(7'amidino-2'-napthyl)-propionic acid (ABAP) to FXa. The synthetic inhibitors docked in the present study are different in size, nature of linkage, and properties. Two sets of simulations were carried out for synthetic inhibitors docking to FXa. In the first set of simulations, no explicit water molecules were included. In the second set of simulations two explicit solvent molecules were considered. In all the computationally predicted synthetic inhibitor complexes of FXa, the specificity pocket residue Asp-189 is involved in hydrogen bonding with the bound inhibitor. The active site water molecule WAT522 is involved in hydrogen bonding with all the bound inhibitors. The computed energies clearly discriminate the high affinity from low affinity binders.

Amidines↗
PubMed2002

3D-QSAR studies on 4-hydroxyphenylpyruvate dioxygenase inhibitors by comparative molecular field analysis (CoMFA).

A comparative molecular field analysis (CoMFA) of alkanoic acid 3-oxo-cyclohex-1-enyl ester and 2-acylcyclohexane-1,3-dione derivatives of 4-hydroxyphenylpyruvate dioxygenase inhibitors has been performed to determine the factors required for the activity of these compounds. The substrate's conformation abstracted from dynamic modeling of the enzyme-substrate complex was used to build the initial structures of the inhibitors. Satisfactory results were obtained after an all-space searching procedure, performing a leave-one out (LOO) cross-validation study with cross-validation q(2) and conventional r(2) values of 0.779 and 0.989, respectively. The results provide the tools for predicting the affinity of related compounds, and for guiding the design and synthesis of new HPPD ligands with predetermined affinities.

4-Hydroxyphenylpyruvate Dioxygenase↗
PubMed1976

A constitutive mutation in a posttranscriptional regulator gene for a phenoloxidase and proteases in Podospora anserina.

A recessive mutation in the gene mod-2 results in the synthesis at low temperatures of a phenoloxidase and an arrest of growth, reversible by beta-phenyl-pyruvic acid, a protease inhibitor. Phenoloxidase synthesis is 5-fluorouracil resistant and cycloheximade sensitive. Suppression of both cold sensitivity and phenoloxidase synthesis by common factors (higher NH4+ concentrations or mutations) suggests that the protease, suspected to be responsible for cold sensitivity, also arises from preexisting mRNA molecules. Instead of being recessive and constitutive, the mod-2 mutations is suppressive and dominant when cold sensitivity and phenoloxidases synthesis are induced as the consequence of the nonallelic gene interactions C/D, C/E, or R/V responsible for protoplasmic incompatibility. Combinations of nonallelic incompatibility systems and several mod-2 mutations lead us to hypothesize that the translational control of the above proteins depends on conformational relationships between incompatibility gene products and mod-2.

Ammonia↗
PubMed1982

Transamination and other metabolic pathways of 3,4-dihydroxyphenylpyruvic acid in rats when simultaneously administered with L-dopa.

In the rat, 3,4-dihydroxyphenylpyruvic acid (DHPPA) was shown to be transaminated to L-dopa when administered orally concomitantly with L-[3H]dopa. As much as 40% of the serum L-dopa and brain dopamine was shown to be formed via transamination. Moreover, it was shown that DHPPA also caused a so-called L-dopa-sparing effect, i.e. more administered L-dopa reached the circulation and consequently more dopamine reached its target than after administration of L-dopa alone. This effect might be due to an inhibition of the deamination of L-[3H]dopa, since in this case the equilibrium of the transamination reaction will be forced into the L-dopa-forming direction. After administration of [14C]DHPPA alone and together with L-dopa, no differences in the absorption and distribution of radioactivity were found.

Animals↗
PubMed1983

Comparative study on the antithrombotic effects of a synthetic thrombin inhibitor and of heparin in animal models.

The antithrombotic effects of the synthetic thrombin inhibitor 4-amidinophenylpyruvic acid and the naturally occurring thrombin inhibitor heparin were studied in a stasis-induced venous thrombosis model and an extracorporeal shunt model in rats. The incidence of venous thrombosis was reduced in a dose-dependent manner by both inhibitors. Thrombus size was reduced in the animals in which thrombi continued to form under treatment. The antithrombotic effect of the synthetic inhibitor was accompanied by considerable prolongation of the plasma thrombin time, whereas the effect of heparin on the thrombin time was less pronounced. The time until thrombotic occlusion of the extracorporeal arterio-venous shunt occurred was prolonged by both inhibitors in dependence upon the dose. The amount of thrombotic occluding material in the shunt was reduced and altered in composition. Synthetic thrombin inhibitors are potential antithrombotic agents whose effectivity corresponds to that of heparin.

Animals↗
PubMed1996

Elevated striatal dopamine levels following administration of D-DOPA and its alpha-keto acid metabolite DHPPA: behavioral and physiological studies in vivo in the rat.

The D stereoisomer of dihydroxyphenylalanine (D-DOPA) and its alpha-keto acid metabolite 3,4-dihydroxyphenylpyruvic acid (DHPPA) when infused into the striatum, significantly increased in vivo extracellular dopamine levels. Following D-DOPA administration, the cumulative increase in dopamine levels was 30% of the increase following L-DOPA: following DHPPA it was 11% that of L-DOPA. Rats with unilateral 6-hydroxydopamine-induced lesions of the substantia nigra demonstrated brisk contralateral turning following each compound. The turning, however, was delayed by 10-20 min and total turning was 40% less following D-DOPA and 57% less following DHPPA than it was following L-DOPA. These data indicate that exogenously administered D-DOPA can be metabolized in vivo within the brain to dopamine and suggest this may occur via a transamination pathway in which DHPPA is an intermediary metabolite. The possible relevance of these findings to the treatment of Parkinson's disease is discussed.

Animals↗
PubMed1979

[Animal experiments on the pharmacokinetics of 4-amidinophenylpyruvic acid (APPA) (author's transl)].

The pharmacokinetics of the synthetic protease inhibitor APPA was studied in rabbits. After intravenous or oral application of 1 and 10 mg of (carboxyl-14C)-4-amidinophenylpyruvic acid hydrochloride/kg to rabbits, the plasma concentration was determined over several days and the excretion in urine during 24 hours. The course of the plasma concentration curves showed no dose-dependence of the pharmacokinetic behaviour. A three-phase course of the plasma concentration curves was observed after intravenous application, the slowest phase having a half-life of about 20 h. This very slow elimination is considered to be caused by tubular re-absorption of APPA. There is neither accumulation in organs, tissues or erythrocytes nor binding with plasma proteins. The thin-layer chromatographic analysis of the plasma revealed no labelled metabolites, but only unchanged APPA. APPA, when applied orally (in the form of an aqueous solution), is absorbed by more than 80%, the maximum plasma level being reached within 2--3 h. Intravenous and oral applications at 24-h intervals result in a cumulative increase in APPA concentration in the plasma. If APPA is applied to pregnant rabbits, it passes into the fetal circulation.

Animals↗
PubMed1976

Bovine spleen cathepsin B1 and collagenolytic cathepsin. A comparative study of the properties of the two enzymes in the degradation of native collagen.

Bovine spleen cathepsin B1 and collagenolytic cathepsin were separated by chromatography on Amberlite IRC-50 and collagenolytic cathepsin was partially purified by chromatography on DEAE-Sephadex (A-50). 2. Collagenolytic cathepsin degraded insoluble tendon collagen maximally at pH 3.5 and 28 degrees C; mainly alpha-chain components were released into solution. At 28 degrees C the telopeptides in soluble skin collagen were also cleaved to yield alpha-chain components. Collagenolytic cathepsin was thus similar to cathepsin B1 in its action against native collagen, but mixtures of these two enzymes exhibited a synergistic effect. 3. The addition of thiol-blocking compounds produced similar inhibition of collagenolytic cathepsin and cathepsin B1. The enzyme responded similarly to all other compounds tested except to 6-aminohexanoic acid, when collagenolytic cathepsin was slightly activated and cathepsin B1 was almost unaffected. 4. Leupeptin, which is a structural analogue of arginine-containing synthetic substrates, inhibited collagenolytic cathepsin as effectively as cathepsin B1. Collagenolytic cathepsin was shown to retain a low residual activity against alpha-N-benzoyl-DL-arginine p-nitroanilide during purification which was equivalent to 0.2% of the activity of cathepsin B1. 5. Cathepsin B1 and collagenolytic cathepsin could not be separated by affinity chromatography on organomercurial-Sepharose 4B. The two enzymes could be resolved on DEAE-Sephadex (A-50) and by isoelectric focusing in an Ampholine pH gradient. The pI of the major cathepsin B1 isoenzyme was 4.9 and the pI of collagenolytic cathepsin was 6.4. 6. From chromatography on Sephadex G-75 (superfine grade) the molecular weights were calculated to be 26000 for cathepsin B1 and 20000 for collagenolytic cathepsin. The difference in molecular weight was confirmed by sodium dodecyl sulphate/polyacrylamide-gel electrophoresis.

2,2'-Dipyridyl↗
PubMed2005

DNA damage and repair in mammalian cells exposed to p-hydroxyphenylpyruvic acid.

Tyrosinemia type 1 (HT1) is an autosomal recessive disorder of the tyrosine metabolism in which the fumarylacetoacetate hydrolase enzyme is defective. This disease is clinically heterogeneous and a chronic and acute form is discerned. Characteristic of the chronic form is the development of cellular hepatocarcinoma. Although p-hydroxyphenylpyruvic acid (pHPPA) is used as one of the diagnostic markers of this disease, it was suggested that it is unlikely to be involved in the pathophysiology of HT1 as it is present in other disorders that does not have hepatorenal symptoms. It was the aim of this study to investigate the possible effect of pHPPA on DNA damage and repair in mammalian cells. The comet assay was used to establish the genotoxicity of pHPPA in human peripheral blood lymphocytes and isolated rat hepatocytes after their exposure to pHPPA. At first glance the damage to DNA caused by pHPPA seemed reparable in both cell types, however, after challenging the DNA repair capacity of metabolite-treated cells with treatment with H(2)O(2), a marked impairment in the DNA repair capability of these cells was observed. We suggest that the main effect of pHPPA is the long-term impairment of the DNA repair machinery rather than the direct damage to DNA and that this effect of pHPPA, together with the other characteristic metabolites, e.g., FAA and MAA, causes cellular hepatocarcinoma to develop in the chronic form of HT1.

Animals↗