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PubMed1975

Metabolism and properties of 3-methoxy-4-hydroxyphenyl-pyruvate; a metabolite of dihydroxyphenylalanine.

The pathway of 3,4-dihydroxyphenylalanine undergoing metabolism via transamination and subsequent oxidative rearrangement to 2,4,5-trihydroxy-phenylacetate was investigated. 3-Methoxytyrosine does not pursue an identical course, since its corresponding keto acid is not subject to action of p-hydroxy-phenylpyruvate hydroxylase. The radiochemical synthesis of 3-methoxy-4-hydroxy[carboxy-14C] pyruvate was accomplished. This metabolite was used to demonstrate that this keto acid does not proceed through oxidative rearrangement both in vitro and in vivo. The keto acid was found to be a competitive inhibitor of the hydroxylase and can help account for some of the metabolites observed in the urine of patients treated with 3,4-dihydroxyphenylalanine.

Animals↗
PubMed2004

[Compared D-amino acid oxidase expression in different Pichia pastoris host strains].

To compare the DAAO expression level in different Pichia pastoris host strains, the gene encoding DAAO from Trigonopsis variabilis was cloned into plasmid pPIC3.5k and then transformed into P. pastoris GS115 and KM71 respectively. The positive transformants PDK13 (MutS) and PD27 (Mut+) were obtained by PCR analysis. Their optimal and different expression conditions were investigated. To compare with PD27, PDK13 was determined to poss a slower consumption of methanol, a longer induction time, a lower oxygen request and apparently higher expression of DAAO. The highest expression levels were reached up to 2700, 2500 IU/L in shaking flask and 10140, 8463.5 IU/L in fermentor respectively. The over-expression of DAAO can meet its large demand for production of 7-ACA, alpha-keto acid and L-amino acid. In addition, the phenylpyruvate and L-phenylalanine were obtained by crude DAAO reacting with DL-phenylalanine at 37 degrees C for 3h.

D-Amino-Acid Oxidase↗
PubMed2005

Ketone bodies affect the enzymatic activity of macrophage migration inhibitory factor.

Macrophage migration inhibitory factor (MIF), a long known proinflammatory cytokine exhibits perplexing enzymatic activities: tautomeric conversion of D-dopachrome and phenylpyruvate. Whether these catalytic activities bear functional relevance regarding MIF's multifaceted roles is under current scrutiny. Nevertheless, intense search has already started for pharmacological agents that target MIF's tautomerase activity. We have probed several antiinflammatory compounds against keto--enol (enolase) and enol--keto (ketonase) conversion of phenylpyruvate by MIF with spectrophotometry. We have identified acidic CH groups as markers of inhibitor potency toward MIF phenylpyruvate tautomerase. Among simple model molecules with strong acidic CH groups we found acetylacetone the best inhibitor particularly against the ketonase activity. Ketones of physiological importance - ketone bodies - also feature acidic CH groups and have been reported to exert certain anti-inflammatory effects. In this paper we report that ketone bodies inhibit preferentially the ketonase activity of MIF in vitro. Future studies should address whether such an interaction might operate in vivo and delineate its possible relevance concerning cytokine and non-cytokine roles of MIF.

Enzyme Inhibitors↗
PubMed1976

Effect of hyperphenylalaninaemia on lipid synthesis from ketone bodies by rat brain.

The effect of hyperphenylalaninaemia on the metabolism of ketone bodies in vivo and in vitro by developing rat brain was investigated. The incorporation in vivo of [14C]acetoacetate into cerebral lipids was decreased by both chronic (for 3 days) and acute (for 6h) hyperphenylalaninaemia induced by injecting phenylalanine into 1-week-old rats. In studies in vitro it was observed that the incorporation of the radioactivity from [14C]acetoacetate and 3-hydroxy[14C]butyrate into cerebral lipids was inhibited by phenyl-pyruvate, but not by phenylalanine. Phenylpyruvate also inhibited the incorporation of 3H from 3H2O into lipids by brain slices metabolizing either 3-hydroxybutyrate or acetoacetate in the presence of glucose. These findings suggest that the decrease in the incorporation in vivo of [14C]acetoacetate into cerebral lipids in hyperphenylalaninaemic rats is most likely caused by phenylpyruvate and not by phenylalanine. Phenylpyruvate as well as phenylalanine had no inhibitory effects on ketone-body-catabolizing enzymes, namely 3-hydroxybutyrate dehydrogenase, 3-oxo acid CoA-transferase and acetoacetyl-CoA thiolase, in rat brain. Phenylpyruvate but not phenylalanine inhibited the activity of the 2-oxoglutarate dehydrogenase complex from rat and human brain. These findings suggest that the metabolism of ketone bodies is impaired in brains of untreated phenylketonuric patients, and in turn may contribute to the diminution of mental development and function associated with phenylketonuria.

Acetoacetates↗
PubMed1979

Aromatic aminotransferases in coryneform bacteria.

Species of coryneform bacteria (Corynebacterium glutamicum, Brevibacterium flavum, and B. ammoniagenes) are capable of transaminating all three of the aromatic pathway intermediates; prephenate, phenylpyruvate, and 4-hydroxy-phenylpyruvate. Two molecular species of aromatic aminotransferase (denoted aminotransferase I and aminotransferase II) were partially purified from C. glutamicum and B. flavum, whereas a single aromatic aminotransferase was isolated from B. ammoniagenes. In both C. glutamicum and B. flavum, aromatic aminotransferase I and aromatic aminotransferase II have molecular weights of about 155,000 and 260,000 respectively. The two aromatic aminotransferases from C. glutamicum and B. flavum, although exhibiting a similar spectrum of overlapping specificities, differ substantially in substrate preference. Pyridoxal-5'-phosphate is tightly associated with these aminotransferases, since little loss of activity was detected when partially purified enzyme preparations were assayed in the absence of exogenous pyridoxal-5'-phosphate. The aminotransferases are quite sensitive to inhibition by phenylhydrazine. This has practical application when assay of prephenate dehydratase is desired in the presence of aromatic aminotransferase activity since potentially trivial interference can be negated by selective phenylhydrazine inhibition of aromatic aminotransferase activity. At 0.1 mM concentrations of phenylhydrazine, 90% inhibitions of aminotransferase activities were achieved in partially purified preparations of B. flavum and C. glutamicum.

Brevibacterium↗
PubMed1975

Effects of alpha-ketomonocarboxylic acids upon insulin secretion and metabolism of isolated pancreatic islets.

In perifused isolated pancreatic islets alpha-ketoisocaproic acid (KIC) or alpha-ketocaproic acid (KC) induced a high insulin secretion rate and a steep increase of the fluorescence of reduced pyridine pyridine nucleotides [NAD(P)H] which fell again to almost prestimulatory levels 6 min after medium change. Insulin release in response to alpha-ketooctanoic (KO) acid started slowly and was accompanied by a decrease of the NAD(P)H-fluorescence trace. Beta-phenylpyruvate which is known to initiate insulin release also caused a fluorescence decrease. Alpha-keto-isovaleric (KIV) acid or pyruvate had no significant effects upon insulin secretion or NAD(P)H-fluorescence. In contrast to l-leucine, l-norleucine or l-valine did not enhance insulin release or fluorescence of NAD(P)H. KIV, alpha-keto-beta-methylvaleric acid (KMV), KIC and KC raised the production their corresponding amino acids by islet cells. From these results it is concluded that alpha-ketomonocarboxylic acids as such trigger insulin release by acting upon receptor sites which differ from those occupied by amino acids.

Amino Acids↗
PubMed1976

Identity of isoenzyme 1 of histidine-pyruvate aminotransferase with serine-pyruvate aminotransferase.

After glucagon injection, rats showed virtually identical percentage increases in hepatic histidine-pyruvate aminotransferase and serine-pyruvate aminotransferase activities, both in the mitochondria and in the cytosol. Histidine-pyruvate aminotransferase isoenzyme 1, with pI8.0, was purified to homogeneity from the mitochondrial fraction of liver from glucagon-injected rats. The purified enzyme catalysed transamination between a number of amino acids and pyruvate or phenylpyruvate. For transamination with pyruvate, the activity with serine reached a constant ratio to that with histidine during purification, which was unchanged by a variety of treatments of the purified enzyme. Serine was found to act as a competitive inhibitor of histidine transamination, and histidine of serine transamination. These results suggest that histidine-pyruvate amino-transferase isoenzymes 1 is identical with serine-pyruvate aminotransferase. The enzyme is probably composed of two identical subunits with mol. wt. approx. 38000. The absorbance maximum at 410 nm and the inhibition by carbonyl reagents strongly indicate the presence of pyridoxal phosphate.

Animals↗
PubMed1973

Synthesis of essential amino acids from their alpha-keto analogues by perfused rat liver and muscle.

Most essential amino acids can be replaced by their alpha-keto-analogues in the diet. These ketoacids have therefore been proposed as substitutes for dietary protein. In order to determine their fate in tissues of normal animals, isolated rat liver and hindquarter (muscle) preparations were perfused with keto-analogues of valine, leucine, isoleucine, methionine, or phenylalanine. When perfused at 1.5-2.0 mM, all five compounds were utilized rapidly by the liver of 48-h starved rats, at rates varying from 49 to 155 mumol/h per 200g rat. The corresponding amino acids appeared in the medium in significantly increased concentrations. Perfusion with phenylpyruvate also led to the appearance of tyrosine. Urea release was unaltered. Measurement of metabolite concentrations in freeze-clamped liver revealed two abnormalities, particularly at ketoacid concentrations of 5 mM or above: a large increase in alpha-ketoglutarate, and a moderate to marked decrease in tissue glutamine. This decrease was quantitatively sufficient to account for nitrogen appearing in newly synthesized amino acids. Isolated hindquarters of fed rats were perfused with the same ketoacids at concentrations of 1.3-8.0 mM. All were utilized at rates varying from 1.4 to 7.0 mumol/h per g muscle perfused. The corresponding amino acids were released at greatly increased rates. Alanine and glutamate levels fell in some perfusions, but the principal nitrogen donor in muscle was not identified; the content of glutamine in tissue, and its rate of release into the perfusate remained constant.

Acetoacetates↗
PubMed1994

Stimulatory effect of ethanol on weak organic acid uptake in rat renal tubules.

Ethanol at relatively low concentrations (10-40 mM) significantly stimulated the uphill uptake of a weak organic acid, fluorescein, in the superficial proximal tubules of rat renal cortex slices, but it did not affect the rate of glucose production from lactate or pyruvate in rat renal cortex fragment suspension. In a low Na+ medium, ethanol failed to stimulate fluorescein uptake, although under the conditions employed in the present study, the baseline weak organic acid uptake was not dependent on external Na+. The stimulation of fluorescein uptake by ethanol (20 mM) was abolished by an inhibitor of alcohol dehydrogenase (EC 1.1.1.1), pyrazole (1 mM), or an inhibitor of aldehyde dehydrogenase (EC 1.2.1.3), cyanamide (0.3 mM), suggesting that oxidation of ethanol mediated its effect on the uptake. Among gluconeogenesis inhibitors tested, only D-malate (2 mM) abolished the stimulatory effect of ethanol, while the rest either did not affect (quinolinate) or even slightly augmented (alpha-cyano-4-hydroxycinnamate and phenylpyruvate) it. The effect of ethanol was markedly increased by an inhibitor of the tricarboxylic acid cycle, fluoroacetate. It was concluded that the stimulation by ethanol of weak organic acid uptake in rat renal tubules was mediated by the production of acetate.

Alcohol Dehydrogenase↗
PubMed1984

Inhibition by L-valine and L-norleucine of 3-phenylpyruvate-induced insulin release.

Insulin release induced by 3-phenylpyruvate in isolated rat pancreatic islets was inhibited by L-valine, L-norleucine or aminooxyacetate. The inhibitory effect of these three agents coincided with a lesser stimulation by 3-phenylpyruvate of 14CO2 output from islets prelabelled with L-[U-14C] glutamine. Conversely, 3-phenylpyruvate augmented the rate of conversion of L-valine to 2-ketoisovalerate and that of L-norleucine to 2-ketocaproate. However, 3-phenylpyruvate, which increased 2-ketoisovalerate oxidative decarboxylation, inhibited 14CO2 production by islets exposed to D, L-[1-14C] norleucine. These findings reveal that distinct nutrient secretagogues (e.g. 3-phenylpyruvate and L-norleucine), which are each able to stimulate insulin release, may act antagonistically upon the secretory process when used in combination. The present results also emphasize the relevance of both mitochondrial oxidation and intracellular transfer of reducing equivalents as determinants of the secretory response to such nutrients as 3-phenylpyruvate and norleucine.

Aminocaproates↗
PubMed1992

Inhibition of chymotrypsin by fluorinated alpha-keto acid derivatives.

A series of fluorinated alpha-keto acid derivatives [PhCHFCOCO2R,PhCH2CHFCOCO2R,PhCF2-COCO2R, and PhCH2CF2COCO2R (R = H, Me, and Et)] was synthesized. They were inhibitors of chymotrypsin, with Ki values ranging from 4700 to 15 microM. Benzylpyruvic derivatives were generally more potent than the corresponding phenylpyruvic analogs. Esters of the first series were also more potent than their corresponding acids, and potency increased with the number of fluorine atoms. By replacing the ethoxy group of PhCH2CF2COCO2Et (15b) with an amino acid chain (i.e., alanyl-leucyl-arginine methyl ester hydrochloride and alanyl-leucyl-valine ethyl ester), the resultant peptides PhCH2CF2COCO-Ala-Leu-Arg-OMe.HCl.H2O (20) and PhCH2CF2COCO-Ala-Leu-Val-OEt.H2O (23) were found to be slow-binding inhibitors of chymotrypsin with considerably lower Ki values (0.19 and 3.6 microM, respectively). 19F NMR studies indicate, in the case of 20, the presence of an enzyme-inhibitor complex with a hemiketal structure similar to those observed between trifluoromethyl ketones and chymotrypsin. The results illustrate that effective protease inhibitors can be designed by enhancing the electrophilic character of the reactive carbonyl group (with an electron-withdrawing group placed on each side of the carbonyl group). Their potency and/or selectivity can also be improved by taking advantage of binding interactions at S' subsites of the protease.

Amino Acid Sequence↗
PubMed1993

Metabolism of endogenous nutrients in islets of Goto-Kakizaki (GK) rats.

The metabolism of endogenous nutrients was examined in pancreatic islets of control and Goto-Kakizaki (GK) rats. At the ultrastructural level, no glycogen was found in the islet cells of GK rats, a situation similar to that prevailing in normal islets. Likewise, by measuring the output of L-lactate from islets first incubated at 16.7 mM D-glucose and then at 2.8 mM D-glucose, no evidence of glycogenolysis was found in the islets of GK rats. The production of NH4+ and that of 14CO2 from islets prelabelled with either L-[U-14C]glutamine or [U-14C]palmitate were higher, however, in GK than in control rats. The changes in NH4+ and 14CO2 production evoked by D-glucose, by a non-metabolized analogue of L-leucine (2-amino-bicyclo[2,2,1]heptane-2-carboxylic acid; BCH) and by 3-phenylpyruvate were qualitatively comparable in control and GK rats. The secretory response to these three secretagogues was severely decreased in the islets of GK rats. This coincided with an impaired enhancing action of D-glucose on the conversion of [2-3H]glycerol into 3HOH. It is concluded that the catabolism of endogenous amino and fatty acids in islets is greater in GK than in control rats, especially at low D-glucose concentration. This may account, in part at least, for the altered secretory response to BCH and 3-phenylpyruvate. For glucose-induced insulin release, however, an impaired acceleration of the glycerol phosphate shuttle apparently also participates in the secretory defect.

Ammonia↗
PubMed1975

Effect of phenylalanine and its metabolites on the metabolism of leucocytes and lymphocytes.

1. The pathogenesis of the mental retardation in phenylketonuria remains obscure. Leucocytes have proved of value in the study of other inborn errors of metabolism. The lymphocyte is a suitable model cell for the study of mammalian metabolism, because of its ability to divide in vitro in response to various stimuli. 2. We have examined the effects of phenylalanine, phenylpyruvate, phenyl-lactate and phenylacetate on the human leucocyte and the resting and phytohaemagglutinin-stimulated rabbit lymphocyte. 3. Phenylpyruvate and phenyl-lactate reduced acetate incorporation into leucocyte lipid by 38% and 48% respectively. Only phenyl-lactate reduced acetate incorporation into the resting and stimulated lymphocyte, by 20% and 34% respectively. 4. Glucose incorporation into leucocyte lipid was unaffected by phenylalanine, phenylpyruvate and phenyl-lactate. Only phenyl-lactate inhibited (46%) the production of CO2 from glucose. 5. Phenylalanine and leucine incorporation into trichloroacetic acid-insoluble material of resting and stimulated lymphocytes was inhibited by phenyl-lactate (10-42%), phenylpyruvate (27-57%) and phenylacetate (19-39%). 6. Uridine incorporation into resting and stimulated cells was inhibited by phenyl-lactate (22-26%), phenylpyruvate (42-52%) and phenylacetate (20%). 7. Thymidine incorporation into resting lymphocytes was reduced by phenyl-lactate, phenylpyruvate, phenylacetate and phenylalanine by 12-26%. Incorporation into the stimulated cell was inhibited by phenylpyruvate and phenyl-lactate (90%) and phenylacetate (66%). 8. Phenylalanine inhibited lymphocyte pyruvate kinase and phenylpyruvate inhibited citrate synthetase. 9. These results are compared with published data relating to experimental hyperphenylalaninaemia and the effects of these metabolites on nervous tissue in vitro.

Acetates↗
PubMed1981

Mechanism of 3-phenylpyruvate-induced insulin release from isolated pancreatic islets.

3-Phenylpyruvate evoked a monophasic insulin release from perifused mouse islets. L-Phenylalanine was not an insulin secretagogue and was oxidized by islets at a very low rate, suggesting that 3-phenylpyruvate does not trigger insulin release by enhancing production of reducing equivalents. Moreover, allosteric activation of glutamate dehydrogenase does not play a role in 3-phenylpyruvate-induced insulin secretion.

Amino Acids↗