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Effect of phenylpyruvate on enzymes involved in fatty acid synthesis in rat brain.

ABSTRACT: 1. The effects of azaserine and nicotinamide, agents which inhibit and stimulate hepatic NAD synthesis respectively, on the content of NAD(+) and NADH in isolated rat islets of Langerhans incubated in vitro were studied. The effects of these compounds on the rates of insulin release, from isolated islets incubated in vitro, in response to various secretagogues were also measured. 2. Preincubation of islets in the presence of azaserine (0.3mm) caused a marked depletion of the normal islet-cell content of both NAD(+) and NADH and prevented the secretion of insulin in response to stimulatory concentrations of d-glucose, xylitol, d-xylulose, l-arginine hydrochloride and l-leucine. 3. Preincubation of islets in the presence of nicotinamide (2mm) increased the islet content of NAD(+) and enhanced the rate of release of insulin in response to d-glucose. Also when nicotinamide was present the inhibitory effect of azaserine on insulin release and the azaserine-induced depletion of the islet content of NAD(+) and NADH was prevented. 4. Preincubation with azaserine was without effect on the stimulation of insulin release caused by theophylline or dibutyryl cyclic AMP. 5. It is suggested that insulin release caused by sugars and amino acids is dependent on the maintenance of NAD concentrations, though this may not be the case for release due to theophylline and dibutyryl cyclic AMP.

SUBMITTER: Deery DJ

PROVIDER: S-EPMC1177843 | biostudies-other | 1973 Jun

REPOSITORIES: biostudies-other

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Effect of phenylpyruvate on enzymes involved in fatty acid synthesis in rat brain.

Project description:1. The activities of, and the effects of phenylpyruvate on, citrate synthase (EC 4.1.3.7), acetyl-CoA carboxylase (EC 6.4.1.2) and fatty acid synthetase derived from the brains of 14-day-old and adult rats were investigated. 2. The brain citrate synthase from 14-day-old rats had a K(m) for oxaloacetate of 2.38mum and for acetyl-CoA of 16.9mum, and a V(max.) of 838nmol of acetyl-CoA incorporation/min per mg of mitochondrial protein. From adult rat brain this enzyme had a K(m) for oxaloacetate of 2.5mum and for acetyl-CoA of 16.6mum and a V(max.) of 1070nmol of acetyl-CoA incorporated/min per mg of mitochondrial protein. Phenylpyruvate inhibited the enzyme from adult and young rat brains in a competitive fashion with respect to acetyl-CoA, with a K(i) of 700mum. 3. The brain acetyl-CoA carboxylase from 14-day-old rats had a K(m) for acetyl-CoA of 21mum and a V(max.) of 0.248nmol/min per mg of protein, and from adult rats a K(m) for acetyl-CoA of 21mum and a V(max.) of 0.173nmol/min per mg of protein. The enzyme from young and adult rats required citrate (K(a)=3mm) for activation and were inhibited non-competitively by phenylpyruvate, with a K(i) of 10mm. 4. The brain fatty acid synthetase from 14-day-old rats had a K(m) for acetyl-CoA of 7.58mum and a V(max.) of 1.1 nmol of malonyl-CoA incorporated/min per mg of protein, and from adult rats a K(m) for acetyl-CoA of 4.9mum and a V(max.) of 0.48nmol of malonyl-CoA incorporated/min per mg of protein. Phenylpyruvate acted as a competitive inhibitor with respect to acetyl-CoA with a K(i) of 250mum for the enzyme from 14-day-old rats. 5. These results are discussed with respect to phenylketonuria, and it is suggested that the inhibition of the brain fatty acid synthetase and possibly the citrate synthetase by phenylpyruvate could explain the defective myelination characteristic of this condition.

| S-EPMC1177842 | biostudies-other

The effect of phenylpyruvate on pyruvate metabolism in rat brain.

Project description:1. The effect of phenylalanine and phenylpyruvate on the metabolism of pyruvate by isolated mitochondria from rat brain was investigated. 2. Phenylpyruvate inhibited the fixation of H(14)CO(3) (-) in the presence of pyruvate by intact rat brain mitochondria, whereas phenylalanine and other metabolites of this amino acid had no inhibitory effect on this process. 3. Pyruvate carboxylase activity in freeze-dried rat brain mitochondrial preparations was also inhibited only by phenylpyruvate, and a ;mixed type' inhibition was observed. 4. The K(m) for pyruvate of rat brain pyruvate carboxylase was about 0.2mm. 5. The concentration of phenylpyruvate required for a 50% inhibition of H(14)CO(3) (-) fixation by the intact mitochondria and of pyruvate carboxylase activity was dependent on the concentration of pyruvate used in the incubation medium. 6. The possible significance of inhibition of pyruvate carboxylase activity by phenylpyruvate in the brains of phenylketonuric patients is discussed.

| S-EPMC1173818 | biostudies-other

Expression of genes and localization of enzymes involved in polyunsaturated fatty acid synthesis in rabbit testis and epididymis.

Project description:The metabolism of polyunsaturated fatty acids (PUFAs) plays an important role in male reproduction. Linoleic and alpha-linolenic acids need to be provided in the diet and they are converted into long chain polyunsaturated fatty acids by steps of elongation and desaturation, exerted by elongases 2 (ELOVL2) and 5 (ELOVL5) and Δ5- (FADS1) and Δ6-desaturase (FADS2). This study aims to assess the gene expression and localization of enzymes involved in the synthesis of n-3 and n-6 long-chain PUFAs in control rabbits and those fed diets containing 10% extruded flaxseed. Enzyme and PUFA localization were assessed in the testes and epididymis by immunofluorescence. Testes showed high gene expression of FADS2, ELOVL2 and ELOVL5 and low expression of FADS1. Intermediate metabolites, enzymes and final products were differently found in Leydig, Sertoli and germinal cells. FADS2 was localized in interstitial cells and elongated spermatids; ELOVL5 in meiotic cells; FADS1 was evident in interstitial tissue, Sertoli cells and elongated spermatids; ELOVL2 in interstitial cells. Epididymal vesicles were positive for FADS1, ELOVL2 and ELOVL5 as well as docosahexaenoic, eicosapentaenoic, and arachidonic acids. This knowledge of fatty acids (FA) metabolism in spermatogenesis and the influence of diet on FA profile could help identify causes of male infertility, suggesting new personalized therapy.

| S-EPMC8850619 | biostudies-literature

Effect of phenylpyruvate on pyruvate dehydrogenase activity in rat brain mitochondria.

Project description:1. The effects of phenylpyruvate, a metabolite produced in phenylketonuria, on the pyruvate dehydrogenase-complex activity were investigated in rat brain mitochondria. 2. Pyruvate dehydrogenase activity was measured by two methods, one measuring the release of (14)CO(2) from [1-(14)C]pyruvate and the other measuring the acetyl-CoA formed by means of the coupling enzyme, pigeon liver arylamine acetyltransferase (EC 2.3.1.5). In neither case was there significant inhibition of the pyruvate dehydrogenase complex by phenylpyruvate at concentrations below 2mm. 3. However, phenylpyruvate acted as a classical competitive inhibitor of the coupling enzyme arylamine acetyltransferase, with a K(i) of 100mum. 4. It was concluded that the inhibition of pyruvate dehydrogenase by phenylpyruvate is unlikely to be a primary enzyme defect in phenylketonuria.

| S-EPMC1177841 | biostudies-other

Effect of n-3 polyunsaturated fatty acid on gene expression of the critical enzymes involved in homocysteine metabolism.

Project description:BACKGROUND: Previous studies showed that plasma n-3 polyunsaturated fatty acid (PUFA) was negatively associated with plasma homocysteine (Hcy). OBJECTIVE: We investigated the regulatory effect of n-3 PUFA on mRNA expression of the critical genes encoding the enzymes involved in Hcy metabolism. METHODS: HepG2 cells were treated with docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), alpha-linolenic acid (ALA) respectively for 48 h. The cells were collected and total RNA was isolated. The mRNA expression levels of the genes were determined by using Real Time-PCR. RESULTS: Compared with controls, the mRNA expression levels of 5-methyltetrahydrofolate reductase (MTHFR) were significantly increased in the DHA group (p < 0.05) and ALA group (p < 0.05); Significantly down-regulated mRNA expression of methionine adenosyltransferase (MAT) was observed with the treatments compared with the controls; the level of MAT expression was significant lower in the DHA group than the ALA group (p < 0.05); Cystathionine-γ-lyase (CSE) expression was significantly increased in the DHA (p < 0.05) and EPA groups (p < 0.05) compared with control. No significant changes were shown in mRNA expression levels of S-adenosylhomocysteine hydrolases (SAHH), cystathionine β-synthase (CBS), and 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR). CONCLUSIONS: Our results suggest that DHA up-regulates CSE and MTHFR mRNA expression and down-regulates MAT mRNA expression involved in Hcy metabolism.

| S-EPMC3292920 | biostudies-literature

Key Enzymes in Fatty Acid Synthesis Pathway for Bioactive Lipids Biosynthesis.

Project description:Dietary bioactive lipids, one of the three primary nutrients, is not only essential for growth and provides nutrients and energy for life's activities but can also help to guard against disease, such as Alzheimer's and cardiovascular diseases, which further strengthen the immune system and maintain many body functions. Many microorganisms, such as yeast, algae, and marine fungi, have been widely developed for dietary bioactive lipids production. These biosynthetic processes were not limited by the climate and ground, which are also responsible for superiority of shorter periods and high conversion rate. However, the production process was also exposed to the challenges of low stability, concentration, and productivity, which was derived from the limited knowledge about the critical enzyme in the metabolic pathway. Fortunately, the development of enzymatic research methods provides powerful tools to understand the catalytic process, including site-specific mutagenesis, protein dynamic simulation, and metabolic engineering technology. Thus, we review the characteristics of critical desaturase and elongase involved in the fatty acids' synthesis metabolic pathway, which aims to not only provide extensive data for enzyme rational design and modification but also provides a more profound and comprehensive understanding of the dietary bioactive lipids' synthetic process.

| S-EPMC8905437 | biostudies-literature

Withaferin A Inhibits Fatty Acid Synthesis in Rat Mammary Tumors.

Project description:Withaferin A (WA), which is a small molecule derived from a medicinal plant (Withania somnifera), inhibits growth of human breast cancer xenografts and mammary tumor development in rodent models without any toxicity. However, the mechanism underlying inhibition of mammary cancer development by WA administration is not fully understood. Herein, we demonstrate that the fatty acid synthesis pathway is a novel target of WA in mammary tumors. Treatment of MCF-7 and MDA-MB-231 cells with WA resulted in suppression of fatty acid metabolizing enzymes, including ATP-citrate lyase (ACLY), acetyl-CoA carboxylase 1 (ACC1), fatty acid synthase (FASN), and carnitine palmitoyltransferase 1A (CPT1A). Expression of FASN and CPT1A was significantly higher in N-methyl-N-nitrosourea-induced mammary tumors in rats when compared with normal mammary tissues. WA-mediated inhibition of mammary tumor development in rats was associated with a statistically significant decrease in expression of ACC1 and FASN and suppression of plasma and/or mammary tumor levels of total free fatty acids and phospholipids. WA administration also resulted in a significant increase in percentage of natural killer cells in the spleen. The protein level of sterol regulatory element binding protein 1 (SREBP1) was decreased in MDA-MB-231 cells after WA treatment. Overexpression of SREBP1 in MDA-MB-231 cells conferred partial but significant protection against WA-mediated downregulation of ACLY and ACC1. In conclusion, circulating and/or mammary tumor levels of fatty acid synthesis enzymes and total free fatty acids may serve as biomarkers of WA efficacy in future clinical trials.Prevention relevanceThe present study shows that breast cancer prevention by WA in rats is associated with suppression of fatty acid synthesis.

| S-EPMC9812931 | biostudies-literature

Shc proteins influence the activities of enzymes involved in fatty acid oxidation and ketogenesis.

Project description:ObjectivesShcKO mice have low body fat and resist weight gain on a high fat diet, indicating that Shc proteins may influence enzymes involved in β-oxidation. To investigate this idea, the activities of β-oxidation and ketone body metabolism enzymes were measured.MethodsThe activities of β-oxidation enzymes (acyl-CoA dehydrogenase, 3-hydroxyacyl-CoA dehydrogenase and ketoacyl-CoA thiolase) in liver and hindlimb skeletal muscle, ketolytic enzymes (acetoacetyl-CoA thiolase, β-hydroxybutyrate dehydrogenase and 3-oxoacid-CoA transferase) in skeletal muscle, and ketogenic enzymes (acetoacetyl-CoA thiolase and β-hydroxybutyrate dehydrogenase) in liver were measured from wild-type and ShcKO mice.ResultsThe activities of β-oxidation enzymes were increased (P<.05) in the ShcKO compared to wild-type mice in the fasted but not the fed state. In contrast, no uniform increases in the ketolytic enzyme activities were observed between ShcKO and wild-type mice. In liver, the activities of ketogenic enzymes were increased (P<.05) in ShcKO compared to wild-type mice in both the fed and fasted states. Levels of phosphorylated hormone sensitive lipase from adipocytes were also increased (P<.05) in fasted ShcKO mice.ConclusionThese studies indicate that the low Shc levels in ShcKO mice result in increased liver and muscle β-oxidation enzyme activities in response to fasting and induce chronic increases in the activity of liver ketogenic enzymes. Decreases in the level of Shc proteins should be considered as possible contributors to the increase in activity of fatty acid oxidation enzymes in response to physiological conditions which increase reliance on fatty acids as a source of energy.

| S-EPMC3442136 | biostudies-literature

The effect of treatment of rats with pituitary growth hormone on the activities of some enzymes involved in fatty acid degradation and synthesis.

Project description:1. Measurements have been made of the activities of acyl-CoA dehydrogenase, enoyl-CoA hydratase, beta-hydroxyacyl-CoA dehydrogenase and ketothiolase in the livers of rats treated for either 12hr. or 3 days with pituitary growth hormone. 2. There was a significant increase in the activity of acyl-CoA dehydrogenase in rats treated with the hormone for 3 days. 3. Measurements were also made of the lipogenic enzymes acetyl-CoA carboxylase and palmitate synthase in the livers of similarly treated animals. 4. There was a depression of the activity of both enzymes after 12hr. treatment and a further decline after 3 days. 5. The results are discussed in relation to the known increase in the rate of fatty acid oxidation and inhibition of fatty acid synthesis in rats treated with growth hormone.

| S-EPMC1207057 | biostudies-other

Dietary n-6 polyunsaturated fatty acid deprivation increases docosahexaenoic acid metabolism in rat brain.

Project description:Dietary n-6 polyunsaturated fatty acid (PUFA) deprivation in rodents reduces brain arachidonic acid (20:4n-6) concentration and 20:4n-6-preferring cytosolic phospholipase A(2) (cPLA(2) -IVA) and cyclooxygenase (COX)-2 expression, while increasing brain docosahexaenoic acid (DHA, 22:6n-3) concentration and DHA-selective calcium-independent phospholipase A(2) (iPLA(2) )-VIA expression. We hypothesized that these changes are accompanied by up-regulated brain DHA metabolic rates. Using a fatty acid model, brain DHA concentrations and kinetics were measured in unanesthetized male rats fed, for 15 weeks post-weaning, an n-6 PUFA 'adequate' (31.4 wt% linoleic acid) or 'deficient' (2.7 wt% linoleic acid) diet, each lacking 20:4n-6 and DHA. [1-(14) C]DHA was infused intravenously, arterial blood was sampled, and the brain was microwaved at 5 min and analyzed. Rats fed the n-6 PUFA deficient compared with adequate diet had significantly reduced n-6 PUFA concentrations in brain phospholipids but increased eicosapentaenoic acid (EPA, 20:5n-3), docosapentaenoic acid n-3 (DPAn-3, 22:5n-3), and DHA (by 9.4%) concentrations, particularly in ethanolamine glycerophospholipid (EtnGpl). Incorporation rates of unesterified DHA from plasma, which represent DHA metabolic loss from brain, were increased 45% in brain phospholipids, as was DHA turnover. Increased DHA metabolism following dietary n-6 PUFA deprivation may increase brain concentrations of antiinflammatory DHA metabolites, which with a reduced brain n-6 PUFA content, likely promotes neuroprotection and alters neurotransmission.

| S-EPMC3296886 | biostudies-literature

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