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Iron-thiolate induced oxidation of methionine to methionine sulfoxide in small model peptides. Intramolecular catalysis by histidine.

Peptides containing either glycine and methionine, or glycine, methionine and histidine at various locations were oxidized by the dithiothreitol/ferric chloride system in phosphate buffer. The yields of peptide degradation and sulfoxide formation were measured as a function of peptide sequence and pH. In general little change of the final yields of peptide degradation is observed whereas the final yields of sulfoxide formation progressively decrease on going from pH 6.0 to 8.0. The pH profiles vary with the structure of the respective peptide. Efficient sulfoxide formation occurred when histidine and methionine were present within the same peptides sequence, and particularly when methionine was located at the C-terminus of the peptide. Added superoxide dismutase, catalase, and methanol did neither promote nor inhibit both the degradation of peptide and the formation of sulfoxide excluding free superoxide, hydrogen peroxide, and hydroxyl radicals as responsible reactive oxygen species. The observations are rationalized by invoking a pH-dependent conversion of an efficiently sulfoxide yielding oxidant into another oxidant which still degrades peptides but does not form methionine sulfoxide. The first might be a metal-bound peroxide or peroxyl species which converts into a metal-bound or 'complexed' hydroxyl radical.

Amino Acid Sequence↗

Determination of D- and L-enantiomers of methionine and [2H3]methionine in plasma by gas chromatography-mass spectrometry.

A method for the stereoselective determination of D- and L-enantiomers of both methionine and [(2)H3]methionine in rat plasma was developed using gas chromatography-mass spectrometry with selected-ion monitoring (GC-MS-SIM). DL-[(2)H7]Methionine was used as analytical internal standard to account for losses associated with the extraction, derivatization and chromatography. The amino acids were purified by cation-exchange chromatography using BondElut SCX cartridge and derivatized with HCl in methanol to form methyl ester followed by subsequent N-acylation with optically active (+)-alpha-methoxy-alpha-trifluoromethylphenylacetyl chloride to form diastereomeric amide. Quantification was performed by SIM of the molecular-related ions of the diastereomers on the chemical ionization mode. Endogenous L-methionine concentrations in 50 microl of rat plasma were measured with relative intra- and inter-day precision of 4.0 and 6.3%, respectively. The intra- and inter-day reproducibility in the amounts of D- and L-[(2)H3]methionine determined were in good agreement with actual amount added.

Animals↗

Chemical pathways of peptide degradation. V. Ascorbic acid promotes rather than inhibits the oxidation of methionine to methionine sulfoxide in small model peptides.

The effect of primary structure and external conditions on the oxidation of methionine to methionine sulfoxide by the ascorbate/Fe3+ system was studied in small model peptides. Degradation kinetics and yield of sulfoxide formation were dependent on the concentration of ascorbate and H+, with a maximum rate observed at pH 6-7. Phosphate buffer significantly accelerated the peptide degradation compared to Tris, HEPES, and MOPS buffers; however, the formation of sulfoxide was low. The oxidation could not be inhibited by the addition of EDTA. Other side products besides sulfoxide were observed, indicating the existence of various other pathways. The influence of methionine location at the C terminus, at the N terminus, and in the middle of the sequence was investigated. The presence of histidine in the sequence markedly increased the degradation rate as well as the sulfoxide production. The histidine catalysis of methionine oxidation occurred intramolecularly with a maximum enhancement of the oxidation rate and sulfoxide production when one residue was placed between the histidine and the methionine residue.

Amino Acid Sequence↗

The utilization by pigs of methionine from five protein concentrates compared with synthetic methionine.

Pigs (n 100) between 28 and 56 d of age were given diets containing one of five protein concentrates ad lib. The utilization of methionine from the protein concentrates was compared with synthetic methionine. Increasing the methionine content of the diets from 1.5 to 2.2 g/kg diet increased the weight gains of the pigs from 61 g/d to 198-292 g/d. The feed conversion efficiencies decreased from 2.56 to 1.34-1.56. The utilization of methionine from the protein concentrates for weight gain, as compared with synthetic methionine, was meat meal A 0.89, meat meal B 0.97, soya-bean meal 1.02, cotton-seed meal 0.87 and dried skim milk 1.04.

Animals↗

Biological efficacy and absorption of DL-methionine hydroxy analogue free acid compared to DL-methionine in chickens as affected by heat stress.

1. The net absorption and the biological efficacy of DL-methionine and of DL-methionine hydroxy analogue free acid (MHA-FA) were evaluated in chickens under heat stress. 2. In a growth assay, finishing broilers 21 to 42 d of age were fed on diets containing graded amounts of the two supplements; the basal diet was composed of practical ingredients. 3. From slope-ratio analysis, equimolar efficacy of MHA-FA relative to DL-methionine was determined to be 83% (confidence limits 61 to 115%) from weight gain responses, and 67% (47 to 91%) from food conversion responses. This indicates that the relative efficacy of MHA-FA is close to previous estimates of about 75% obtained under thermoneutral conditions. 4. In a balance study with caecectomised cockerels, net absorption (intake - excretion in faeces and urine) of DL-methionine and of MHA-FA, respectively, were determined to be 97.2 and 90.8%. The net absorption of MHA-FA was significantly lower than that of DL-methionine.

Animals↗

Performance, breast meat yield and abdominal fat deposition of male broiler chickens fed diets supplemented with DL-methionine or DL-methionine hydroxy analogue free acid.

1. An experiment was conducted to compare the relative bioefficacy of DL-methionine hydroxy analogue free acid (DL-MHA-FA) with DL-methionine in broiler chickens. Responses used for comparison were weight gain and food efficiency between 7 and 35 d of age, and breast meat deposition, food cost per kg of breast meat, and abdominal fat at 41 d of age. 2. A total of 2160 seven-day-old male broiler chicks were used. The feeding programme consisted of a starter diet from 7 to 21 d, and a finisher diet till the end of the experiment. The starter basal diet contained 6.1 g/kg total sulphur-containing amino acids (TSAA), and an estimated metabolisable energy (ME) content of 13.2 MJ/kg. The finisher diet contained 5.8g/kg TSAA and an estimated ME content of 13.6 MJ/kg. Four concentrations of DL-methionine and DL-MHA-FA were added at 0.5 g/kg increments on an equimolar basis. Therefore, there were 9 experimental treatments which were each applied to 6 replicates of 40 chicks. Weight gain and food efficiency were determined at 35 d of age. Breast yield and carcase fat were measured at 41 d. 3. Significant responses to graded amounts of both methionine sources were observed in weight gain, food efficiency, breast meat percentage, and food cost per kg of breast meat. The responses fitted exponential regression curves. Based on the regression coefficients, equimolar bioefficacy of DL-MHA-FA relative to DL-methionine was 80% for daily gain, 83% for food efficiency, 51% for breast meat yield, and 66% for food cost per kg of breast meat. Differences between the 2 sources were significant (P < 0.05) for breast meat yield and food cost per kg of meat and (P < 0.10) for food efficiency.

Abdomen↗

Methionine and 2-hydroxy-4-methylthiobutanoic acid are partially converted to nonabsorbed compounds during passage through the small intestine and heat exposure does not affect small intestinal absorption of methionine sources in broiler chicks.

Broiler chicks were fed diets supplemented with DL-methionine or DL-2-hydroxy-4-methyl-thiobutanoic acid. At 4 wk of age the chicks were subdivided into thermoneutral (22 degrees C) and heat-exposed (32 degrees C) groups and maintained under these conditions for 48 h. Highly purified 3H-L-methionine (3H-L-Met) and 3H-L-2-hydroxy-4-methyl-thiobutanoic acid (3H-L-HMB) were used to evaluate treatment effects on the small intestinal passage of sources of supplemental methionine and on the transport of methionine sources across purified small intestinal brush border vesicles. 3H-L-Met was efficiently absorbed in the upper regions of the small intestine; however, 2.5-3.5% of dietary 3H from birds fed 3H-L-Met remained unabsorbed in the distal small intestine. Dietary 3H (15%) initially associated with 3H-L-HMB was not absorbed during passage down the length of the gut. The HPLC analysis indicated that only 10% of the radiolabeled material remaining in the terminal ileum eluted at the time expected for HMB. Partial breakdown of HMB to nonabsorbed, nonmethionine products during passage down the small intestine may contribute to the difference in biopotency of the two sources of supplemental dietary methionine. Heat exposure did not affect in vivo small intestinal passage or in vitro transport of 3H-L-Met and 3H-L-HMB across small intestinal brush border membrane vesicles.

Animals↗

Neither methionine nor nitrous oxide inactivation of methionine synthase affect the concentration of 5,10-methylenetetrahydrofolate in rat liver.

5,10-Methylenetetrahydrofolate occupies a key position in folate-dependent one-carbon metabolism. It is involved directly in the biosynthesis of deoxythymidine, it can be converted to 10-formyltetrahydrofolate for purine synthesis and it may be reduced to 5-methyltetrahydrofolate for methylation of homocysteine to methionine. We have developed a HPLC method for measuring 5,10-methylenetetrahydrofolate in liver and we have used this method to investigate two conditions that perturb one-carbon metabolism: 1) administration of methionine and 2) administration of the anesthetic gas, nitrous oxide (N(2)O). Rats were given 1.3 mmol/kg of methionine, and folate coenzymes in liver were measured. As expected, giving methionine resulted in an apparent increase in the concentration of 10-formyl- and tetrahydrofolate and an apparent decrease in 5-methyltetrahydrofolate concentration at 30 and 60 min. After 120 min, the concentrations of these coenzymes appeared to revert to control values. There was no apparent change in the concentration of 5,10-methylenetetrahydrofolate. Exposing rats to an atmosphere containing N(2)O results in inactivation of methionine synthase and accumulation of 5-methyltetrahydrofolate at the expense of other folate coenzymes. In liver from rats breathing N(2)O, 5-methyltetrahydrofolate increased, whereas there was no change in 5- or 10-formyltetrahydrofolates (P > 0.7 and P > 0.8, respectively). Tetrahydrofolate was not detected in liver from the N(2)O group, whereas it constituted 24% of folates in the control group. The concentration of 5,10-methylenetetrahydrofolate was not significantly affected by N(2)O (P > 0.18). These results suggest that the concentration of 5,10-methylenetetrahydrofolate is tightly regulated in liver.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗

Estimation of bioavailability of DL-methionine hydroxy analogue relative to DL-methionine in layers with exponential and slope-ratio models.

An experiment was conducted using molted hens to estimate the bioavailability of DL-methionine hydroxy analogue-free acid (MHA-FA) relative to DL-methionine (DLM). In this experiment, 5 supplemental levels (0.012, 0.024, 0.036, 0.048, and 0.060%) of DLM or equimolar concentrations of MHA-FA were added to a basal diet containing 14.97% protein and 0.27% methionine. The low protein diet was used to increase the sensitivity of laying hens to methionine deficiency. Feed consumption, egg production, egg mass, and egg weight increased (P < 0.05), and feed conversion decreased (P < 0.05) when DLM or MHA-FA was added to the basal diet for some supplemental methionine levels. There was no difference (P > 0.05) in feed consumption between hens fed DLM and hens fed MHA-FA. Regression analysis showed that the bioavailability of MHA-FA relative to DLM on a molar basis was 88.7% (egg production), 88.0% (egg mass), and 84.6% (egg weight) with the exponential model, and was 89.7% (egg production), 89.6% (egg mass), and 86.8% (egg weight) with the slope-ratio model. The average bioavailability of MHA-FA relative to DLM was 88% on a molar basis.

Animal Feed↗

Amino acid distribution and metabolism in pituitary adenomas using positron emission tomography with D-[11C]methionine and L-[11C]methionine.

Four patients with hormonally inactive pituitary adenomas were examined with positron emission tomography (PET) after injection, during different examinations, of L-[methyl-11C]methionine and D-[methyl-11C]methionine, respectively. After the rapid distribution phase, the enantiomer L-[11C]methionine, which is metabolically active, showed a considerable continuous irreversible trapping attributed to amino acid metabolism. The stereoisomer D-[11C]methionine, which does not participate in protein synthesis, showed a rapid distribution within the whole adenoma tissue, with a distribution space on the order of 100%. A minimal irreversible trapping was observed which could be explained by technical factors. It is concluded that PET using the two enantiomers allows a separation of passive distribution and metabolism, and that L-[11C]methionine can be used for in vivo quantitative studies of amino acid metabolism of pituitary adenomas.

Adenoma↗

Methionine degradation by Pseudomonas fluorescens UK1 and its methionine-utilizing mutant.

Pseudomonas fluorescens UK1, and a mutant derived from it that can use methionine as its sole source of carbon and nitrogen, were used to study methionine degradation. Radioactive 2-oxomethionine, 2-oxobutyric acid and carbon dioxide comprised 95% of [I-14C]methionine consumed by the mutant. Demethiolating activity was detected in both strains when they were grown with methionine. The ability to grow on methionine depended on the decarboxylation of 2-oxobutyric acid derived from it. This decarboxylating activity was lost if the growth media contained an additional carbon source. No evidence was obtained for the operation of the cystathionine pathway.

Butyrates↗

Enhanced anticancer effect of vincristine with methionine infusion after methionine-depleting total parenteral nutrition in tumor-bearing rats.

Methionine-depleting total parenteral nutrition (Met(-) TPN), in which an amino acid solution devoid of L-methionine and L-cysteine is infused, is thought to reduce tumor cell growth through acting as a partial late S-G2 (i.e., late-S and G2 phases) blocker. The antitumor effect of vincristine (VCR), which acts on mitotic phase cells, was examined with methionine infusion immediately after Met(-) TPN in Yoshida sarcoma (YS)-bearing rats. Rats were given Met(-) TPN for 8 days immediately after inoculation with YS cells (days 0 to 8), which was followed by methionine-containing (Met(+)) regular TPN for 3 days (days 9-11) along with intraperitoneal administration of 0.05 mg/kg/day VCR. All rats were then fed solid food and water ad libitum until they died, with 0.1 mg/kg VCR administration on days 12 and 13. As controls, a Met(-) TPN only group, Met(+) TPN groups with and without VCR, and freely fed groups with and without VCR were studied. The progression of YS was markedly suppressed by Met(-) TPN with VCR. The median survival time in days was 25 days, significantly longer (P<0.001) (generalized Wilcoxon's tests) by 11 to 14 days than that of any of the other groups. In conclusion, VCR appears to have greater efficacy as an anticancer agent when administered together with methionine after Met(-) TPN.

Animals↗

An in vivo kinetic model with L-[35S]methionine for the determination of local cerebral rates for methionine incorporation into protein in the rat.

A method has been developed for the simultaneous in vivo measurement of local rates for methionine incorporation into cerebral protein in the rat. It is based on the use of L-[35S]methionine as a tracer for reflecting the bidirectional exchange of methionine between plasma and brain and its incorporation into cerebral protein, using a dynamic three-compartment model. An operational equation based on this model has been derived in terms of determinable variables. The method has been applied to the normal freely moving rat and to the rat under chloral hydrate anesthesia. In the freely moving rat, the values of methionine incorporation into cerebral protein in the gray matter vary widely from structure to structure (50-300 nmol/100 g/min), with the highest values in structures related to neurosecretory functions, e.g., supraoptic and paraventricular nuclei. The values for white matter are more uniform (24-28 nmol/100 g/min) at levels approximately six- to seven-fold lower than for gray matter. Chloral hydrate anesthesia depresses the rate of methionine incorporation in all the structures examined. Anesthesia did not reduce the heterogeneity normally present within gray matter.

Animals↗

In vivo metabolism of L-methionine in mice: evidence for stereoselective formation of methionine-d-sulfoxide and quantitation of other major metabolites.

Flavin-containing monooxygenases (FMOs) 1-4 oxidize methionine (Met) to methionine sulfoxide (MetO). FMO3, the primary isoform expressed in adult human liver, has the lowest Km and favors methionine-d-sulfoxide (Met-d-O) formation over methionine-l-sulfoxide. Because female mice, but not males, also express FMO3 in liver, levels of Met and its major metabolites were determined in male or female mice dosed with 400 mg/kg Met i.p. The results show that Met levels in male and female mouse liver or plasma increased significantly at both 15 and 30 min after the Met treatment; Met plasma and liver levels at 30 min were similar to or lower than the corresponding levels at 15 min. Liver and plasma MetO levels increased significantly in both sexes at 30 min, and Met-d-O was the major MetO diastereomer detected. Interestingly, less than 0.1% of the Met dose was excreted in the urine (0-24 h) as Met and Met-d-O. S-Adenosylmethionine (SAM) was the major metabolite detected in liver at 15 min. Liver SAM levels at 30 min were lower than the levels at 15 min, and the plasma SAM levels at both 15 and 30 min were much lower than the corresponding levels in the liver. Increases in liver and/or plasma S-adenosyl-l-homocysteine, 5'-deoxy-5'-(methylthio)adenosine, and N-acetyl-l-methionine were also detected. Taken together, these results suggest that mice extensively and rapidly used the Met dose. Although mice exhibited increases in tissue MetO levels, a major role for FMO3 in Met-d-O formation is not certain since the MetO increases were mostly similar in both males and females.

Animals↗

S-adenosyl methionine-mediated repression of methionine biosynthetic enzymes in Saccharomyces cerevisiae.

S-adenosylmethionine (SAM) has been shown to provoke repression of some methionine-specific enzymes in wild-type cells, namely, adenosine triphosphate sulfurylase, sulfite reductase, and homocysteine synthetase. Repressive effects observed in SAM-supplemented cultures should be due to SAM per se, since the intracellular pool of SAM increases while the intracellular pool of methionine remains low and constant. Derepression brought about by methionine limitation is accompanied by a severe decrease in SAM as well as methionine pool sizes, although methionine adenosyl transferase is slightly derepressed. Different hypotheses have been considered to account for the previously reported implication of methionyl transfer ribonucleic acid and the presently reported SAM effects in this regulatory process.

Adenosine↗

Reduction of methionine sulfoxide to methionine by Escherichia coli.

L-Methionine-dl-sulfoxide can support the growth of an Escherichia coli methionine auxotroph, suggesting the presence of an enzyme(s) capable of reducing the sulfoxide to methionine. This was verified by showing that a cell-free extract of E. coli catalyzes the conversion of methionine sulfoxide to methionine. This reaction required reduced nicotinamide adenine dinucleotide phosphate and a generating system for this compound. The specific activity of the enzyme increased during logarithmic growth and was maximal when the culture attained a density of about 10(9) cells per ml.

Escherichia coli↗

Capacity in the liver of the broiler chick for conversion of supplemental methionine activity to L-methionine.

The objective of the present experiments was to determine whether the levels of supplemental methionine sources currently used in practical diets exceed the capacity of the chick to convert the supplement to L-methionine. Supplemental sources examined included DL-2-hydroxy-4-(methylthio(butanoic acid (DL-HMB, Alimet, or MHA) and DL-methionine (DL-Met). Two approaches were taken: first, the amount of enzyme activity available for conversion of the two supplemental methionine sources was determined using optimum reaction conditions for each and chick liver homogenate as the enzyme source. These experiments showed that total liver enzyme conversion activity was 564 mumol/h for DL-HMB and 529 mumol/h for DL-Met. The total activities for the two sources were not different when measured at saturating substrate concentration. Second, to address the question of whether the enzyme is limiting for either source under practical feeding conditions, birds were fed starter diets supplemented with DL-HMB or DL-Met at .25% of the diet for 3 wk. When hepatic levels of free HMB and methionine were determined, birds fed DL-HMB contained 7.6 nmol HMB/g of liver and 84.7 nmol methionine/g of liver. Birds fed DL-Met had levels of 7.6 nmol HMB/g liver and 80.3 nmol methionine/g liver. These results indicate no accumulation of HMB or DL-Met, which might occur if conversion capacity were saturated. By calculation, a bird consuming 100 g/day of a diet supplemented with .25% activity would need to convert about 70 mumol/h, indicating a sevenfold excess of enzyme in the liver alone.

Animals↗

Influences of supplementary dietary tungsten on methionine metabolism in rabbits fed a low-cholesterol plus methionine diet.

Hyperhomocysteinemia results from an impaired methionine metabolism. Sulfite oxidase, which is an important enzyme in methionine metabolism, contains molybdenum. In contrast, tungsten has a molybdenum-antagonistic effect. Thus, we hypothesized that dietary tungsten may decrease plasma homocysteine levels and influence methionine metabolism. Male New Zealand White rabbits (n=15) were fed a low-cholesterol basal diet and then placed on three different diets: 0.1% cholesterol (Chol), Chol plus 1% methionine (Met), and Chol plus Met plus 0.1% tungsten (W). The animals received these diets for 20 weeks. Biochemical tests of blood and urine were performed. Plasma homocysteine levels were significantly lower in the Chol+Met+W group than in the Chol+Met group. Plasma levels of total cholesterol, triglyceride, lipid peroxide, and urinary 24-h taurine concentrations were higher in the Chol + Met + W group than in the Chol + Met group. In comparison, concentrations of 2, 3-diphosphoglycerate (2, 3-DPG), reduced glutathione (GSH) in erythrocytes, and urinary 24-h SO4(2) were lower in the Chol+Met+W group than in the Chol+Met group. From these results, tungsten could be expected to exhibit an antiatherogenic effect. Conversely, it may have effects on atherogenic factors. Thus, tungsten may play a number of roles in the methionine metabolism.

2,3-Diphosphoglycerate↗