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PubMed1992

Regional cerebral L-[14C-methyl]methionine incorporation into proteins: evidence for methionine recycling in the rat brain.

The specific activity (SA) of free methionine was measured in plasma and in different regions of the rat brain at 15, 30, or 60 min after intravenous infusion of L-[14C-methyl]methionine. Within these time periods, an apparent steady state of labeled free methionine in plasma and in brain was reached. However, the brain-to-plasma free methionine SA ratio was found to be approximately 0.5, showing that an isotopic equilibrium between brain and plasma was not attained. This suggests the presence of an endogenous source of brain free methionine (likely originating from protein breakdown), in addition to the plasma source. The contribution of this endogenous source to the content of free methionine varies significantly among the different brain regions. Our results indicate that the regional rates of protein synthesis measured with L-[11C-methyl]methionine using positron emission tomography would be underestimated, since the local fraction of brain methionine derived from protein degradation would not be considered.

Algorithms↗
PubMed1976

Carboxymethylation of methionine residues in bovine pituitary luteinizing hormone and its subunits. Location of specifically modified methionine residues.

Bovine lutropin (luteinizing hormone) was carboxymethylated at pH3.0 for 12 h at 37 degrees C with iodoacetic acid for specific modification of methionine residues. To facilitate the location of preferentially modified methionine residues, iodoE114C]acetic acid was added as tracer. The alpha and beta subunits of bovine lutropin were carboxymethylated with a 2- or 5-fold molar excess of iodoacetic acid either in the presence or absence of their counterpart subunits. The modified subunits were separated and isolated by counter-current distribution followed by gel filtration on Sephadex G-100. To locate the modified methiones, the isolated alpha or beta chain was reduced. S-carboxymethylated and subjected to tryptic hydrolysis. The tryptic peptides were fractionated by gel filtration on Bio-Gel P-10. From analyses of the purified 14C-labelled tryptic peptides, it was observed that methionine-8 and -33 in bovine lutropin alpha chain and methionine-52 in the beta chain were preferentially modified. Similar results were obtained when isolated alpha and beta subunits were individually carboxymethylated in the absence of their counterpart subunit under identical conditions. The fact that a recombinant of native human lutropin alpha chain, in which a valine residue is present in the position corresponding to methionine-8 of bovine lutropin alpha chain, and carboxymethylated bovine lutropin beta chain regenerated a substantial amount of receptor-site-binding activity indicated that methionine-8 in bovine alpha chain was biologically not essential. These studies showed clearly that both methionine-33 in the alpha chain and methionine-52 in the beta subunit were involved for optimum binding between bovine lutropin and its receptors for expression of hormonal activity.

Amino Acid Sequence↗
PubMed2000

Oxidation of either methionine 351 or methionine 358 in alpha 1-antitrypsin causes loss of anti-neutrophil elastase activity.

Hydrogen peroxide is a component of cigarette smoke known to be essential for inactivation of alpha(1)-antitrypsin, the primary inhibitor of neutrophil elastase. To establish the molecular basis of the inactivation of alpha(1)-antitrypsin, we determined the sites oxidized by hydrogen peroxide. Two of the nine methionines were particularly susceptible to oxidation. One was methionine 358, whose oxidation was known to cause loss of anti-elastase activity. The other, methionine 351, was as susceptible to oxidation as methionine 358. Its oxidation also resulted in loss of anti-elastase activity, an effect not previously recognized. The equal susceptibility of methionine 358 and methionine 351 to oxidation was confirmed by mass spectrometry. To verify this finding, we produced recombinant alpha(1)-antitrypsins in which one or both of the susceptible methionines were mutated to valine. M351V and M358V were not as rapidly inactivated as wild-type alpha1-antitrypsin, but only the double mutant M351V/M358V was markedly resistant to oxidative inactivation. We suggest that inactivation of alpha(1)-antitrypsin by oxidation of either methionine 351 or 358 provides a mechanism for regulation of its activity at sites of inflammation.

Humans↗
PubMed1983

Absorption of methionine and methionine sulphoxide in rat intestine and the effect of glutathione.

The absorption of methionine and methionine sulphoxide was compared in inverted rings from three sections of rat intestine. In all sections, absorption of unoxidized methionine was 20-40% higher than that of methionine at low physiological substrate concentrations. At higher substrate levels, the difference was not so pronounced. Inhibition studies indicated that absorption of methionine and of methionine sulphoxide took place by different absorption systems. Glutathione increased the absorption of methionine and, to a greater extent, the absorption of methionine sulphoxide.

Animals↗
PubMed1985

The effect of increasing methionine supply on the methionine conversion to cyst(e)ine in sheep.

The conversion of methionine to cyst(e)ine was determined in sheep infused with different amounts of methionine (0-5 g/d) into the duodenum by assaying the incorporation of 35S from intravenously-infused L-[35S]methionine into cyst(e)ine in wool, plasma albumin and the free plasma pool. The percentage of cystine-S in the plasma originating from methionine increased linearly from 4.5 to 18 with increasing supplemental methionine supply. The percentage of cysteine-S in albumin increased from 15 to 50; methionine supply increased to 3 g/d but then remained constant, indicating that the transsulphuration pathway of the liver was exceeded. The percentage of wool cysteine-S originating from methionine was high (approximately 70) at all methionine supplementation rates.

Animals↗
PubMed1996

Studies on metabolism of broilers by using 14C-labelled DL-methionine and DL-methionine hydroxy analogue Ca-salt.

The metabolization of DL-methionine and a hydroxy analogue form, DL-MHA-Ca, was studied by means of 14C-labelled substances. For this purpose 60 male day-old chicks were administered 1-14C-labelled substances DL-methionine and DL-MHA-Ca into the birds' crop. In 20 birds the 14CO2 activity excretion with the expired air was measured for a period of 24 hours post administration by means of radiorespirometry. The birds were killed 24, 48 and 72 hours post administration and the 14C-activity determined in the following fractions: excrements, gastrointestinal contents, digestive tract, blood, kidney, liver and gallbladder, lung, heart, spleen, leg and breast muscles and the residual fraction. Over the experimental period as a whole 17.0% of the administered dose was recovered in the excrements of the 1-14C-DL-MHA-Ca labelled birds and 4.4% in the 1-14C-DL-methionine treated birds. The maximum 14CO2 excretion in the expired air was reached after 1.5 hours, irrespective of whether 1-14C-DL-methionine or 1-14C-DL-MHA-Ca had been administered. Within 24 hours post administration, 15.8% of 1-14C-DL-methionine were excreted as 14CO2 via the lungs, as against 11.4% following application of 1-14C-DL-MHA-Ca. While no significant differences between the groups were recorded for the 14C-incorporation of the liver, the kidneys generally contained a higher 14C-activity after the administration of 1-14C-DL-methionine than after 1-14C-DL-MHA-Ca. The relative incorporated 14C-activity was distributed in the following proportions: 25% in the leg and breast muscles, about 25% in the remaining organs and about 50% in the residual fraction. The 14C-activity found in the protein of the leg and breast muscles was separated by thin layer chromatography and recovered exclusively in methionine. The 14C-activity in the lipids of the leg and breast muscles accounted for only a very small proportion of the total incorporated 14C-activity. Irrespective of the adaptation diet, the rate of incorporation of 14C into the birds' body was found to be higher after administration of 14C-DL-methionine than after 1-14C-DL-MHA-Ca.

Amino Acids↗
PubMed1998

Methionine and cysteine kinetics at different intakes of methionine and cysteine in elderly men and women.

Earlier nitrogen balance studies led to the conclusion that requirements for methionine in older individuals are much higher than those in younger adults. Hence, we examined the kinetics of whole-body methionine, cysteine, and leucine metabolism postabsorptively using a continuous intravenous infusion of L-[C2H3, 1-(13)C]methionine, L-[2H3]leucine, and [3,3-2H2]cysteine in 12 elderly men (n = 5) and women (n = 7) given as a 3-h infusion after a 12-h fast (study 1) and in 8 elderly men (n = 4) and women (n = 4) as an 8-h infusion according to a 3-h fasted, 5-h fed protocol (study 2) for 6 d. Before tracer infusion, each of 3 L-amino acid diets supplying the following nominal, but known, amounts (mg x kg(-1) x d(-1)) of methionine and cysteine, respectively, were used in study 2: diet 1: 13 and 0; diet 3: 6.5 and 5.2; and diet 5: 6.5 and 21. Studies 1 and 2 gave values for plasma methionine flux that agreed with the leucine flux data, which, in turn, also appeared to be comparable with findings in healthy younger adults. In study 2, methionine oxidation rates were the same across all diets in the fasted state and the same with diets 1 and 3 in the fed state but lower with diet 5, suggesting a modest sparing effect of dietary cystine on methionine oxidation. Estimated daily methionine balance was at equilibrium for diet 1 and negative (significantly different from zero, P<0.05) with diets 3 and 5. The results were evaluated against our previous findings in younger adults.

Age Factors↗
PubMed1999

Regulation of L-methionine and L-lysine uptake in chicken jejunal brush-border membrane by dietary methionine.

In the chicken intestine, L-methionine is transported by systems that are specific for neutral amino acids (L- and B-like) and by systems that can also transport cationic amino acids (y(+)m and b(0,+)-like). These four uptake pathways have been investigated in brush-border membrane vesicles from the jejunum of chickens fed a diet enriched with 0.4% L-methionine. Methionine supplementation from the 1st to the 6th wk of age has no effect on body weight or on the efficiency of food utilization. The kinetic analysis of L-methionine influx across the transport systems specific for neutral amino acids shows, for system L, no dietary effect on the Michaelis constant (Km) and a 30% reduction in maximal velocity (Vmax); for system B it shows a decrease in Km (30%) and in Vmax (51%). Transport systems shared by cationic and neutral amino acids show no dietary effect on b(0,+) activity and a significant reduction in y(+)m Vmax, similar for L-methionine and L-lysine, both in the absence and in the presence of Na+ (L-methionine, 30 and 26% reduction; L-lysine, 19 and 28% reduction, respectively). The downregulation induced by L-methionine supplementation may be an adaptive response to reduce the risk of intoxication by dietary excess of L-methionine. These results support the view that the toxicity of the supplemented substrate can be an important factor in the regulation of amino acid transport by dietary content.

Administration, Oral↗
PubMed1999

[13C]Methionine NMR and metal-binding studies of recombinant human transferrin N-lobe and five methionine mutants: conformational changes and increased sensitivity to chloride.

The N-lobe of human serum transferrin (hTF/2N) and single point mutants in which each of the five methionine residues was individually mutated have been produced in a mammalian tissue-culture expression system. Since the five methionine residues are well distributed in the transferrin N-lobe, (13)C NMR of the [epsilon-(13)C]methionine-labelled proteins has been used to monitor conformational changes of the protein during metal binding. All five methionine residues have been assigned [Beatty, Cox, Frenkiel, Tam, Mason, MacGillivray, Sadler and Woodworth (1996) Biochemistry 35, 7635-7642]. The tentative two-dimensional NMR assignment for two of the five methionine residues, namely Met(26) and Met(109), has been corrected. A series of NMR spectra for the complexes of (13)C-Met-labelled hTF/2N with six different metal ions, Fe(III), Cu(II), Cr(III), Co(III), Ga(III) and In(III), demonstrate that the conformational change of the protein upon metal binding can be observed by means of the changes in the NMR chemical shifts associated with certain methionine residues, regardless of whether diamagnetic or paramagnetic metals are used. Changing any of the methionine residues should have minimal effects on transferrin function, since structural analysis shows that none of these residues contacts functional amino acids or has any obvious role in iron uptake or release. In fact, UV-visible spectra show little perturbation of the electronic spectra of any of the mutants. Nevertheless, the M109L mutant (Met(109)-->Leu) releases iron at half the rate of the wild-type N-lobe, and chloride shows a significantly greater retarding effect on the rate of iron release from all five mutants. All the methionine mutants (especially in the apo form) show a poor solubility in Hepes buffer lacking anions such as bicarbonate. These findings imply a more general effect of anion binding to surface residues than previously realized.

1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium ↗
PubMed2002

Differences in the efficiency of reductive activation of methionine synthase and exogenous electron acceptors between the common polymorphic variants of human methionine synthase reductase.

Methionine synthase reductase (MSR) catalyzes the conversion of the inactive form of human methionine synthase to the active state of the enzyme. This reaction is of paramount physiological importance since methionine synthase is an essential enzyme that plays a key role in the methionine and folate cycles. A common polymorphism in human MSR has been identified (66A --> G) that leads to replacement of isoleucine with methionine at residue 22 and has an allele frequency of 0.5. Another polymorphism is 524C --> T, which leads to the substitution of serine 175 with leucine, but its allele frequency is not known. The I22M polymorphism is a genetic determinant for mild hyperhomocysteinemia, a risk factor for cardiovascular disease. In this study, we have examined the kinetic properties of the M22/S175 and I22/S175 and the I22/L175 and I22/S175 pairs of variants. EPR spectra of the semiquinone forms of variants I22/S175 and M22/S175 are indistinguishable and exhibit an isotropic signal at g = 2.00. In addition, the electronic absorption and reduction stoichiometries with NADPH are identical in these variants. Significantly, the variants activate methionine synthase with the same V(max); however, a 3-4-fold higher ratio of MSR to methionine synthase is required to elicit maximal activity with the M22/S175 and I22/L175 variant versus the I22/S175 enzyme. Differences are also observed between the variants in the efficacies of reduction of the artificial electron acceptors: ferricyanide, 2,6-dichloroindophenol, 3-acetylpyridine adenine dinucleotide phosphate, menadione, and the anticancer drug doxorubicin. These results reveal differences in the interactions between the natural and artificial electron acceptors and MSR variants in vitro, which are predicted to result in less efficient reductive repair of methionine synthase in vivo.

2,6-Dichloroindophenol↗
PubMed1975

The role of methionine transport-defective mutations in resistance to methionine sulphoximine in Salmonella typhimurium.

Two classes of Salmonella typhimurium mutants resistant to inhibitory methionine analogues and defective in methionine transport have been examined. A mutant of the first class, resistant to alpha-methylmethionine, was shown by conjugation analysis to possess a single mutation in the metP gene which specifies a methionine transport system. Mutants of the second class, resistant to alpha-methylmethionine and methionine sulphoximine, possess two mutations. One is in the metP gene, which accounts for resistance to alpha-methylmethionine, and the other is in a gene designated glnP which results in reduced L-glutamine transport. Both of these mutations are required for resistance to methionine sulphoximine. A transduction analysis of three metP mutations was performed, based on the fact that they prevent growth of methionine-requiring strains on D-methionine. Two of the mutants are closely linked and therefore probably in the same gene, whereas the third mutant might be in a different gene.

Biological Transport↗
PubMed2003

Crystal structures of methionine adenosyltransferase complexed with substrates and products reveal the methionine-ATP recognition and give insights into the catalytic mechanism.

Methionine adenosyltransferases (MATs) are a family of enzymes in charge of synthesising S-adenosylmethionine (SAM), the most important methyl donor present in living organisms. These enzymes use methionine and ATP as reaction substrates, which react in a S(N)2 fashion where the sulphur atom from methionine attacks C5' from ATP while triphosphate chain is cleaved. A MAT liver specific isoenzyme has been detected, which exists in two distinct oligomeric forms, a dimer (MAT III) and a tetramer (MAT I). Our previously reported crystal structure of MAT I complexed with an inhibitor led to the identification of the methionine-binding site. We present here the results obtained from the complex of MAT I with a competitive inhibitor of methionine, (2S,4S)-amino-4,5-epoxypentanoic acid (AEP), which presents the same features at the methionine binding site reported before. We have also analysed several complexes of this enzyme with methionine and ATP and analogues of them, in order to characterise the interaction that is produced between both substrates. The crystal structures of the complexes reveal how the substrates recognise each other at the active site of the enzyme, and suggest a putative binding site for the product SAM. The residues involved in the interactions of substrates and products with MAT have been identified, and the results agree with all the previous data concerning mutagenesis experiments and crystallographic work. Moreover, all the information provided from the analysis of the complexes has allowed us to postulate a catalytic mechanism for this family of enzymes. In particular, we propose a key role for Lys182 in the correct positioning of the substrates, and Asp135(*), in stabilising the sulphonium group formed in the product (SAM).

Adenosine Triphosphate↗
PubMed1975

Methionine-and S-adenosyl methionine-mediated repression in a methionyl-transfer ribonucleic-acid synthetase mutant of Saccharomyces cerevisiae.

A Saccharomyces cerevisiae mutant strain unable to grow at 38 C and bearing a modified methionyl-transfer ribonucleic acid (tRNA) synthetase has been studied. It has been shown that, in this mutant, the percentage of tRNAmet charged in vivo paralleled the degree of repressibility of methionine biosynthetic enzymes by exogenous methionine. On the contrary, the repression mediated by exogenous S-adenosylmethionine does not correlate with complete acylation of tRNAmet. Althought McLaughlin and Hartwell reported previously that the thermosensitivity and the defect in the methionyl-tRNA synthetase were due to the same genetic lesion (1969), no diffenence could be found in the methionyl-tRNA synthetase activity or in the pattern of repressibility of methionine biosynthetic pathway after growth at the premissive and at a semipermissive temperature. It appears that the mutant also exhibits some other modified characters that render unlikely the existence of only one genetic lesion in this strain. A genetic study of this mutant was undertaken which led to the conclusion that the thermosensitivity and the other defects are not related to the methionyl-tRNA synthetase modification. It was shown that the modified repressibility of methionine biosynthetic enzymes by methionine and the lack of acylation of tRNAmet in vivo follow the methionyl-tRNA synthetase modification. These results are in favor of the idea that methionyl-tRNAmet, more likely than methionine, is implicated in the regulation of the biosynthesis of methionine.

Amino Acyl-tRNA Synthetases↗
PubMed2003

A second human methionine sulfoxide reductase (hMSRB2) reducing methionine-R-sulfoxide displays a tissue expression pattern distinct from hMSRB1.

Peptide methionine sulfoxide reductases are important enzymes in the defense against cellular oxidative stress as they reduce methionine sulfoxide, the product of methionine oxidation by physiologically relevant reactive oxygen species. Two distinct enzyme classes, MSRA and MSRB, have evolved for selectively reducing the two epimers, methionine-S-sulfoxide and methionine-R-sulfoxide. A new human MSR enzyme (hMSRB2) specifically reducing methionine-R-sulfoxide, which showed a conversion rate for peptide-bound methionine-S-sulfoxide similar to hMSRB1, was characterized with respect to its tissue expression. As previously found for hMSRB1, expression of hMSRB2 mRNA was weak in brain, but strong in heart and skeletal muscle. In contrast to hMSRB1, its expression was high in smooth muscle-containing organs (digestive system, bladder), lung and aorta, while hMSRB1 displayed a higher expression than hMSRB2 in liver and kidney.

Blotting, Northern↗
PubMed2000

The quantitative oxidation of methionine to methionine sulfoxide by peroxynitrite.

Both peroxynitrous acid and peroxynitrite react with methionine, k(acid) = (1.7 +/- 0.1) x 10(3) M(-1) s(-1) and k(anion) = 8.6 +/- 0.2 M(-1) s(-1), respectively, and with N-acetylmethionine k(acid) = (2.8 +/- 0.1) x 10(3) M(-1) s(-1) and k(anion) = 10.0 +/- 0.1 M(-1) s(-1), respectively, to form sulfoxides. In contrast to the results of Pryor et al. (1994, Proc. Natl. Acad. Sci. USA 91, 11173-11177), a linear correlation between k(obs) and [met] was obtained. Surprisingly, for every two sulfoxides and nitrites formed, one peroxynitrite is converted to nitrate. Thus, methionine also catalyzes the isomerization of peroxynitrite to nitrate. Neither the pH nor the concentration of methionine affected the distribution of the yields of nitrite, nitrate, and methionine sulfoxide, which were the only products detected. No products other than nitrite, nitrate, and methioninesulfoxide could be detected. The reactions of methionine and N-acetylmethionine with peroxynitrous acid and peroxynitrite are simple bimolecular reactions that do not involve an activated form of peroxynitrous acid or of peroxynitrite. Nitrite, produced together with methionine sulfoxide, or present as a contamination in the peroxynitrite preparation, is not innocuous, but oxidizes methionine by one electron, which leads to the formation of methional and ethylene.

Aldehydes↗
PubMed1982

Impaired metabolism of methionine in severe liver diseases. I. Clinical and pathophysiological significance of elevated serum methionine levels.

Serum methionine levels increased to a greater extent in patients with severe liver diseases such as fulminant hepatitis and liver cirrhosis with and without hepatic encephalopathy. However, the concentrations remained unchanged in non-encephalopathic cirrhotic cases associated with hepatocellular carcinoma, and their serum methionine levels increased only moderately even at the time of encephalopathy. At least two different mechanisms of serum methionine elevations, possibly due to release from injured hepatocytes or diminished catabolisms of this amino acid in the damaged liver, could be differentiated; the former would be involved mainly in fulminant hepatitis and the latter in liver cirrhosis. A methionine-loading test performed in cirrhotic patients supported the validity of these considerations. No significant increase of serum methionine levels in cirrhotic patients with hepatocellular carcinoma was observed, possibly by remarkable consumption of this amino acid in hepatoma tissues. During the clinical course of several patients, serial determinations of serum methionine concentrations indicated that the levels varied depending upon alterations in the pathophysiological state of the damaged liver; much higher levels were observed concomitantly with decompensated signs such as ascites, jaundice and hepatic encephalopathy. These results suggest that monitoring of serum methionine levels would be very valuable, especially for judging prognosis and predicting hepatic encephalopathy in severe liver disease.

Amino Acids↗
PubMed1982

Impaired metabolism of methionine in severe liver diseases. II. Clinical and experimental studies on role of impaired methionine metabolism in pathogenesis of hepatic encephalopathy.

Hepatic encephalopathy in patients with severe liver disease was associated with marked elevation of either serum methionine or blood ammonia levels or with simultaneous moderate increases in both parameters. CSF methionine levels also increased in encephalopathic patients with fulminant hepatitis and liver cirrhosis. Increased influx of methionine into the brain over the theoretical values predicted from Pardridge's equation suggested that accelerated transport of serum methionine across the blood-brain barrier was observed in these cases with hepatic encephalopathy. Hepatic encephalopathy in acute carbon tetrachloride liver injury could be obtained experimentally following intraperitoneal injection of ammonium acetate in rats, which already received intragastric administration of methionine. However, similar encephalopathy could not be observed by the administration of glycine or leucine in place of methionine. These results suggest at least that methionine and ammonia act synergistically on inducing hepatic encephalopathy.

Ammonia↗
PubMed1991

A nonradioactive assay for N5-methyltetrahydrofolate-homocysteine methyltransferase (methionine synthase) based on o-phthaldialdehyde derivatization of methionine and fluorescence detection.

The enzyme N5-methyltetrahydrofolate-homocysteine methyltransferase (methionine synthase, EC 2.1.1.13) catalyzes the conversion of homocysteine to methionine in the presence of a reducing system. N5-Methyltetrahydrofolate serves as a methyl donor in this reaction. An assay for the enzyme is described, which is based on methionine quantitation by o-phthaldialdehyde (OPA) derivatization and reversed-phase liquid chromatography. The enzymatic reaction is linear for at least 120 min under reducing conditions (125 mM 2-mercaptoethanol) and running the assay below an oil layer. This reducing system does not interfere with formation of the methionine-OPA adduct, which is separated from interfering compounds and an internal standard (norvaline) by a mobile phase adjusted to pH 5.0. The inclusion of internal standard increases the precision of the assay and corrects for the variable fluorescence yield due to occasional inaccurate pH adjustment before the derivatization step. Norvaline was suitable for this purpose because it elutes close to methionine and is not a natural amino acid present in biological extracts. This nonradioactive assay for methionine synthase was evaluated by comparison with a conventional method based on isolation of radioactive methionine by anion-exchange chromatography and by determination of enzyme activity in extract from cultured cells and liver.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗