Cystathionine beta synthase deficiency and brain edema associated with methionine excess under betaine supplementation: Four new cases and a review of the evidence.

CBS deficient individuals undergoing betaine supplementation without sufficient dietary methionine restriction can develop severe hypermethioninemia and brain edema. Brain edema has also been observed in individuals with severe hypermethioninemia without concomitant betaine supplementation. We systematically evaluated reports from 11 published and 4 unpublished patients with CBS deficiency and from additional four cases of encephalopathy in association with elevated methionine. We conclude that, while betaine supplementation does greatly exacerbate methionine accumulation, the primary agent causing brain edema is methionine rather than betaine. Clinical signs of increased intracranial pressure have not been seen in patients with plasma methionine levels below 559 μmol/L but occurred in one patient whose levels did not knowingly exceed 972 μmol/L at the time of manifestation. While levels below 500 μmol/L can be deemed safe it appears that brain edema can develop with plasma methionine levels close to 1000 μmol/L. Patients with CBS deficiency on betaine supplementation need to be regularly monitored for concordance with their dietary plan and for plasma methionine concentrations. Recurrent methionine levels above 500 μmol/L should alert clinicians to check for clinical signs and symptoms of brain edema and review dietary methionine intake. Levels approaching 1000 μmol/L do increase the risk of complications and levels exceeding 1000 μmol/L, despite best dietetic efforts, should be acutely addressed by reducing the prescribed betaine dose

Dysregulated Choline, Methionine, and Aromatic Amino Acid Metabolism in Patients with Wilson Disease: Exploratory Metabolomic Profiling and Implications for Hepatic and Neurologic Phenotypes.

Wilson disease (WD) is a genetic copper overload condition characterized by hepatic and neuropsychiatric symptoms with a not well-understood pathogenesis. Dysregulated methionine cycle is reported in animal models of WD, though not verified in humans. Choline is essential for lipid and methionine metabolism. Defects in neurotransmitters as acetylcholine, and biogenic amines are reported in WD; however, less is known about their circulating precursors. We aimed to study choline, methionine, aromatic amino acids, and phospholipids in serum of WD subjects. Hydrophilic interaction chromatography-quadrupole time-of-flight mass spectrometry was employed to profile serum of WD subjects categorized as hepatic, neurologic, and pre-clinical. Hepatic transcript levels of genes related to choline and methionine metabolism were verified in the Jackson Laboratory toxic milk mouse model of WD (tx-j). Compared to healthy subjects, choline, methionine, ornithine, proline, phenylalanine, tyrosine, and histidine were significantly elevated in WD, with marked alterations in phosphatidylcholines and reductions in sphingosine-1-phosphate, sphingomyelins, and acylcarnitines. In tx-j mice, choline, methionine, and phosphatidylcholine were similarly dysregulated. Elevated choline is a hallmark dysregulation in WD interconnected with alterations in methionine and phospholipid metabolism, which are relevant to hepatic steatosis. The elevated phenylalanine, tyrosine, and histidine carry implications for neurologic manifestations and are worth further investigation

Influence of methionine supplementation of growing diets enriched with lysine on feedlot performance and characteristics of digestion in Holstein steer calves.

ObjectiveTwo trials were conducted in order to examine the effects of level of supplemental methionine on productive performance, dietary energetic, plasma amino acid concentration, and digestive function.MethodsDietary treatments consisted of a steam-flaked corn-based diet containing urea as the only source of supplemental nitrogen supplemented with no supplemental amino acid (control), or control plus 1.01% lysine and 0.032%, 0.064%, 0.096%, or 0.128% methionine. In Trial 1, 150 Holstein steer calves (127±4.9 kg) were utilized to evaluate the influence of treatments on growth-performance, dietary energetic, plasma amino acid concentration during the first 112 days of growing period. During the initial 56-d period calves received the 5 experimental diets. During the subsequent 56-d period all calves were fed the control diet.ResultsDuring the initial 56-d period, methionine supplementation increased (linear effect, p<0.01) plasma methionine. In the presence of supplemental lysine, increases on level of methionine in diet did not affect average daily gain. However, increased gain efficiency (quadratic effect, p = 0.03) and estimated dietary net energy (NE; linear effect, p = 0.05). Estimated metabolizable methionine supply was closely associated (R2 = 0.95) with efficiency NE utilization for maintenance and gain. During the subsequent 56-d period, when all calves received the control diet (no amino acid supplementation), plasma amino acid concentrations and growth performance was not different among groups. However, the effects of methionine supplementation during the initial 56-period carried over, so that following a 56-d withdrawal of supplementation, the overall 112-d effects on gain efficiency (quadratic effect, p = 0.05) dietary NE (linear effect, p≤0.05) remained appreciable. In Trial 2, 5 cannulated Holstein steers were used to evaluate treatment effects on characteristics of digestion and amino acid supply to the small intestine. There were no treatment effects on flow of dietary and microbial N to the small intestine. Postruminal N digestion increased (p = 0.04) with increasing level of supplemental methionine. Methionine supplementation linearly increased (p<0.01) duodenal flow of methionine. Likewise, lysine supplementation increased an average of 4.6% (p = 0.04) duodenal flow of lysine. In steers that received non-supplemented diet, observed intestinal amino acid supply were in good agreement with expected.ConclusionWe conclude that addition of rumen-protected methionine and lysine to diets may enhance gain efficiency and dietary energetics of growing Holstein calves. Observed amino acid supply to the small intestine were in good agreement with expected, supportive of NRC (2000, Level 1)

Methionine synthesis in Neurospora. The isolation of cystathionine

Among artificially produced biochemical mutants of Neurospora, those which have lost the ability to synthesize methionine form the largest class. At the present writing 87 occurrences of the methionineless character have been observed in this laboratory following treatment of wild type spores with high frequency radiations (1) or mustard gas (2). Methionineless mutants differ from wild type Neurospora in that they fail to grow on a medium containing only sugar, inorganic salts, and biotin, but do grow if, in addition to these constituents, methionine is supplied. In many of the mutants failure of methionine synthesis results from a block in the reduction of sulfate, which, except for a trace of biotin, is the sole source of sulfur in the basal medium. These strains can utilize reduced forms of inorganic sulfur for growth, as well as methionine and other organic sulfur compounds. On the other hand, some of the mutants require organically bound sulfur for growth, an indication that in these strains the block in methionine synthesis comes at a later stage than sulfate reduction. Similar classes of methionine-requiring mutants have been reported in the mold Ophiostoma by Fries (3) and in Escherichia coli by Lampen et al. (4-6)

Developments in plant breeding for improved nutritional quality of soya beans I. Protein and amino acid content

Soya beans, like other legumes, contain low concentrations of the nutritionally essential sulphur amino acid, methionine. Cysteine, although not an essential amino acid because it can be synthesized from methionine, also influences the nutritional quality of soya bean products when it is only present in low levels. A low cysteine content will also aggravate a methionine deficiency. Soya bean lines deficient in 7S protein subunits have been identified. The 7S proteins contain substantially less methionine and cysteine than the 11S proteins. With the myriad of genetic null alleles for these subunits it may be possible to tailor the 7S/11S storage protein ratio and their total composition in seeds to include only those subunits with the richest sulphur amino acid composition. Cotyledon feeding experiments, using isolated soya bean cotyledons, demonstrated that addition of methionine to the culture media caused increased synthesis of both proteins and free amino acids but the mechanism by which this takes place is not clear

Dimethylthetin and dimethyl-β-propriothetin in methionine synthesis

In a previous communication it was shown that choline and betaine are effective in promoting methionine synthesis from homocysteine in tissue homogenates (1). Data presented in this paper indicate that dimethylthetin, (CH3)2+SCH2COO-, which has been shown by Welch (2) to be lipotropic and has been reported by du Vigneaud (3) to promote growth on a methionine-free, homocysteine-containing diet, is 20 times as active as betaine in methionine formation. Dimethyl-β-propiothetin, (CH3)2+S(CH2)2COO-, recently isolated from Polysiphonia fastigiata by Challenger and Simpson (4) is also highly active. The enzyme for this transmethylation is found in the liver and kidney of all animals tested. Its high activity and general distribution suggest its biological importance in methionine synthesis

Recombinant methioninase effectively targets a Ewing's sarcoma in a patient-derived orthotopic xenograft (PDOX) nude-mouse model.

Methionine dependence is due to the overuse of methionine for aberrant transmethylation reactions in cancer. Methionine dependence may be the only general metabolic defect in cancer. In order to exploit methionine dependence for therapy, our laboratory previously cloned L-methionine α-deamino-γ-mercaptomethane lyase [EC 4.4.1.11]). The cloned methioninase, termed recombinant methioninase, or rMETase, has been tested in mouse models of human cancer cell lines. Ewing's sarcoma is recalcitrant disease even though development of multimodal therapy has improved patients'outcome. Here we report efficacy of rMETase against Ewing's sarcoma in a patient-derived orthotopic xenograft (PDOX) model. The Ewing's sarcoma was implanted in the right chest wall of nude mice to establish a PDOX model. Eight Ewing's sarcoma PDOX mice were randomized into untreated control group (n = 4) and rMETase treatment group (n = 4). rMETase (100 units) was injected intraperitoneally (i.p.) every 24 hours for 14 consecutive days. All mice were sacrificed on day-15, 24 hours after the last rMETase administration. rMETase effectively reduced tumor growth compared to untreated control. The methionine level both of plasma and supernatants derived from sonicated tumors was lower in the rMETase group. Body weight did not significantly differ at any time points between the 2 groups. The present study is the first demonstrating rMETase efficacy in a PDOX model, suggesting potential clinical development, especially in recalcitrant cancers such as Ewing's sarcoma

Tunable, Functional Diblock Copolypeptide Hydrogels Based on Methionine Homologs.

The preparation of new diblock copolypeptide hydrogels derived from homologs of l-methionine, that is, l-homomethionine and l-6-(methylthio)-l-norleucine is described. Compared to l-methionine residues, use of l-methionine homologs allow improved copolymerization with l-leucine residues to give well-defined block copolypeptides. These copolypeptides are subsequently modified using robust thioether alkylation reactions employing a variety of functional epoxides, which yield samples capable of forming transparent, self-healing hydrogels in water. The facile variation of different functional epoxides for postpolymerization modification is found to allow predictable functionalization and tuning of hydrogel properties by the modification of simple precursors

Methylation of guanidoacetic acid by homocystine plus choline with rat liver slices

The methylation of guanidoacetic acid by liver slices is accelerated by methionine; choline, under these conditions, exerts no significant accelerating effect (1). In view of the fact that homocystine plus choline can replace methionine for growth (2), and of the isotope experiments which proved the transfer in viva of the methyl groups of choline to creatine,(3) it has been suggested, from indirect evidence, that the pathway of the methyl group to creatine is more direct from methionine than from choline.(4) More specific evidence is desirable, especially as neither homocystine nor homocysteine has been identified in animal tissues