Methionine Flux Research Articles

Abstract C053: Autophagy regulates MAT2A in response to hypoxia in pancreatic cancer cells

Abstract Methionine adenosyltransferase 2A (MAT2A) is an essential enzyme responsible for biosynthesis of S-adenosylmethionine, a methyl-group donor of various methyltransferases. Pancreatic ductal adenocarcinoma PDAC is characterized by severe hypoxia and upregulates autophagy and lysosomal biogenesis to enhance nutrient recycling and stress resistance. Here we show that a subset of MAT2A is targeted via the autophagy pathway for degradation by the lysosome under normoxia in PDAC cells, but is subsequently protected against degradation under hypoxia. Mechanistically, we show that the autophagy cargo receptor SQSTM1 (p62) binds to MAT2A in a ubiquitin-dependent manner under normoxia to regulate its autophagic capture. Under hypoxic conditions, stabilized MAT2A potentially facilities increased flux of methionine towards increased SAM, suggesting that protection of MAT2A against lysosomal degradation might enable alterations in methionine metabolism that drive epigenetic and metabolic adaptation to stress. Citation Format: Yang Yang, Wenping Wang, Gilles Rademaker, Mirunalini Ravichandran, Jingjie Hu, Alexander Li, Joseph D. Mancias, Jessie Yanxiang Guo, Rushika M. Perera. Autophagy regulates MAT2A in response to hypoxia in pancreatic cancer cells [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C053.

Spic regulates one-carbon metabolism and histone methylation in ground-state pluripotency.

Understanding mechanisms of epigenetic regulation in embryonic stem cells (ESCs) is of fundamental importance for stem cell and developmental biology. Here, we identify Spic, a member of the ETS family of transcription factors (TFs), as a marker of ground state pluripotency. We show that Spic is rapidly induced in ground state ESCs and in response to extracellular signal-regulated kinase (ERK) inhibition. We find that SPIC binds to enhancer elements and stabilizes NANOG binding to chromatin, particularly at genes involved in choline/one-carbon (1C) metabolism such as Bhmt, Bhmt2, and Dmgdh. Gain-of-function and loss-of-function experiments revealed that Spic controls 1C metabolism and the flux of S-adenosyl methionine to S-adenosyl-L-homocysteine (SAM-to-SAH), thereby, modulating the levels of H3R17me2 and H3K4me3 histone marks in ESCs. Our findings highlight betaine-dependent 1C metabolism as a hallmark of ground state pluripotency primarily activated by SPIC. These findings underscore the role of uncharacterized auxiliary TFs in linking cellular metabolism to epigenetic regulation in ESCs.

Elevated Methionine Flux Drives Pyroptosis Evasion in Persister Cancer Cells.

Methionine enables cancer cells to persist by evading pyroptotic osmotic lysis, which leads to genome-wide hypermethylation that allows persisters to gain proliferative advantages.

Stemness of Normal and Cancer Cells: The Influence of Methionine Needs and SIRT1/PGC-1α/PPAR-α Players.

Stem cells are a population of undifferentiated cells with self-renewal and differentiation capacities. Normal and cancer stem cells share similar characteristics in relation to their stemness properties. One-carbon metabolism (OCM), a network of interconnected reactions, plays an important role in this dependence through its role in the endogenous synthesis of methionine and S-adenosylmethionine (SAM), the universal donor of methyl groups in eukaryotic cells. OCM genes are differentially expressed in stem cells, compared to their differentiated counterparts. Furthermore, cultivating stem cells in methionine-restricted conditions hinders their stemness capacities through decreased SAM levels with a subsequent decrease in histone methylation, notably H3K4me3, with a decrease in stem cell markers. Stem cells' reliance on methionine is linked to several mechanisms, including high methionine flux or low endogenous methionine biosynthesis. In this review, we provide an overview of the recent discoveries concerning this metabolic dependence and we discuss the mechanisms behind them. We highlight the influence of SIRT1 on SAM synthesis and suggest a role of PGC-1α/PPAR-α in impaired stemness produced by methionine deprivation. In addition, we discuss the potential interest of methionine restriction in regenerative medicine and cancer treatment.

The Amount of Dietary Methionine Required to Maximize Synthesis of Transmethylated Products Is Higher Than That Needed for Protein Synthesis in Neonatal Piglets

ObjectivesMethionine is an indispensable sulfur-containing amino acid required for synthesizing protein as well as other critical nutrients. Methionine is the primary methyl donor for >50 transmethylation reactions to produce metabolites including creatine, phosphatidylcholine (PC), and methylated DNA. In piglets, because only one-third of methionine flux is incorporated into protein compared to transmethylation reactions (∼2/3), non-protein demands need to be considered when determining methionine requirement. Our objective was to quantify how much dietary methionine is required to maximize synthesis of protein as well as key transmethylated products. We hypothesized that more dietary methionine will be needed to maximize creatine synthesis, with lower levels required to maximize PC and protein synthesis. MethodsTwenty surgically altered Yucatan miniature piglets (∼8 d old; ∼1.6 kg) were fed complete diets for 5 d and then randomized to 20 test diets with methionine intakes ranging from 20%-220% of requirement (0.05–0.55 g/kg/d). After 24 h of test diet, [3H-methyl]-methionine was infused for 6 h to measure methyl incorporation into creatine, PC, and methylated DNA, and then a3H-phenylalanine flooding dose was given to measure protein synthesis. Break-point analysis was used to identify the methionine required to maximize product synthesis. ResultsPlasma methionine increased above 0.3 g methionine/kg/d, reflecting the whole body requirement. Creatine synthesis maximized at ∼0.3 g methionine/kg/d, while muscle protein synthesis was maximized at 0.2 g methionine/kg/d, suggesting growth is prioritized when methionine is limiting. PC synthesis was low up to 0.35 g methionine/kg/d and increased linearly with higher intakes, suggesting PC synthesis was not maximized at 200% of requirement.3H-DNA did not change with dietary methionine, and plasma homocysteine was positively correlated with dietary methionine. ConclusionsThese data suggest that more methionine is required to accommodate demands for creatine and PC synthesis than that for protein synthesis. Therefore, methionine requirement estimates for infants, which rely on protein synthesis outcomes, are likely insufficient to achieve maximal synthesis of key methylated metabolites creatine and PC. Funding SourcesNSERC.

<p class="Default"><strong>Changes in expression of polyamines and ethylene biosynthesis genes in groundnut (<em>Arachis hypogaea </em>L.) genotypes during <em>Sclerotium rolfsii</em> infection</strong></p>

Stem rot disease caused by fungal pathogen, Sclerotium rolfsii Sacc., is potential threat to groundnut production in warm and humid condition. After host-pathogen interaction, a multitude of plant resistance associated reactions are initiated. In the present investigation we studied the role of polyamines and ethylene during host-pathogen interaction in stem rot tolerant (CS319, GG17 and GG31) and susceptible (TG37A) groundnut genotypes at 24, 48 and 72 h after infection. Stem rot tolerant genotypes showed higher expression of polyamine biosynthesis genes ornithine decarboxylase (Ordec), spermine synthase (Sms) and lipoxygenase1 (LOX1) gene at 72 h after infection than that of susceptible genotype TG37A. The expression analysis of ethylene biosynthesis genes (1-aminocyclopropane-1-carboxylate oxidase: ACCO and (ACCS) showed up regulation in stem rot susceptible genotype TG37A than that of tolerant genotypes after infection at all stages (24, 48 and 72 h after infection). The expression of amine oxidase (AMO) gene was observed highest in stem rot susceptible genotype TG37A while minimum in GJG31. Expression of this gene was remarkably induced in TG37A which may leads to higher accumulation of H2O2. Higher content of a polyamine, putrescine was found in the leaves of stem rot tolerant genotypes at 48 and 72 h after infection. These results implied that tolerant genotypes induced higher polyamine biosynthesis which may involve in plant defense and impart tolerance/ resistance. While, susceptible genotype (TG37A), utilized higher flux of S-Adenosyl methionine (SAM) for ethylene biosynthesis which may leads to necrosis of plants. Thus, stem rot resistant genotypes may be developed through genetic manipulation of polyamine biosynthesis pathway.

Effects of guanidinoacetic acid supplementation on nitrogen retention and methionine flux in cattle.

Creatine stores high-energy phosphate bonds in muscle and is synthesized in the liver through methylation of guanidinoacetic acid (GAA). Supplementation of GAA may therefore increase methyl group requirements, and this may affect methyl group utilization. Our experiment evaluated the metabolic responses of growing cattle to postruminal supplementation of GAA, in a model where methionine (Met) was deficient, with and without Met supplementation. Seven ruminally cannulated Holstein steers (161 kg initial body weight [BW]) were limit-fed a soybean hull-based diet (2.7 kg/d dry matter) and received continuous abomasal infusions of an essential amino acid (AA) mixture devoid of Met to ensure that no AA besides Met limited animal performance. To provide energy without increasing the microbial protein supply, all steers received ruminal infusions of 200 g/d acetic acid, 200 g/d propionic acid, and 50 g/d butyric acid, as well as abomasal infusions of 300 g/d glucose. Treatments, provided abomasally, were arranged as a 2 × 3 factorial in a split-plot design, and included 0 or 6 g/d of l-Met and 0, 7.5, and 15 g/d of GAA. The experiment included six 10-d periods. Whole body Met flux was measured using continuous jugular infusion of 1-13C-l-Met and methyl-2H3-l-Met. Nitrogen retention was elevated by Met supplementation (P < 0.01). Supplementation with GAA tended to increase N retention when it was supplemented along with Met, but not when it was supplemented without Met. Supplementing GAA linearly increased plasma concentrations of GAA and creatine (P < 0.001), but treatments did not affect urinary excretion of GAA, creatine, or creatinine. Supplementation with Met decreased plasma homocysteine (P < 0.01). Supplementation of GAA tended (P = 0.10) to increase plasma homocysteine when no Met was supplemented, but not when 6 g/d Met was provided. Protein synthesis and protein degradation were both increased by GAA supplementation when no Met was supplemented, but decreased by GAA supplementation when 6 g/d Met were provided. Loss of Met through transsulfuration was increased by Met supplementation, whereas synthesis of Met from remethylation of homocysteine was decreased by Met supplementation. No differences in transmethylation, transsulfuration, or remethylation reactions were observed in response to GAA supplementation. The administration of GAA, when methyl groups are not limiting, has the potential to improve lean tissue deposition and cattle growth.

BIMG-18. ELEVATED CYSTATHIONINE IN MEDULLOBLASTOMA DEMONSTRATES TUMOR-SPECIFIC METHIONINE METABOLISM

We investigated tumor-specific metabolism medulloblastoma using a non-biased MS-imaging screen and identified a pattern of methionine flux that may present a therapeutic opportunity. We studied brain tumors that form in mice genetically engineered to develop Sonic Hedgehog (SHH)-driven medulloblastoma. We subjected sagittal sections including brain and medulloblastoma to MS-imaging, generating concentration maps for hundreds of metabolites MW 100–400. We then confirmed results by analyzing tumor, brain and blood by LC-MS/MS, high-resolution NMR and 2D NMR-TOCSY, and used immunohistochemistry to determine the cellular localization of implicated enzymes. MS imaging, accomplished by matrix-assisted laser desorption electrospray ionization (MALDESI), detected cystathionine at an order of magnitude higher concentration in medulloblastomas compared to adjacent brain. No other metabolite showed such a strong, tumor-specific localization. LC-MS/MS and NMR methods confirmed cystathionine elevation. As cystathionine is the product of homocysteine and serine, catalyzed by cystathionine beta-synthase (CBS), we investigated CBS expression by IHC. Consistent with prior studies, we found that only astrocytes expressed CBS, both in the normal brain and within the tumors. ScRNA-seq confirmed Cbs only in astrocytes, and showed tumor cells express methionine-metabolizing enzymes Mat2a, Dnmt1, Ancy and Mtr. Together, these findings show that tumor cells generate and export homocysteine, which astrocytes convert to cystathionine. Tumor cystathionine generation responded to changes in methionine- cycle metabolites. In vivo, systemic administration of homocysteine increased tumor cystathionine which decreased in response to systemic folate, the methyl donor for homocysteine methyltransferase. Cystathionine itself was inert in tumors as tumor cells cultured in up to 8 mM cystathionine showed no change in cell cycle progression. Our studies show that medulloblastomas utilize methionine and generate homocysteine, but avoid folate-dependent homocysteine-methionine recycling by exporting homocysteine for detoxification by local astrocytes. This model suggests that treatments that impose methionine scarcity, folate scarcity or CBS inhibition may produce anti-tumor effects in medulloblastoma.

Effects of Guanidinoacetic Acid on Lean Growth and Methionine Flux in Cattle

Effects of Guanidinoacetic Acid on Lean Growth and Methionine Flux in Cattle

Maternal Methyl-Cycle Amino Acid Profile and Kinetics: Relation with Placental Growth

Maternal intake of quality protein regulates placental development and function thereby affecting fetal growth. Considering the prevalence of inadequate intakes of quality protein in Indian pregnant women, understanding the interplay between maternal supply of protein, its metabolism and fetoplacental growth becomes important. A secondary analysis of data from an open labelled-randomized intervention trial with 500 ml milk/day on south Indian pregnant women with marginally low vitamin B12 status, was performed to assess the relations between placental parameters and maternal trimester 3 methyl-cycle amino acid status as well as kinetics. This analysis was performed for 42 pregnancies from the trial where placentae had been collected and placental parameters had been measured. For these pregnancies, data on trimester 3 methionine, serine and glycine kinetics as well as plasma free amino acid concentrations were available. Protein intake and plasma citrulline concentrations were positively correlated at trimester 3 (ρ = 0.34, P = 0.027). Placental weight correlated positively with methyl-cycle specific amino acid concentrations [methionine (ρ = 0.32, P = 0.0388), serine (ρ = 0.49, P = 0.0009)], methionine kinetics [total methionine flux rates (ρ = 0.42, P = 0.006), RM (ρ = 0.45, P = 0.003), TS (ρ = 0.32, P = 0.046), TM (ρ = 0.45, P = 0.004)] and with birth weight (ρ = 0.57, P &amp;lt; 0.001). Findings from the current study indicate that maternal amino acid availability and more importantly, maternal methionine kinetics, positively influenced placental growth, likely mediated by key amino acids such as citrulline, which is known to regulate placental blood flow and function. As an appropriately functioning placenta is indispensable for fetal growth, these findings will form the basis for detailed mechanistic explorations into the placental regulation of maternal supply of amino acid to the fetus for designing effective intervention strategies towards optimizing fetomaternal health during and after pregnancy.

Methionine and methionine sulfoxide treatment induces M1/classical macrophage polarization and modulates oxidative stress and purinergic signaling parameters.

Methionine is an essential amino acid involved in critical metabolic process, and regulation of methionine flux through metabolism is important to supply this amino acid for cell needs. Elevation in plasma methionine commonly occurs due to mutations in methionine-metabolizing enzymes, such as methionine adenosyltransferase. Hypermethioninemic patients exhibit clinical manifestations, including neuronal and liver disorders involving inflammation and tissue injury, which pathophysiology is not completely established. Here, we hypothesize that alterations in macrophage inflammatory response may contribute to deleterious effects of hypermethioninemia. To this end, macrophage primary cultures were exposed to methionine (1mM) and/or its metabolite methionine sulfoxide (0.5mM), and M1/proinflammatory or M2/anti-inflammatory macrophage polarization was evaluated. In addition, inflammation-related pathways including oxidative stress parameters, as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activities; reactive oxygen species (ROS) production, and purinergic signaling, as ATP/ADP/AMPase activities, were investigated. Methionine and/or methionine sulfoxide induced M1/classical macrophage activation, which is related to proinflammatory responses characterized by increased iNOS activity and TNF-α release. Further experiments showed that treatments promoted alterations on redox state of macrophages by differentially modulated SOD and CAT activities and ROS levels. Finally, methionine and/or methionine sulfoxide treatment also altered the extracellular nucleotide metabolism, promoting an increase of ATPase/ADPase activities in macrophages. In conclusion, these findings contribute to better understand the participation of proinflammatory responses in cell injury observed in hypermethioninemic patients.

Dietary methyl donors affect in vivo methionine partitioning between transmethylation and protein synthesis in the neonatal piglet.

Methionine metabolism is critical during development with significant requirements for protein synthesis and transmethylation reactions. However, separate requirements of methionine for protein synthesis and transmethylation are difficult to define because after transmethylation, demethylated methionine is either irreversibly oxidized to cysteine during transsulfuration, or methionine is regenerated by the dietary methyl donors, choline (via betaine) or folate during remethylation. We hypothesized that remethylation contributes significantly to methionine availability and affects partitioning between protein and transmethylation. 4-8-day-old neonatal piglets were fed a diet devoid (MD-) (n=8) or replete (MS+) (n=8) of folate, choline and betaine to limit remethylation. After 5days, dietary methionine was reduced to 80% of requirement in both groups of piglets to ensure methionine availability was limited. On day 7, an intragastric infusion of [13C1]methionine and [2H3-methyl]methionine was administered to measure methionine cycle flux. In MD- piglets, in vivo remethylation was 60% lower despite 23-fold greater conversion of choline to betaine (P<0.05) and transmethylation was 56% lower (P<0.05), suggesting dietary methyl donors spared 425µmol methyl/day for transmethylation. The priority of protein synthesis versus transmethylation was clear during MD- feeding (P<0.05), as an additional 6% of methionine flux was for protein synthesis in those piglets (P<0.05). However, whole body transsulfuration was unaffected in vivo despite reduced in vitro cystathionine-β-synthase capacity in MD- piglets (P<0.05). Our data show that remethylation contributes significantly to methionine availability and that transmethylation is sacrificed to maintain protein synthesis when methionine is limiting in neonates, which should be considered when determining the methionine requirement.

The dynamics of methionine supply and demand during early development.

Methionine is an indispensable amino acid that, when not incorporated into protein, is converted into the methyl donor S-adenosylmethionine as entry into the methionine cycle. Following transmethylation, homocysteine is either remethylated to reform methionine or irreversibly trans-sulfurated to form cysteine. Methionine flux to transmethylation and to protein synthesis are both high in the neonate and this review focuses on the dynamics of methionine supply and demand during early development, when growth requires expansion of pools of protein and transmethylation products such as creatine and phosphatidylcholine (PC). The nutrients folate and betaine (derived from choline) donate a methyl group during remethylation, providing an endogenous supply of methionine to meet the methionine demand. During early development, variability in the dietary supply of these methionine cycle-related nutrients can affect both the supply and the demand of methionine. For example, a greater need for creatine synthesis can limit methionine availability for protein and PC synthesis, whereas increased availability of remethylation nutrients can increase protein synthesis if dietary methionine is limiting. Moreover, changes to methyl group availability early in life can lead to permanent changes in epigenetic patterns of DNA methylation, which have been implicated in the early origins of adult disease phenomena. This review aims to summarize how changes in methyl supply and demand can affect the availability of methionine for various functions and highlights the importance of variability in methionine-related nutrients in the infant diet.

Whole body methionine kinetics, transmethylation, transulfuration and remethylation during pregnancy

There is evidence from a study of pregnant American women that methionine transmethylation (TM) and remethylation (RM) rates increases and transulfuration (TS) decreases as pregnancy progresses from trimester 1 to 3. To determine whether pregnant Indian women can make this adaptation successfully, methionine kinetics, TS, TM, and RM were measured in Indian women in early and late pregnancy. Measurements were made in the postabsorptive and fed states in the 1st and 3rd trimesters of pregnancy by infusing 1-(13)C,(2)H3-methionine in 24 women, 12 with low (≤150 pmol L(-1)) and 12 with normal (≥200 pmol L(-1)) vitamin B12 status at recruitment. From trimester 1 to 3, except RM which decreased significantly, there was no change in any weight-specific methionine kinetic parameter. When expressed per whole body, methionine flux from protein breakdown increased significantly from trimester 1 to 3 in the fed and postabsorptive states. Flux to protein synthesis also increased significantly in the fed state. Rates of TM, TS and RM did not change, regardless of vitamin B12 status at recruitment. Protein and methionine intakes correlated with TM and RM rates and the change in RM from trimester 1 to 3 correlated with the change in dietary protein intake. These results suggest that methionine flux and its utilization for protein synthesis increases in Indian women as pregnancy progresses from trimester 1 to 3. TM and RM rates do not increase however, possibly because of inadequate protein intake and not because of vitamin B12 deficiency at trimester 1.

The nutritional burden of methylation reactions

Methyl group metabolism is a metabolically demanding process that has significant nutritional implications. Methionine is required not only for protein synthesis but also as the primary source of methyl groups. However, demethylated methionine can be remethylated by methyl groups from methylneogenesis (via folate) and betaine (synthesized from choline). This review discusses the impact of methylation precursors and products on the methionine requirement. Recent evidence has clearly demonstrated that transmethylation reactions can consume a significant proportion of the flux of methionine. In particular, synthesis of creatine and phosphatidylcholine consume most methyl groups and their dietary provision could spare methionine. Importantly, methionine can become limiting for protein and phosphatidylcholine synthesis when creatine synthesis is upregulated. Other research has shown that betaine and choline seem to be more effective than folate at reducing hyperhomocysteinemia and impacting cardiovascular outcomes suggesting they may be limiting. It appears that methyl groups can become limiting when dietary supply is inadequate or if transmethylation reactions are upregulated. These situations can impact methionine availability for protein synthesis, which can reduce growth. The methionine requirement can likely be spared by methyl donor and methylated product supplementation.

Sulfur amino acid metabolism and requirements

The sulfur amino acids (SAA) are methionine and cysteine. Methionine is indispensable.1–5 It donates its sulfur atom to cysteine during the process of trans-sulfuration, making cysteine a dispensable amino acid.6 The carbon skeleton of cysteine, however, is donated by serine.6 Methionine is metabolized via three major metabolic pathways: transmethylation, remethylation, and trans-sulfuration. It serves as the major methyl group donor in vivo,7,8 while cysteine is the rate-limiting substrate for the synthesis of the antioxidant glutathione (GSH).9–11 Both amino acids are important for protein synthesis. The total sulfur amino acid (TSAA) requirement, when fulfilled by the provision of methionine, can be significantly reduced only by adding cysteine to the diet. This phenomenon has been firmly established in animals12–15 and in humans16–18; it is consistent across the lifespan, having been observed in neonates,5–20 children,21 and adults.17,18 In the present issue of this journal, F. Jahoor examines the role the availability of sulfur amino acids plays in severe childhood undernutrition.22 The present editorial complements that work by providing an overview of SAA metabolism and requirements. ### Methionine In healthy adults, the metabolism of methionine is regulated toward anabolism23 in the fed state, and methionine flux is increased relative to that observed in the fasted state. Feeding results in decreased methionine release from protein breakdown and increased transmethylation, trans-sulfuration, and remethylation. In the fasted state, methionine utilization for protein synthesis is increased relative to transmethylation, resulting in the conservation of methionine when SAA availability is low. When SAAs are absent from the diet of healthy adults,17 methionine is used preferentially for protein synthesis relative to transmethylation, confirming previous findings that methionine is conserved via protein synthesis when SAA …

Hypermethioninemias of genetic and non‐genetic origin: A review

This review covers briefly the major conditions, genetic and non-genetic, sometimes leading to abnormally elevated methionine, with emphasis on recent developments. A major aim is to assist in the differential diagnosis of hypermethioninemia. The genetic conditions are: (1) Homocystinuria due to cystathionine β-synthase (CBS) deficiency. At least 150 different mutations in the CBS gene have been identified since this deficiency was established in 1964. Hypermethioninemia is due chiefly to remethylation of the accumulated homocysteine. (2) Deficient activity of methionine adenosyltransferases I and III (MAT I/III), the isoenzymes the catalytic subunit of which are encoded by MAT1A. Methionine accumulates because its conversion to S-adenosylmethionine (AdoMet) is impaired. (3) Glycine N-methyltrasferase (GNMT) deficiency. Disruption of a quantitatively major pathway for AdoMet disposal leads to AdoMet accumulation with secondary down-regulation of methionine flux into AdoMet. (4) S-adenosylhomocysteine (AdoHcy) hydrolase (AHCY) deficiency. Not being catabolized normally, AdoHcy accumulates and inhibits many AdoMet-dependent methyltransferases, producing accumulation of AdoMet and, thereby, hypermethioninemia. (5) Citrin deficiency, found chiefly in Asian countries. Lack of this mitochondrial aspartate-glutamate transporter may produce (usually transient) hypermethioninemia, the immediate cause of which remains uncertain. (6) Fumarylacetoacetate hydrolase (FAH) deficiency (tyrosinemia type I) may lead to hypermethioninemia secondary either to liver damage and/or to accumulation of fumarylacetoacetate, an inhibitor of the high K(m) MAT. Additional possible genetic causes of hypermethioninemia accompanied by elevations of plasma AdoMet include mitochondrial disorders (the specificity and frequency of which remain to be elucidated). Non-genetic conditions include: (a) Liver disease, which may cause hypermethioninemia, mild, or severe. (b) Low-birth-weight and/or prematurity which may cause transient hypermethioninemia. (c) Ingestion of relatively large amounts of methionine which, even in full-term, normal-birth-weight babies may cause hypermethioninemia.

Ontogeny of methionine utilization and splanchnic uptake in critically ill children

To determine the rates of methionine splanchnic uptake and utilization in critically ill pediatric patients we used two kinetic models: the plasma methionine enrichment and the "intracellular" homocysteine enrichment. Twenty four patients, eight infants, eight children, and eight adolescents, were studied. They received simultaneous, primed, constant, intravenous infusions of l-[(2)H(3)]methylmethionine and enteral l-[1-(13)C]methionine. The ratio of [(13)C]homocysteine to [(13)C]methionine enrichment was 1.0 ± 0.15, 0.80 ± 0.20, and 0.66 ± 0.10, respectively, for the infants, children, and adolescents, and it was different between the infants and adolescents (P < 0.01). Methionine splanchnic uptake was 63, 45, and 36%, respectively, in the infants, children, and adolescents, and it was higher (P < 0.01) in the infants compared with the adolescents. The infants utilized 73% of methionine flux for nonoxidative disposal, while 27% was used for transulfuration (P < 0.001). Conversely, in the adolescents, 40% was utilized for nonoxidative disposal, while 60% was used for transulfuration. There is ontogeny on the rates of methionine splanchnic uptake and on the fate of methionine utilization in critically ill children, with greater methionine utilization for synthesis of proteins and methionine-derived compounds (P < 0.01) and decreased transulfuration rates in the infants (P < 0.01), while the opposite was observed in the adolescents. The plasma model underestimated methionine kinetics in children and adolescents but not in the infants, suggesting lesser dilution and greater compartmentation of methionine metabolism in the infant population. All patients were in negative methionine balance, indicating that the current enteral nutritional support is inadequate in these patients.

Methionine splanchnic uptake is increased in critically ill children.

During critical illness the splanchnic area is profoundly affected. There is no information on splanchnic uptake of amino acids in vivo, in critically ill children.Hypothesis:Methionine splanchnic uptake in critically ill children will differ from estimates in healthy adults.Methods:We studied 24 critically ill children. Eight infants (age 6±3months; wt 6±1.4 kg), eight children (age 5±2 y; wt 14±3 kg and 8 adolescents (15±1.94 y; wt 63.3±21kg), who received continuous enteral feedings, providing protein and energy intake at full maintenance needs. We conducted a simultaneous, intravenous, primed, constant, 9h tracer infusion of L‐[2H3methyl] methionine at 2.5 μmol.kg −1h1 and enteral infusion of L‐[13C] methionine at 5μmol.kg−1h1.Results:Plasma methionine fluxes obtained with the enteral 13C and the intravenous 2H3 labels were 85±13 and 30±8, 71±5 and 41±15, and 68±7 and 35±7 μmol.kg−1h−1, respectively for infants, children and adolescents. First pass disappearance of methionine tracer, respectively, was 63, 43 and 47%. The rates of intestinal methionine oxidation were 24±10, 18±6 and 23±8 μmol.kg−1h1Conclusions:Methionine splanchnic uptake is higher in critically ill infants when compared to children and adolescents (p&lt;0.05), and higher than values of about 15% reported in healthy adults. NIH DK‐62363, T32 HD‐007445, Ajinomoto 3‐ARP; USDA/ARS 25337387, Sophia Foundation for Scientific Research

Sulfur amino acid metabolism in children with severe childhood undernutrition: methionine kinetics

Children with edematous but not nonedematous severe childhood undernutrition (SCU) have lower plasma and erythrocyte-free concentrations of cysteine and methionine, which suggests a decreased availability of methionine for cysteine synthesis. We propose that methionine production and metabolism will be slower in children with edematous SCU than in those with nonedematous SCU. We aimed to measure methionine flux, its transmethylation and its transsulfuration, and homocysteine remethylation in children with SCU. Methionine kinetics were measured in 2 groups of children with edematous (n = 11) and nonedematous (n = 11) SCU when they were infected and malnourished (clinical phase 1), when they were still severely malnourished but no longer infected (clinical phase 2), and when they had recovered (clinical phase 3). At clinical phase 1, children with edematous SCU had rates of total methionine flux, flux from protein breakdown, and flux to protein synthesis that were slower than the rates of the nonedematous group. There were no significant differences in homocysteine remethylation or methionine transsulfuration and transmethylation between the groups at clinical phase 1. These findings suggest that, in the acutely malnourished and infected state, children with edematous SCU have slower methionine production than do children with nonedematous SCU because of a slower rate of release from protein breakdown. This slower methionine production is not, however, associated with slower rates of methionine transsulfuration and transmethylation or homocysteine remethylation.