Division of labour: how does folate metabolism partition between one-carbon metabolism and amino acid oxidation?

2015 ◽  
Vol 472 (2) ◽  
pp. 135-146 ◽  
Author(s):  
Margaret E. Brosnan ◽  
Luke MacMillan ◽  
Jennifer R. Stevens ◽  
John T. Brosnan
Keyword(s):  
Amino Acids ◽  
Carbon Metabolism ◽  
Division Of Labour ◽  
Acid Oxidation ◽  
Formyl Group ◽  
Amino Acid Oxidation ◽  
Major Function ◽  
Key Enzyme ◽  
One Carbon Metabolism ◽  
Thymidylate Synthesis

One-carbon metabolism is usually represented as having three canonical functions: purine synthesis, thymidylate synthesis and methylation reactions. There is however a fourth major function: the metabolism of some amino acids (serine, glycine, tryptophan and histidine), as well as choline. These substrates can provide cells with more one-carbon groups than they need for these three canonical functions. Therefore, there must be mechanisms for the disposal of these one-carbon groups (when in excess) which maintain the complement of these groups required for the canonical functions. The key enzyme for these mechanisms is 10-formyl-THF (tetrahydrofolate) dehydrogenase (both mitochondrial and cytoplasmic isoforms) which oxidizes the formyl group to CO2 with the attendant reduction of NADP+ to NADPH and release of THF. In addition to oxidizing the excess of these compounds, this process can reduce substantial quantities of NADP+ to NADPH.

scholarly journals 107 Roles of Amino Acids in One-carbon Metabolism and Nutition.

2018 ◽  
Vol 96 (suppl_3) ◽  
pp. 387-387
Author(s):  
R Bertolo ◽  
J Brosnan
Keyword(s):  
Amino Acids ◽  
Carbon Metabolism ◽  
One Carbon Metabolism

Quantitative analysis of amino acid oxidation and related gluconeogenesis in humans

1992 ◽  
Vol 72 (2) ◽  
pp. 419-448 ◽  
Author(s):  
R. L. Jungas ◽  
M. L. Halperin ◽  
J. T. Brosnan
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Urea Cycle ◽  
Liver Mitochondria ◽  
Carbon Flow ◽  
Acid Oxidation ◽  
Peripheral Tissues ◽  
Amino Acid Oxidation ◽  
Atp Production ◽  
Acid Load

Significant gaps remain in our knowledge of the pathways of amino acid catabolism in humans. Further quantitative data describing amino acid metabolism in the kidney are especially needed as are further details concerning the pathways utilized for certain amino acids in liver. Sufficient data do exist to allow a broad picture of the overall process of amino acid oxidation to be developed along with approximate quantitative assessments of the role played by liver, muscle, kidney, and small intestine. Our analysis indicates that amino acids are the major fuel of liver, i.e., their oxidative conversion to glucose accounts for about one-half of the daily oxygen consumption of the liver, and no other fuel contributes nearly so importantly. The daily supply of amino acids provided in the diet cannot be totally oxidized to CO2 in the liver because such a process would provide far more ATP than the liver could utilize. Instead, most amino acids are oxidatively converted to glucose. This results in an overall ATP production during amino acid oxidation very nearly equal to the ATP required to convert amino acid carbon to glucose. Thus gluconeogenesis occurs without either a need for ATP from other fuels or an excessive ATP production that could limit the maximal rate of the process. The net effect of the oxidation of amino acids to glucose in the liver is to make nearly two-thirds of the total energy available from the oxidation of amino acids accessible to peripheral tissues, without necessitating that peripheral tissues synthesize the complex array of enzymes needed to support direct amino acid oxidation. As a balanced mixture of amino acids is oxidized in the liver, nearly all carbon from glucogenic amino acids flows into the mitochondrial aspartate pool and is actively transported out of the mitochondria via the aspartate-glutamate antiport linked to proton entry. In the cytoplasm the aspartate is converted to fumarate utilizing urea cycle enzymes; the fumarate flows via oxaloacetate to PEP and on to glucose. Thus carbon flow through the urea cycle is normally interlinked with gluconeogenic carbon flow because these metabolic pathways share a common step. Liver mitochondria experience a severe nonvolatile acid load during amino acid oxidation. It is suggested that this acid load is alleviated mainly by the respiratory chain proton pump in a form of uncoupled respiration.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Radiometric studies on the oxidation of (U-14C) L-amino acids by drug-susceptible and drug-resistant mycobacteria

1987 ◽  
Vol 29 (5) ◽  
pp. 312-316
Author(s):  
Edwaldo E. Camargo ◽  
Teresa M. Kopajtic ◽  
Glinda K. Hopkins ◽  
Nancy P. Cannon ◽  
Henry N. Wagner Jr
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Reaction System ◽  
Tuberculosis H37rv ◽  
Assay System ◽  
Acid Oxidation ◽  
Resistant Organism ◽  
Drug Resistant ◽  
Amino Acid Oxidation ◽  
Radiometric Assay

A radiometric assay system has been used to study oxidation patterns of (U-14C) L-amino acids by drug-susceptible and drug-resistant mycobacteria. Drug-susceptible M. tuberculosis (H37Rv TMC 102 and Erdman) along with the drug-resistant organism M. tuberculosis (H37 Rv TMC 303), M. bovis, M. avium, M. intracellulare, M. kansasii and M. chelonei were used. The organisms were inoculated into a sterile reaction system with liquid 7H9 medium and one of the (U-14C) L-amino acids. Each organism displayed a different pattern of amino acid oxidation, but these patterns were not distinctive enough for identification of the organism. Complex amino acids such as proline, phenylalanine and tyrosine were of no use in identification of mycobacteria, since virtually all organisms failed to oxidize them. There was no combination of substrates able to separate susceptible from resistant organisms.

scholarly journals Formate concentrations in maternal plasma during pregnancy and in cord blood in a cohort of pregnant Canadian women: relations to genetic polymorphisms and plasma metabolites

2019 ◽  
Vol 110 (5) ◽  
pp. 1131-1137 ◽  
Author(s):  
John T Brosnan ◽  
Lesley Plumptre ◽  
Margaret E Brosnan ◽  
Theerawat Pongnopparat ◽  
Shannon P Masih ◽  
...  
Keyword(s):  
Cord Blood ◽  
Early Pregnancy ◽  
Carbon Metabolism ◽  
Critical Role ◽  
Plasma Concentrations ◽  
Maternal Blood ◽  
Plasma Metabolites ◽  
Blood Samples ◽  
One Carbon Metabolism ◽  
Thymidylate Synthesis

ABSTRACT Background One-carbon metabolism, responsible for purine and thymidylate synthesis and transmethylation reactions, plays a critical role in embryonic and fetal development. Formate is a key player in one-carbon metabolism. In contrast to other one-carbon metabolites, it is not linked to tetrahydrofolate, is present in plasma at appreciable concentrations, and may therefore be distributed to different tissues. Objective The study was designed to determine the concentration of formate in cord blood in comparison with maternal blood taken earlier in pregnancy and at delivery and to relate formate concentrations to potential precursors and key fetal genotypes. Methods Formate and amino acids were measured in plasma during early pregnancy (12–16 wk), at delivery (37–42 wk), and in cord blood samples from 215 mothers, of a prospective cohort study. Three fetal genetic variants in one-carbon metabolism were assessed for their association with cord plasma concentrations of formate. Results The formate concentration was ∼60% higher in the cord blood samples than in mothers’ plasma. The maternal formate concentrations did not differ between the early pregnancy samples and those taken at delivery. Plasma concentrations of 4 formate precursors (serine, glycine, tryptophan, and methionine) were increased in cord blood compared with the maternal samples. Cord blood formate was influenced by fetal genotype, being ∼12% higher in infants harboring the MTHFR A1298C (rs1801131) AC or CC genotypes and 10% lower in infants harboring the MTHFD1 G1958A (rs2236225) GA or AA genotypes. Conclusions The increased formate concentrations in cord blood may support the increased activity of one-carbon metabolism in infants. As such, it would support increased rates of purine and thymidylate synthesis and the provision of methionine for methylation reactions.

scholarly journals Kinetic Modeling of Storage Effects on Biomarkers Related to B Vitamin Status and One-Carbon Metabolism

2012 ◽  
Vol 58 (2) ◽  
pp. 402-410 ◽  
Author(s):  
Steinar Hustad ◽  
Simone Eussen ◽  
Øivind Midttun ◽  
Arve Ulvik ◽  
Puck M van de Kant ◽  
...  
Keyword(s):  
Amino Acids ◽  
Carbon Metabolism ◽  
Room Temperature ◽  
Nonlinear Models ◽  
Methionine Sulfoxide ◽  
Flavin Mononucleotide ◽  
Storage Effects ◽  
One Carbon Metabolism ◽  
Accumulation Kinetics ◽  
B Vitamin

Abstract BACKGROUND Biomarkers and metabolites related to B vitamin function and one-carbon metabolism have been studied as predictors of chronic diseases in studies based on samples stored in biobanks. For most biomarkers, stability data are lacking or fragmentary. METHODS Degradation and accumulation kinetics of 32 biomarkers were determined at 23 °C in serum and plasma (EDTA, heparin, and citrate) collected from 16 individuals and stored for up to 8 days. In frozen serum (−25 °C), stability was studied cross-sectionally in 650 archival samples stored for up to 29 years. Concentration vs time curves were fitted to monoexponential, biexponential, linear, and nonlinear models. RESULTS For many biomarkers, stability was highest in EDTA plasma. Storage effects were similar at room temperature and at −25 °C; notable exceptions were methionine, which could be recovered as methionine sulfoxide, and cystathionine, which decreased in frozen samples. Cobalamin, betaine, dimethylglycine, sarcosine, total homocysteine, total cysteine, tryptophan, asymetric and symmetric dimethyl argenine, creatinine, and methylmalonic acid were essentially stable under all conditions. Most B vitamins (folate and vitamins B2 and B6) were unstable; choline increased markedly, and some amino acids also increased, particularly in serum. The kynurenines showed variable stability. For many biomarkers, degradation (folate and flavin mononucleotide) or accumulation (pyridoxal, riboflavin, choline, amino acids) kinetics at room temperature were non–first order. CONCLUSIONS Data on stability and deterioration kinetics for individual biomarkers are required to optimize procedures for handling serum and plasma, and for addressing preanalytical bias in epidemiological and clinical studies.

scholarly journals Diurnal response in endogenous amino acid oxidation of meal-fed rats

1980 ◽  
Vol 190 (3) ◽  
pp. 663-671 ◽  
Author(s):  
R W Wannemacher ◽  
R E Dinterman
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Dietary Protein ◽  
Normal Diet ◽  
Acid Oxidation ◽  
Body Protein ◽  
Amino Acid Oxidation ◽  
Collagen Protein ◽  
Meal Feeding ◽  
Endogenous Amino Acid

A model has been developed to measure the effects of dietary protein on daily fluctuations in the rate of endogenous amino acid oxidation in meal-fed and starved rats. In addition, N tau-methylhistidine and hydroxyproline were utilized to determine changes in the rate of degradation of myofibrillar and collagen proteins. In rats meal-fed a normal diet of 18% (w/w) casein, a diurnal response was observed in rate of oxidation of radioactive amino acids contained in endogenous labelled body protein, with a nadir 16—20 h and maximum 4—8 h after beginning the feeding. This observation in part may be related to alterations in flux of amino acids from non-hepatic tissues to site of oxidation in liver, as well as alterations in rates of amino acid oxidation after a protein meal. When meal-fed a 70% protein diet, the maximal rates of endogenous amino acid oxidation were significantly increased by 4—8 h after meal-feeding, with no change in fractional rates of degradation of myofibrillar- or collagen-protein breakdown. This could suggest increases in activities of enzymes involved in amino acid oxidation, in rats meal-fed 70% compared with 18% dietary protein. In contrast, meal-feeding of a protein-free diet muted the diurnal response in the rate of oxidation of endogenously labelled amino acids, which correlated with a decrease in the fractional rate of degradation of myofibrillar or collagen protein. Thus dietary protein is apparently responsible for the observed diurnal rhythm rhythms in the rate of amino acid oxidation, whereas carbohydrates tend to mute the response.

PSX-A-17 Late-Breaking: Methionine and total sulfur amino acid requirements for pups (>14 wk to 9 months), adults, and senior Labrador Retrievers using the indicator amino acid oxidation (IAAO) technique

2021 ◽  
Vol 99 (Supplement_3) ◽  
pp. 374-374
Author(s):  
Jessica L Varney ◽  
Charlene Watson ◽  
Nicole Colopy ◽  
John Moss ◽  
Jordan T Weil ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Control Diet ◽  
Age Groups ◽  
Isotope Ratio Mass Spectrometry ◽  
Co2 Production ◽  
Acid Oxidation ◽  
Total Sulfur ◽  
Amino Acid Oxidation ◽  
Labrador Retrievers

Abstract Methionine and cystine are often considered limiting amino acids in canine diets but limited requirement studies have been conducted especially for different life stages. Eighteen Labrador Retrievers (6 pups (>14 wk-9 month), 6 adults, and 6 seniors [>8yr)] were utilized in feeding studies to evaluate the changing requirements of methionine (Met) and total sulfur amino acids (TSAA) as canines age. For this study, the indicator amino acid oxidation (IAAO) technique was utilized to determine the amino acid (AA) requirements in each of the three age groups. Dogs were subjected to diets ranging from deficient to excess, with indispensable amino acids formulated at 1.6x NRC values. To allow for adaptation, a control diet with same dietary ingredients, protein and amino acid levels was fed for two days prior to feeding the test diets on the third day. On test day, a baseline breath sample was collected for determining CO2 production using a respiration mask (Oxymax, Columbus Instruments). A priming dose of L-[1-13C] phenylalanine (Cambridge Isotope Laboratories, Inc.) based on body weight was utilized, followed by [1-13C] Phe doses every 30 minutes, spanning a four hour period. After each dose 13CO2 was collected, and enrichment was determined by isotope ratio mass spectrometry (IRMS). Results for IRMS were converted to atom percent excess (APE) and analyzed using a piecewise model of best fit (JMP® Pro 16). A segmented line regression showed Met and TSAA mean and population requirements for pups (>14 wk-9 mo.) were 0.78 ± 0.16 and 1.53 ± 0.21 g/1000kcal (mean ± 2SD), respectively. Meanwhile, for adults, mean and population requirements for Met and TSAA were estimated to be 0.68 ± 0.19 and 1.4 ± 0.30 g/1000kcal (mean ± 2SD), respectively, and for seniors, Met and TSAA mean and population requirements were determined to be 0.62 ± 0.17 and 1.27 ± 0.23 g/1000kcal (mean ± 2SD), respectively.

scholarly journals Prolonged maternal amino acid infusion in late-gestation pregnant sheep increases fetal amino acid oxidation

2009 ◽  
Vol 297 (3) ◽  
pp. E638-E646 ◽  
Author(s):  
Paul J. Rozance ◽  
Michelle M. Crispo ◽  
James S. Barry ◽  
Meghan C. O'Meara ◽  
Mackenzie S. Frost ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Protein Supplementation ◽  
Late Gestation ◽  
Acid Oxidation ◽  
Leucine Incorporation ◽  
Oxygen Utilization ◽  
Amino Acid Oxidation ◽  
Amino Acid Infusion ◽  
Pregnant Sheep

Protein supplementation during human pregnancy does not improve fetal growth and may increase small-for-gestational-age birth rates and mortality. To define possible mechanisms, sheep with twin pregnancies were infused with amino acids (AA group, n = 7) or saline (C group, n = 4) for 4 days during late gestation. In the AA group, fetal plasma leucine, isoleucine, valine, and lysine concentrations were increased ( P < 0.05), and threonine was decreased ( P < 0.05). In the AA group, fetal arterial pH (7.365 ± 0.007 day 0 vs. 7.336 ± 0.012 day 4, P < 0.005), hemoglobin-oxygen saturation (46.2 ± 2.6 vs. 37.8 ± 3.6%, P < 0.005), and total oxygen content (3.17 ± 0.17 vs. 2.49 ± 0.20 mmol/l, P < 0.0001) were decreased on day 4 compared with day 0. Fetal leucine disposal did not change (9.22 ± 0.73 vs. 8.09 ± 0.63 μmol·min−1·kg−1, AA vs. C), but the rate of leucine oxidation increased 43% in the AA group (2.63 ± 0.16 vs. 1.84 ± 0.24 μmol·min−1·kg−1, P < 0.05). Fetal oxygen utilization tended to be increased in the AA group (327 ± 23 vs. 250 ± 29 μmol·min−1·kg−1, P = 0.06). Rates of leucine incorporation into fetal protein (5.19 ± 0.97 vs. 5.47 ± 0.89 μmol·min−1·kg−1, AA vs. C), release from protein breakdown (4.20 ± 0.95 vs. 4.62 ± 0.74 μmol·min−1·kg−1), and protein accretion (1.00 ± 0.30 vs. 0.85 ± 0.25 μmol·min−1·kg−1) did not change. Consistent with these data, there was no change in the fetal skeletal muscle ubiquitin ligases MaFBx1 or MuRF1 or in the protein synthesis regulators 4E-BP1, eEF2, eIF2α, and p70S6K. Decreased concentrations of certain essential amino acids, increased amino acid oxidation, fetal acidosis, and fetal hypoxia are possible mechanisms to explain fetal toxicity during maternal amino acid supplementation.

scholarly journals Development of the Indicator Amino Acid Oxidation Technique to Determine the Availability of Amino Acids from Dietary Protein in Pigs

2005 ◽  
Vol 135 (12) ◽  
pp. 2866-2870 ◽  
Author(s):  
Soenke Moehn ◽  
Robert F. P. Bertolo ◽  
Paul B. Pencharz ◽  
Ronald O. Ball
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Dietary Protein ◽  
Acid Oxidation ◽  
Amino Acid Oxidation
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