Role of branched-chain 2-oxo acid dehydrogenase and pyruvate dehydrogenase in 2-oxobutyrate metabolism

Paxton, Ralph; Ścisłowski, P. W. D.; Davis, Eric; Harris, Robert A.

doi:10.1042/bj2340295

Cited by 56 publications

(42 citation statements)

References 42 publications

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“…Decreased levels of 2-oxobutyrate in combination with an increase in 2-aminobutyrate might favor the hypothesis of increased amino acid catabolism of threonine (Paxton et al 1986; Steele 1982). On the other hand, lower urinary excretion might also reflect an increased uptake of amino acids by the tumor for protein biosynthesis, accompanied by cellular turnover and tumor growth.…”

Section: Discussionmentioning

confidence: 99%

Changes in urinary metabolic profiles of colorectal cancer patients enrolled in a prospective cohort study (ColoCare)

et al. 2014

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Introduction Metabolomics is a valuable tool for biomarker screening of colorectal cancer (CRC). In this study, we profiled the urinary metabolomes of patients enrolled in a prospective patient cohort (ColoCare). We aimed to describe changes in the metabolome in the longer clinical follow-up and describe initial predictors as candidate markers with possibly prognostic significance Methods In total, 199 urine samples from CRC patients pre-surgery (n=97), 1–8 days post-surgery (n=12) and then after 6 and 12 months (n=52 and 38, respectively) were analyzed using both GC-MS and 1H-NMR. Both datasets were analyzed separately with built in uni- and multivariate analyses of Metaboanalyst 2.0. Furthermore, adjusted linear mixed effects regression models were constructed. Results Many concentrations of the metabolites derived from the gut microbiome were affected by CRC surgery, presumably indicating a tumor-induced shift in bacterial species. Associations of the microbial metabolites with disease stage indicate an important role of the gut microbiome in CRC. We were able to differentiate the metabolite profiles of CRC patients prior to surgery from those at any post-surgery timepoint using a multivariate model containing 20 marker metabolites (AUCROC=0.89; 95% CI:0.84–0.95). Conclusion To the best of our knowledge, this is one of the first metabolomic studies to follow CRC patients in a prospective setting with repeated urine sampling over time. We were able to confirm markers initially identified in case-control studies and pin point metabolites which may serve as candidates for prognostic biomarkers of CRC.

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Section: Discussionmentioning

confidence: 99%

Changes in urinary metabolic profiles of colorectal cancer patients enrolled in a prospective cohort study (ColoCare)

et al. 2014

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“…It has been reported that the branched-chain ␣-keto acid dehydrogenase complex (BCKDC, the rate-limiting enzyme in the BCAA catabolic pathway) affects methionine catabolism in the liver (13,14) and that leucine administration activates hepatic BCKDC in rats (15). Notwithstanding the fact that the activity level of hepatic BCKDC is markedly lower in humans than in rats (16,17), BCAA intake-induced upregulation in the liver BCKDC may be involved in the mechanism responsible for the decrease in plasma methionine concentration.…”

Section: Resultsmentioning

confidence: 99%

Effects of Squat Exercise and Branched-Chain Amino Acid Supplementation on Plasma Free Amino Acid Concentrations in Young Women

Shimomura

Kobayashi

Mawatari

et al. 2009

J Nutr Sci Vitaminol

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SummaryThe present study was conducted to examine alterations in plasma free amino acid concentrations induced by squat exercise and branched-chain amino acid (BCAA) supplementation in young, untrained female subjects. In the morning on the exercise session day, participants ingested drinks containing either BCAA (isoleucine : leucine : valine ϭ 1 : 2.3 : 1.2) or dextrin (placebo) at 0.1 g/kg body weight 15 min before a squat exercise session, which consisted of 7 sets of 20 squats, with 3 min intervals between sets. In the placebo trial, plasma BCAA concentrations were decreased subsequent to exercise, whereas they were significantly increased in the BCAA trial until 2 h after exercise. Marked changes in other free amino acids in response to squat exercise and BCAA supplementation were observed. In particular, plasma concentrations of methionine and aromatic amino acids were temporarily decreased in the BCAA trial, being significantly lower than those in the placebo trial. These results suggest that BCAA intake before exercise affects methionine and aromatic amino acid metabolism. Key Words squat exercise, branched-chain amino acids, plasma free amino acids, untrained young women It is well known that amino acid metabolism is affected by exercise ( 1 ). In particular, exercise has been shown to promote branched-chain amino acid (BCAA) catabolism in rats and humans ( 2 , 3 ). Therefore, the popularity of BCAAs as a supplement for people who practice sports is growing. However, despite the common use of BCAAs, little information is available with regard to the effects of BCAA intake on the concentrations of plasma components including free amino acids other than the BCAAs. In a recent study, we have found that BCAA supplementation before squat exercise noticeably suppressed the muscle pain that occurred on the next day after exercise and lasted for a few days (delayed-onset muscle soreness (DOMS)) in young, untrained women ( 4 ). In the present study, we examined alterations in the plasma concentrations of free amino acids induced by squat exercise and BCAA supplementation. Materials and MethodsExperiments were conducted essentially as described previously ( 4 ), except for the following points: (i) 12 young, healthy female volunteers who did not exercise in a regular basis participated in this study, (ii) the subjects ingested the test drink containing BCAA mixture or dextrin at 0.1 g/kg body weight, and (iii) blood samples were collected for preparations of plasma and serum before exercise and at several time points after exercise (see below). The compositions of the test drinks were as follows: a BCAA drink (200 mL) containing 5.5 g of a BCAA mixture (isoleucine, leucine, and valine at a ratio of 1 : 2.3 : 1.2 ( 5 )), 1 g instant green tea powder (Ajinomoto General Foods, Tokyo) and 1.2 g nonnutritive sweetener (Pal Sweet, Ajinomoto, Tokyo), and a placebo drink containing the same ingredients as the BCAA drink except for 5.5 g dextrin instead of the BCAAs ( 4 ). The age of the participants was 22.2 Ϯ 0.5 (mean...

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“…The amount of keto acid (2-oxobutyrate) accumulated in the culture medium was lower than the observed decrease in L-threonine levels. This may be explained by the cellular oxidation of 2-oxobutyrate through either the mitochondrial branched-chain oxoacid dehydrogenase complex or pyruvate dehydrogenase (31).…”

Section: Discussionmentioning

confidence: 99%

Serine Racemase Modulates Intracellular D-Serine Levels through an α,β-Elimination Activity

Foltyn

Bendikov

Miranda

et al. 2005

Journal of Biological Chemistry

201

196

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D-Serine is a D-amino acid that occurs at high levels in the mammalian brain and is an endogenous ligand of the "glycine site" of N-methyl D-aspartate (NMDA) 1 receptors (1-4). NMDA receptors play key roles in excitatory synaptic transmission, plasticity, and learning and memory (5). Overactivation of the NMDA receptor and the resultant influx of calcium into cells is a major culprit in the cell death that occurs following stroke and neurodegenerative diseases. Blockers of the "glycine site" of the receptor are neuroprotective in animal models of stroke (5). Endogenous D-serine is required for NMDA receptor activation, and its removal markedly decreases NMDA receptor activity (3). In the vertebrate retina, endogenous D-serine may also mediate the light-dependent increase in neuronal activity by activating NMDA receptors (6). More recently, D-serine was suggested to play a role in the long term potentiation of synaptic transmission in the hippocampus, indicating a role of endogenous D-serine in long term synaptic plasticity (7).D-Serine is synthesized by serine racemase, a pyridoxal phosphate (PLP)-dependent enzyme enriched in the mammalian brain (8, 9). Serine racemase has high sequence homology with the fold-type II group of PLP enzymes, such as serine/threonine dehydratase and D-serine dehydratase (10, 11). In addition to converting L-to D-serine, serine racemase catalyzes the ␣,␤-elimination of water from L-serine to form pyruvate and ammonia (12). The initial rates of racemization and ␣,␤-elimination of L-serine by serine racemase are strongly stimulated by magnesium and ATP, indicating that the complex Mg⅐ATP is a physiological ligand of the enzyme (12).In accordance with accepted mechanisms of PLP-catalyzed reactions (13-16), a mechanism for racemization and ␣,␤-elimination catalyzed by serine racemase is depicted in Scheme 1. PLP, bound to the enzyme through an internal aldimine with The termination of signaling by a neurotransmitter in the brain normally requires its re-uptake and metabolism. D-Serine signaling is thought to involve its release from cells to

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Role of branched-chain 2-oxo acid dehydrogenase and pyruvate dehydrogenase in 2-oxobutyrate metabolism

Cited by 56 publications

References 42 publications

Changes in urinary metabolic profiles of colorectal cancer patients enrolled in a prospective cohort study (ColoCare)

Changes in urinary metabolic profiles of colorectal cancer patients enrolled in a prospective cohort study (ColoCare)

Effects of Squat Exercise and Branched-Chain Amino Acid Supplementation on Plasma Free Amino Acid Concentrations in Young Women

Serine Racemase Modulates Intracellular D-Serine Levels through an α,β-Elimination Activity

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