Mice have a transcribed L-threonine aldolase/GLY1 gene, but the human GLY1 gene is a non-processed pseudogene

Edgar, Alasdair J.

doi:10.1186/1471-2164-6-32

Cited by 46 publications

(25 citation statements)

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“…LST8 is part of the TOR (target of rapamycin) pathway, involved in cancer and other human diseases (30)(31)(32) and acts with LST4, LST7, and SEC13 in regulating amino acid fluxes in yeast (18,33). Although relatively little is known about threonine aldolase in mammals, it appears to function in mice but not humans (34). Additional studies will be needed to examine the potential importance of these pathway interactions in human disease.…”

Section: Discussionmentioning

confidence: 99%

Buffering of deoxyribonucleotide pool homeostasis by threonine metabolism

Hartman

2007

Proc. Natl. Acad. Sci. U.S.A.

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Synergistically interacting gene mutations reveal buffering relationships that provide growth homeostasis through their compensation of one another. This analysis in Saccharomyces cerevisiae revealed genetic modules involved in tricarboxylic acid cycle regulation (RTG1, RTG2, RTG3), threonine biosynthesis (HOM3, HOM2, HOM6, THR1, THR4), amino acid permease trafficking (LST4, LST7), and threonine catabolism (GLY1). These modules contribute to a molecular circuit that regulates threonine metabolism and buffers deficiency in deoxyribonucleotide biosynthesis. Phenotypic, genetic, and biochemical evidence for this buffering circuit was obtained through analysis of deletion mutants, titratable alleles of ribonucleotide reductase genes, and measurements of intracellular deoxyribonucleotide pool concentrations. This circuit provides experimental evidence, in eukaryotes, for the presence of a high-flux backbone of metabolism, which was previously predicted from in silico modeling of global metabolism in bacteria. This part of the high-flux backbone appears to buffer deficiency in ribonucleotide reductase by enabling a compensatory increase in de novo purine biosynthesis that provides additional rate-limiting substrates for dNTP production and DNA synthesis. Hypotheses regarding unexpected connections between these metabolic pathways were facilitated by genome-wide but also highly quantitative phenotypic assessment of interactions. Validation of these hypotheses substantiates the added benefit of quantitative phenotyping for identifying subtleties in gene interaction networks that modulate cellular phenotypes.genetic buffering ͉ high-flux backbone of metabolism ͉ protein trafficking ͉ ribonucleotide reductase ͉ mitochondria-to-nucleus retrograde signaling pathway C ells are complex genetic systems, having evolved compensatory molecular networks that provide growth homeostasis (robustness). Conceptually, gene interactions underlie robustness by buffering environmental or genetic perturbations (1-3). Synergistic effects on the phenotype resulting from two genetic deficiencies or chemical inhibition in combination with a genetic deficiency reveal buffering relationships when the double limitation is more severe than either single limitation. Genome-wide phenotypic analysis, as possible with RNAi or use of the complete set of yeast gene deletion mutants, has enabled new approaches to investigate buffering relationships systematically (2, 4, 5). It has been shown that quantitative (strength) and qualitative (pattern) aspects of gene interaction profiles reveal how genes organize in a pathway or cellular process (4, 6). Conceptually, such sets of genes represent genetic modules that contribute buffering capacity to the cell, providing insight into how molecular circuitry is arranged to achieve robustness (7,8). Comprehensive and quantitative methods for genotypephenotype analysis are becoming available for gaining a more global and precise understanding of buffering networks (4, 6, 9). These methods permit unbiased experimental...

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Section: Discussionmentioning

confidence: 99%

Buffering of deoxyribonucleotide pool homeostasis by threonine metabolism

Hartman

2007

Proc. Natl. Acad. Sci. U.S.A.

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“…0.25 mM (210) (HMDB: url-http://www.hmdb.ca/). It can also be synthesized from glucose via glycolytically produced 3-phosphoglycerate (3-PGA) (Figure 4), via the choline-betaine pathway (211) or from other sources such as threonine in some organisms, though not humans (212). It appears that the glycine precursor for purine biosynthesis is synthesized de novo from serine via glycolysis or mitochondrially via the glycine cleavage system (213) (Figure 4), and there may even be a net efflux of glycine in proliferating cells (214,215).…”

Section: Stable Isotope Tracing Of Nucleotide Synthesismentioning

confidence: 99%

Regulation of mammalian nucleotide metabolism and biosynthesis

Lane

Fan

2015

Nucleic Acids Research

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631

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Nucleotides are required for a wide variety of biological processes and are constantly synthesized de novo in all cells. When cells proliferate, increased nucleotide synthesis is necessary for DNA replication and for RNA production to support protein synthesis at different stages of the cell cycle, during which these events are regulated at multiple levels. Therefore the synthesis of the precursor nucleotides is also strongly regulated at multiple levels. Nucleotide synthesis is an energy intensive process that uses multiple metabolic pathways across different cell compartments and several sources of carbon and nitrogen. The processes are regulated at the transcription level by a set of master transcription factors but also at the enzyme level by allosteric regulation and feedback inhibition. Here we review the cellular demands of nucleotide biosynthesis, their metabolic pathways and mechanisms of regulation during the cell cycle. The use of stable isotope tracers for delineating the biosynthetic routes of the multiple intersecting pathways and how these are quantitatively controlled under different conditions is also highlighted. Moreover, the importance of nucleotide synthesis for cell viability is discussed and how this may lead to potential new approaches to drug development in diseases such as cancer.

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“…High dietary intake of threonine is the most common cause of hyperthreoninemia, which is associated with certain forms of seizures (Reddi 1978;Clayton et al 2003). Threonine is not metabolized extensively in the brain (Pardridge 1983), but can follow either of two catabolic pathways: threonine dehydratase ultimately producing succinyl-CoA via propionyl-CoA and threonine 3-dehydrogenase producing glycine and acetyl-CoA (Gaitonde 1975;Edgar 2005). Considering the reduced propionyl-CoA level in this model (Willis et al 2010) and the reduced 13 C labeling of TCA cycle metabolites (Fig.…”

Section: Triheptanoin Reduces Threonine Levels In Chronically Epileptmentioning

confidence: 99%

Triheptanoin partially restores levels of tricarboxylic acid cycle intermediates in the mouse pilocarpine model of epilepsy

Hadera

Smeland

McDonald

et al. 2013

Journal of Neurochemistry

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Triheptanoin, the triglyceride of heptanoate, is anticonvulsant in various epilepsy models. It is thought to improve energy metabolism in the epileptic brain by re-filling the tricarboxylic acid (TCA) cycle with C4-intermediates (anaplerosis). Here, we injected mice with [1,2-13 C]glucose 3.5-4 weeks after pilocarpine-induced status epilepticus (SE) fed either a control or triheptanoin diet. Amounts of metabolites and incorporations of 13 C were determined in extracts of cerebral cortices and hippocampal formation and enzyme activity and mRNA expression were quantified. The percentage enrichment with two 13 C atoms in malate, citrate, succinate, and GABA was reduced in hippocampal formation of control-fed SE compared with control mice. Except for succinate, these reductions were not found in triheptanoin-fed SE mice, indicating that triheptanoin prevented a decrease of TCA cycle capacity. Compared to those on control diet, triheptanoin-fed SE mice showed few changes in most other metabolite levels and their 13 C labeling. Reduced pyruvate carboxylase mRNA and enzyme activity in forebrains and decreased [2,3-13 C]aspartate amounts in cortex suggest a pyruvate carboxylation independent source of C-4 TCA cycle intermediates. Most likely anaplerosis was kept unchanged by carboxylation of propionyl-CoA derived from heptanoate. Further studies are proposed to fully understand triheptanoin's effects on neuroglial metabolism and interaction.

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Mice have a transcribed L-threonine aldolase/GLY1 gene, but the human GLY1 gene is a non-processed pseudogene

Cited by 46 publications

References 46 publications

Buffering of deoxyribonucleotide pool homeostasis by threonine metabolism

Buffering of deoxyribonucleotide pool homeostasis by threonine metabolism

Regulation of mammalian nucleotide metabolism and biosynthesis

Triheptanoin partially restores levels of tricarboxylic acid cycle intermediates in the mouse pilocarpine model of epilepsy

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