Regulation of the Balance of One-carbon Metabolism inSaccharomyces cerevisiae

Piper, Matthew D.W.; Hong, Seung Pyo; Ball, Graham E.; Dawes, Ian W.

doi:10.1074/jbc.m004248200

Cited by 90 publications

(100 citation statements)

References 28 publications

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“…Piper et al (16) demonstrated that this response is mediated by a decrease in cytoplasmic levels of 5,10-CH 2 -H 4 folate. Given the central role of H 4 folate intermediates in one-carbon metabolism, it was proposed that this novel "glycine response" might represent a more general one-carbon metabolic transcriptional control system (regulon).…”

Section: Resultsmentioning

confidence: 99%

“…GCV2 expression is decreased, but still glycine-responsive, in a met13 strain, which lacks the main methylenetetrahydrofolate reductase activity of the cell (16). The effect of this mutation is thus to reduce synthesis of 5-CH 3 -H 4 folate from 5,10-CH 2 -H 4 folate.…”

Section: Figmentioning

confidence: 98%

“…These genes are up-regulated following addition of glycine to the medium (12)(13)(14) via a glycine response element with the consensus sequence CATCN 7 CTTCTT (15). Previously, it was demonstrated that this glycine effect is a response to a decrease in cytosolic 5,10-CH 2 -H 4 folate levels rather than directly to glycine (16). This was proposed to reflect inhibition of SHMT through the formation of a "dead-end" complex with glycine and 5-HCO-H 4 folate (17,18).…”

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confidence: 99%

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Identification of a Novel One-carbon Metabolism Regulon in Saccharomyces cerevisiae

Gelling

Piper²,

Hong³

et al. 2004

Journal of Biological Chemistry

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Glycine specifically induces genes encoding subunits of the glycine decarboxylase complex (GCV1, GCV2, and GCV3), and this is mediated by a fall in cytoplasmic levels of 5,10-methylenetetrahydrofolate caused by inhibition of cytoplasmic serine hydroxymethyltransferase. Here it is shown that this control system extends to genes for other enzymes of one-carbon metabolism and de novo purine biosynthesis. Northern analysis of the response to glycine demonstrated that the induction of the GCV genes and the induction of other amino acid metabolism genes are temporally distinct. The genomewide response to glycine revealed that several other genes are rapidly co-induced with the GCV genes, including SHM2, which encodes cytoplasmic serine hydroxymethyltransferase. These results were refined by examining transcript levels in an shm2⌬ strain (in which cytoplasmic 5,10-methylenetetrahydrofolate levels are reduced) and a met13⌬ strain, which lacks the main methylenetetrahydrofolate reductase activity of yeast and is effectively blocked at consumption of 5,10-methylene tetrahydrofolate for methionine synthesis. Glycine addition also caused a substantial transient disturbance to metabolism, including a sequence of changes in induction of amino acid biosynthesis and respiratory chain genes. Analysis of the glycine response in the shm2⌬ strain demonstrated that apart from the one-carbon regulon, most of these transient responses were not contingent on a disturbance to onecarbon metabolism. The one-carbon response is distinct from the Bas1p purine biosynthesis regulon and thus represents the first example of transcriptional regulation in response to activated one-carbon status.

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Section: Resultsmentioning

confidence: 99%

Section: Figmentioning

confidence: 98%

mentioning

confidence: 99%

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Identification of a Novel One-carbon Metabolism Regulon in Saccharomyces cerevisiae

Gelling

Piper²,

Hong³

et al. 2004

Journal of Biological Chemistry

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“…Flux through these reactions is generally oxidative in the mitochondria and reductive in the cytoplasm; however, C1 metabolic pathways are under considerable regulatory control and can be adapted to specific genetic backgrounds and growth conditions (Kastanos et al 1997;Piper et al 2000). Two groups have independently shown that C1 enzymes are controlled dynamically by glycine at the transcriptional level.…”

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confidence: 99%

Systems-Level Engineering of Nonfermentative Metabolism in Yeast

Kennedy

Boyle²,

Waks

et al. 2009

Genetics

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We designed and experimentally validated an in silico gene deletion strategy for engineering endogenous one-carbon (C1) metabolism in yeast. We used constraint-based metabolic modeling and computer-aided gene knockout simulations to identify five genes (ALT2, FDH1, FDH2, FUM1, and ZWF1), which, when deleted in combination, predicted formic acid secretion in Saccharomyces cerevisiae under aerobic growth conditions. Once constructed, the quintuple mutant strain showed the predicted increase in formic acid secretion relative to a formate dehydrogenase mutant ( fdh1 fdh2), while formic acid secretion in wild-type yeast was undetectable. Gene expression and physiological data generated post hoc identified a retrograde response to mitochondrial deficiency, which was confirmed by showing Rtg1-dependent NADH accumulation in the engineered yeast strain. Formal pathway analysis combined with gene expression data suggested specific modes of regulation that govern C1 metabolic flux in yeast. Specifically, we identified coordinated transcriptional regulation of C1 pathway enzymes and a positive flux control coefficient for the branch point enzyme 3-phosphoglycerate dehydrogenase (PGDH).Together, these results demonstrate that constraint-based models can identify seemingly unrelated mutations, which interact at a systems level across subcellular compartments to modulate flux through nonfermentative metabolic pathways.

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“…In photosynthetic tissues of plants, the GCC consumes large amounts of glycine produced during photorespiration (18), but the activity is still essential in Arabidopsis even under non-photorespiratory conditions (21). In Saccharomyces cerevisiae, mutants lacking any of the GCCspecific subunits can grow on minimal medium but cannot use glycine as a nitrogen source (20).…”

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confidence: 99%

The Role of the Mitochondrial Glycine Cleavage Complex in the Metabolism and Virulence of the Protozoan Parasite Leishmania major

Scott

Hickerson

Vickers

et al. 2008

Journal of Biological Chemistry

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For the human pathogen Leishmania major, a key metabolic function is the synthesis of thymidylate, which requires 5,10-methylenetetrahydrofolate (5,10-CH 2 -THF). 5,10-CH 2 -THF can be synthesized from glycine by the mitochondrial glycine cleavage complex (GCC). Bioinformatic analysis revealed the four subunits of the GCC in the L. major genome, and the role of the GCC in parasite metabolism and virulence was assessed through studies of the P subunit (glycine decarboxylase (GCVP)). First, a tagged GCVP protein was expressed and localized to the parasite mitochondrion. Second, a gcvP ؊ mutant was generated and shown to lack significant GCC activity using an indirect in vivo assay after incorporation of label from [2-14 C]glycine into DNA. The gcvP ؊ mutant grew poorly in the presence of excess glycine or minimal serine; these studies also established that L. major promastigotes require serine for optimal growth. Although gcvP ؊ promastigotes and amastigotes showed normal virulence in macrophage infections in vitro, both forms of the parasite showed substantially delayed replication and lesion pathology in infections of both genetically susceptible or resistant mice. These data suggest that, as the physiology of the infection site changes during the course of infection, so do the metabolic constraints on parasite replication. This conclusion has great significance to the interpretation of metabolic requirements for virulence. Last, these studies call attention in trypanosomatid protozoa to the key metabolic intermediate 5,10-CH 2 -THF, situated at the junction of serine, glycine, and thymidylate metabolism. Notably, genome-based predictions suggest the related parasite Trypanosoma brucei is totally dependent on the GCC for 5,10-CH 2 -THF synthesis.

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Regulation of the Balance of One-carbon Metabolism inSaccharomyces cerevisiae

Cited by 90 publications

References 28 publications

Identification of a Novel One-carbon Metabolism Regulon in Saccharomyces cerevisiae

Identification of a Novel One-carbon Metabolism Regulon in Saccharomyces cerevisiae

Systems-Level Engineering of Nonfermentative Metabolism in Yeast

The Role of the Mitochondrial Glycine Cleavage Complex in the Metabolism and Virulence of the Protozoan Parasite Leishmania major

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