Serine one-carbon catabolism with formate overflow

Meiser, Johannes; Tumanov, Sergey; Maddocks, Oliver D.K.; Labuschagne, Christiaan F.; Athineos, Dimitris; Broek, Nynke van den; Mackay, Gillian; Gottlieb, Eyal; Blyth, Karen; Vousden, Karen H.; Kamphorst, Jurre J.; Vazquez, Alexei

doi:10.1126/sciadv.1601273

Cited by 148 publications

(267 citation statements)

References 32 publications

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“…4e). By contrast, we did not find significant differences in the levels of other 1C-cycle metabolites such as serine, a major source of plasma formate17 (Extended Data Fig. 10d).…”

Section: Formaldehyde Is a Meaningful Source Of 1c Unitscontrasting

confidence: 66%

“…For functional validation, each strain was tested for growth in various drop-out media lacking some or most supplements. In addition, these strains were metabolically verified by incubation with [U- 13 C]serine and tracing of the labelled carbon into glycine, ATP and excreted formate17 (Extended Data Fig. 3b, c).…”

Section: Tetrahydrofolate Is Intrinsically Genotoxicmentioning

confidence: 99%

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Mammals divert endogenous genotoxic formaldehyde into one-carbon metabolism

Burgos-Barragan

Wit

Meiser

et al. 2017

Nature

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287

277

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The folate-driven one-carbon (1C) cycle is a fundamental metabolic hub in cells that enables the synthesis of nucleotides and amino acids and epigenetic modifications. This cycle might also release formaldehyde, a potent protein and DNA crosslinking agent that organisms produce in substantial quantities. Here we show that supplementation with tetrahydrofolate, the essential cofactor of this cycle, and other oxidation-prone folate derivatives kills human, mouse and chicken cells that cannot detoxify formaldehyde or that lack DNA crosslink repair. Notably, formaldehyde is generated from oxidative decomposition of the folate backbone. Furthermore, we find that formaldehyde detoxification in human cells generates formate, and thereby promotes nucleotide synthesis. This supply of 1C units is sufficient to sustain the growth of cells that are unable to use serine, which is the predominant source of 1C units. These findings identify an unexpected source of formaldehyde and, more generally, indicate that the detoxification of this ubiquitous endogenous genotoxin creates a benign 1C unit that can sustain essential metabolism.

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“…4e). By contrast, we did not find significant differences in the levels of other 1C-cycle metabolites such as serine, a major source of plasma formate17 (Extended Data Fig. 10d).…”

Section: Formaldehyde Is a Meaningful Source Of 1c Unitscontrasting

confidence: 66%

Section: Tetrahydrofolate Is Intrinsically Genotoxicmentioning

confidence: 99%

Mammals divert endogenous genotoxic formaldehyde into one-carbon metabolism

Burgos-Barragan

Wit

Meiser

et al. 2017

Nature

Self Cite

287

277

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“…This process allows cells to synthetize serine/glycine and pentose phosphate pathway components from glycolytic intermediates. The role of serine in one-carbon metabolism to support the methionine cycle is well documented (Meiser et al 2016) and was also implicated recently in de novo ATP synthesis . After p73KD, we observed enhanced rates of de novo purine synthesis and nucleoside, which may hint at an enhanced contribution to RNA and DNA synthesis.…”

Section: Discussionmentioning

confidence: 97%

TAp73 is a marker of glutamine addiction in medulloblastoma

et al. 2017

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Medulloblastoma is the most common solid primary brain tumor in children. Remarkable advancements in the understanding of the genetic and epigenetic basis of these tumors have informed their recent molecular classification. However, the genotype/phenotype correlation of the subgroups remains largely uncharacterized. In particular, the metabolic phenotype is of great interest because of its druggability, which could lead to the development of novel and more tailored therapies for a subset of medulloblastoma. p73 plays a critical role in a range of cellular metabolic processes. We show overexpression of p73 in a proportion of non-WNT medulloblastoma. In these tumors, p73 sustains cell growth and proliferation via regulation of glutamine metabolism. We validated our results in a xenograft model in which we observed an increase in survival time in mice on a glutamine restriction diet. Notably, glutamine starvation has a synergistic effect with cisplatin, a component of the current medulloblastoma chemotherapy. These findings raise the possibility that glutamine depletion can be used as an adjuvant treatment for p73-expressing medulloblastoma.

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“…Glycolysis itself consumes NAD + , so synthesis of one molecule of serine from glucose requires two molecules of NAD + . As a result, mitochondrial inhibition, which prevents NAD + regeneration, has been shown to inhibit serine synthesis from glucose, increasing the dependence on exogenous serine (38,39). Serine can provide carbon for nucleotide biosynthesis and is further metabolized to produce cysteine and glycine, implying an NAD + cost to synthesizing these amino acids from glucose.…”

Section: Amino Acidsmentioning

confidence: 99%

The redox requirements of proliferating mammalian cells

Hosios

Heiden

2018

Journal of Biological Chemistry

117

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Cell growth and division requires nutrients, and proliferating cells use a variety of sources to acquire the amino acids, lipids, and nucleotides that support macromolecule synthesis. Lipids are more reduced than other nutrients, whereas nucleotides and amino acids are typically more oxidized. Cells must therefore generate reducing and oxidizing (redox) equivalents to convert consumed nutrients into biosynthetic precursors. To that end, redox cofactor metabolism plays a central role in meeting cellular redox requirements. In this review, we highlight the biosynthetic pathways that involve redox reactions and discuss their integration with metabolism in proliferating mammalian cells.

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Serine one-carbon catabolism with formate overflow

Abstract: Serine catabolism results in formate efflux that exceeds anabolic demands for purine synthesis.

Cited by 148 publications

References 32 publications

Mammals divert endogenous genotoxic formaldehyde into one-carbon metabolism

Mammals divert endogenous genotoxic formaldehyde into one-carbon metabolism

TAp73 is a marker of glutamine addiction in medulloblastoma

The redox requirements of proliferating mammalian cells

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