l-Serine in disease and development

Koning, Tom J. de; Snell, Keith; Durán, Marinus; Berger, Ruud; Poll-Thé, Bwee Tien; Surtees, Robert

doi:10.1042/bj20021785

Cited by 240 publications

(202 citation statements)

References 113 publications

(120 reference statements)

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“…This idea is supported by our finding that neurons cannot maintain synthesis of serinederived lipids without an external supply of L-serine (10). Severe neurological consequences, such as congenital microcephaly, psychomotor retardation, and convulsions associated with human PHGDH deficiency, also highlight the significance of the phosphorylated pathway in normal brain development and function (11).…”

supporting

confidence: 68%

“…Finally, the microcephaly evident in the Phgdh null embryos (Figs. 3 and 4) has also been reported to be a major symptom of patients with human Phgdh deficiency (11). Thus, our mutant mice may serve as a useful animal model for studying how diminished L-serine levels impair development and function of the central nervous system.…”

Section: Phgdh Expression In Mutant Embryosmentioning

confidence: 99%

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Targeted Disruption of the Mouse 3-Phosphoglycerate Dehydrogenase Gene Causes Severe Neurodevelopmental Defects and Results in Embryonic Lethality

Yoshida

Furuya²,

Osuka³

et al. 2004

Journal of Biological Chemistry

129

107

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D-3-Phosphoglyceratedehydrogenase (Phgdh; EC 1.1.1.95) is the first committed enzyme of L-serine biosynthesis in the phosphorylated pathway. To determine the physiological importance of Phgdh-dependent L-serine biosynthesis in vivo, we generated Phgdh-deficient mice using targeted gene disruption in embryonic stem cells. The absence of Phgdh led to a drastic reduction of Lserine metabolites such as phosphatidyl-L-serine and sphingolipids. Phgdh null embryos have small bodies with abnormalities in selected tissues and died after days post-coitum 13.5. Striking abnormalities were evident in the central nervous system in which the Phgdh null mutation culminated in hypoplasia of the telencephalon, diencephalon, and mesencephalon; in particular, the olfactory bulbs, ganglionic eminence, and cerebellum appeared as indistinct structures. These observations demonstrate that the Phgdh-dependent phosphorylated pathway is essential for normal embryonic development, especially for brain morphogenesis.

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supporting

confidence: 68%

Section: Phgdh Expression In Mutant Embryosmentioning

confidence: 99%

Targeted Disruption of the Mouse 3-Phosphoglycerate Dehydrogenase Gene Causes Severe Neurodevelopmental Defects and Results in Embryonic Lethality

Yoshida

Furuya²,

Osuka³

et al. 2004

Journal of Biological Chemistry

129

107

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“…Because the feedback loop effectively increases the relative concentration of 3-PG, this increase in chemical potential favors the flow of glucose metabolites into other pathways that branch from glycolysis at 3-PG. Once such pathway is used to generate serine and glycine from glucose (de Koning et al 2003). Therefore, use of the alternative glycolytic pathway promoted by PKM2 inhibition is predicted to redirect glucose metabolism into serine biosynthesis (Fig.…”

Section: Redirection Of Glucose Carbon Into Serine Biosynthesis To Sumentioning

confidence: 99%

Metabolic Pathway Alterations that Support Cell Proliferation

Heiden

Lunt

Dayton

et al. 2011

Cold Spring Harbor Symposia on Quantitative Biology

258

203

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Proliferating cells adapt metabolism to support the conversion of available nutrients into biomass. How cell metabolism is regulated to balance the production of ATP, metabolite building blocks, and reducing equivalents remains uncertain. Proliferative metabolism often involves an increased rate of glycolysis. A key regulated step in glycolysis is catalyzed by pyruvate kinase to convert phosphoenolpyruvate (PEP) to pyruvate. Surprisingly, there is strong selection for expression of the less active M2 isoform of pyruvate kinase (PKM2) in tumors and other proliferative tissues. Cell growth signals further decrease PKM2 activity, and cells with less active PKM2 use another pathway with separate regulatory properties to convert PEP to pyruvate. One consequence of using this alternative pathway is an accumulation of 3-phosphoglycerate (3PG) that leads to the diversion of 3PG into the serine biosynthesis pathway. In fact, in some cancers a substantial portion of the total glucose flux is directed toward serine synthesis, and genetic evidence suggests that glucose flux into this pathway can promote cell transformation. Environmental conditions can also influence the pathways that cells use to generate biomass with the source of carbon for lipid synthesis changing based on oxygen availability. Together, these findings argue that distinct metabolic phenotypes exist among proliferating cells, and both genetic and environmental factors influence how metabolism is regulated to support cell growth.All cells rely on a source of nutrients for growth and survival. These nutrients are taken up from the environment and directed into metabolic pathways to maintain homeostasis and fuel cell-type-specific functions. For all cells, these processes include maintenance of ion gradients across membranes, transport of materials between intracellular compartments, and other housekeeping functions such as protein turnover. Many of these processes are thermodynamically unfavorable and thus are coupled to ATP hydrolysis as a source of free energy. To provide metabolic support for these functions, cells have evolved pathways, such as the oxidative metabolism of glucose, that when coupled to mitochondrial oxidative phosphorylation can efficiently generate ATP from available nutrients.Proliferating cells, including cancer cells, metabolize nutrients to support these same housekeeping functions. They also must take up additional nutrients, metabolize these nutrients through pathways that produce ATP, and generate all the components necessary to duplicate the mass of the cell and allow for cell division (Fig.

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“…Also critical for cell proliferation are serine and glycine, two non-essential amino acids in mammals [9,10], which are known for their functions in phospholipid synthesis and cystathionine formation in central nervous system [11,12]. Interestingly, it has been reported recently that these two amino acids play important roles in cancer progression [13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

cMyc-mediated activation of serine biosynthesis pathway is critical for cancer progression under nutrient deprivation conditions

et al. 2015

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Cancer cells are known to undergo metabolic reprogramming to sustain survival and rapid proliferation, however, it remains to be fully elucidated how oncogenic lesions coordinate the metabolic switch under various stressed conditions. Here we show that deprivation of glucose or glutamine, two major nutrition sources for cancer cells, dramatically activated serine biosynthesis pathway (SSP) that was accompanied by elevated cMyc expression. We further identified that cMyc stimulated SSP activation by transcriptionally upregulating expression of multiple SSP enzymes. Moreover, we demonstrated that SSP activation facilitated by cMyc led to elevated glutathione (GSH) production, cell cycle progression and nucleic acid synthesis, which are essential for cell survival and proliferation especially under nutrient-deprived conditions. We further uncovered that phosphoserine phosphatase (PSPH), the final rate-limiting enzyme of the SSP pathway, is critical for cMyc-driven cancer progression both in vitro and in vivo, and importantly, aberrant expression of PSPH is highly correlated with mortality in hepatocellular carcinoma (HCC) patients, suggesting a potential causal relation between this cMyc-regulated enzyme, or SSP activation in general, and cancer development. Taken together, our results reveal that aberrant expression of cMyc leads to the enhanced SSP activation, an essential part of metabolic switch, to facilitate cancer progression under nutrient-deprived conditions.

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l-Serine in disease and development

Cited by 240 publications

References 113 publications

Targeted Disruption of the Mouse 3-Phosphoglycerate Dehydrogenase Gene Causes Severe Neurodevelopmental Defects and Results in Embryonic Lethality

Targeted Disruption of the Mouse 3-Phosphoglycerate Dehydrogenase Gene Causes Severe Neurodevelopmental Defects and Results in Embryonic Lethality

Metabolic Pathway Alterations that Support Cell Proliferation

cMyc-mediated activation of serine biosynthesis pathway is critical for cancer progression under nutrient deprivation conditions

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