Abstract
The serine, glycine, one-carbon (SGOC) metabolic network is implicated in cancer pathogenesis, but its general functions are unknown. We carried out a computational reconstruction of the SGOC network and then characterized its expression across thousands of cancer tissues. Pathways including methylation and redox metabolism exhibited heterogeneous expression indicating a strong context dependency of their usage in tumors. From an analysis of coexpression, simultaneous up- or downregulation of nucleotide synthesis, NADPH, and glutathione synthesis was found to be a common occurrence in all cancers. Finally, we developed a method to trace the metabolic fate of serine using stable isotopes, high-resolution mass spectrometry, and a mathematical model. Although the expression of single genes didn't appear indicative of flux, the collective expression of several genes in a given pathway allowed for successful flux prediction. Altogether, these findings identify expansive and heterogeneous functions for the SGOC metabolic network in human cancer.
Highlights
Serine and glycine are nutrients that fuel metabolic pathways including one carbon metabolism and sulfur metabolism
We constructed a network that represents the metabolism of serine and glycine through one carbon metabolism and other immediate pathways including the transsulfuration pathway that together lead to defined cellular outputs
Each gene involved in the Kyoto Encyclopedia of Genes and Genomes (KEGG)-defined pathways, Glycine - Serine and Threonine metabolism, Cysteine and Methionine metabolism, and Folate biosynthesis was selected
Summary
Serine and glycine are nutrients that fuel metabolic pathways including one carbon metabolism and sulfur metabolism. This metabolic unit referred to as the serine, glycine and one carbon (SGOC) network provides an integration point in cellular metabolism that allows for cells to achieve diverse biological functions by converting serine and glycine into several metabolic outputs These outputs include building blocks for nucleotide, lipid, and protein synthesis. The importance of onecarbon metabolism in NADPH production through the oxidation of folates was demonstrated in cancer cells in a number of recent studies (Fan et al, 2014; Lewis et al, 2014a; Tedeschi et al, 2013; Vazquez et al, 2011) These studies showed that in addition to providing cells with nucleotide units, one-carbon metabolism has an important role in redox balance. The general coordinated usages and different contexts in which serine and glycine flux contributes to different metabolic functions within and across cancer types and normal tissues remain largely unknown
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