Serine synthesis through PHGDH coordinates nucleotide levels by maintaining central carbon metabolism

Abstract

Phosphoglycerate dehydrogenase (PHGDH) catalyzes the committed step in de novo serine biosynthesis. Paradoxically, PHGDH and serine synthesis are required in the presence of abundant environmental serine even when serine uptake exceeds the requirements for nucleotide synthesis. Here, we establish a mechanism for how PHGDH maintains nucleotide metabolism. We show that inhibition of PHGDH induces alterations in nucleotide metabolism independent of serine utilization. These changes are not attributable to defects in serine-derived nucleotide synthesis and redox maintenance, another key aspect of serine metabolism, but result from disruption of mass balance within central carbon metabolism. Mechanistically, this leads to simultaneous alterations in both the pentose phosphate pathway and the tri-carboxylic acid cycle, as we demonstrate based on a quantitative model. These findings define a mechanism whereby disruption of one metabolic pathway induces toxicity by simultaneously affecting the activity of multiple related pathways.

Reprogramming of serine metabolism is an actionable vulnerability inFLT3-ITDdriven acute myeloid leukaemia

“…Furthermore, FLT3-ITD inhibition with quizartinib or inhibition of PHGDH with WQ-2101 resulted in dramatic alterations in the abundance of TCA cycle intermediates (SupplementaryFigure 5D). Of note, PHGDH inhibition significantly increased the abundance of citrate/isocitrate and succinate, consistent with previous reports(44). To functionally examine serine uptake dynamics in AML cells, MV4-11, MOLM-13 and OCI-AML3 cells were pre-treated with quizartinib or WQ-2101 for 24 hours, and the uptake of radiolabelled serine was measured.…”

“…Of note, doubling the exogenous supply of serine (to ~572 µM) largely phenocopied the effects of purine supplementation, further supporting the contention that serine contributes to purine biosynthesis. As multiple metabolic processes are located upstream and downstream of PHGDH, MV4-11 culture media was therefore supplemented with metabolites relevant to PHGDH metabolism to determine the impact on cytotoxicity associated with FLT3-ITD inhibition(44). Supplementation with hypoxanthine, an adenine purine nucleobase derivative that undergoes conversion into the purine nucleotide inosine monophosphate (IMP), was sufficient to significantly reduce the apoptotic effects of quizartinib (Figure 5D).To determine if these findings could be recapitulated in primary human samples, a genetic signature encompassing genes involved in de novo serine synthesis, the one-carbon/folate cycle, and key ratelimiting enzymes of the de novo purine synthesis pathway was devised as described by Manning and colleagues (43) (see also Supplementary Materials and Methods).…”

Quantitative analysis of the physiological contributions of glucose to the TCA cycle

“…Thus, more constraints must be introduced to reduce the dimensionality of the feasible solution space. For example, our study includes constraints from circulatory fluxes (Hui et al, 2017), and some MFA model uses fixed biomass fluxes as boundary conditions (Reid et al, 2018). However, the precision and generalizability of these external constraints have not been rigorously validated, and they may introduce bias.…”

Carbohydrate and Amino Acid Metabolism as Hallmarks for Innate Immune Cell Activation and Function

“…The role for serine and glycine in innate immune cells has not been fully elucidated, but what has been uncovered will be discussed below. Immune cells can acquire serine through de novo synthesis or extracellular uptake [78]. Briefly, de novo synthesis of serine is an offshoot of glycolysis in which the glycolytic intermediate 3-phosphoglycerate is enzymatically converted into serine.…”