PHGDH and you may PSAT1 knockout hindered brand new TCA period form and you may mitochondrial breathing during the IDHdos-high cells

Therefore, also the increased glycolysis, IDH2 diverts new glycolytic intermediates to help you serine and you may glycine synthesis, that’s required for this new bioenergetic request and you will precursors you to definitely assistance cancers growth

To predict the potential metabolic vulnerability of IDH2 we applied GSMM, incorporating the proteomic data of the IDH2-perturbed cell lines. Constraint-based modeling with the iMAT algorithm computed the most likely metabolic activity in the cells, and the minimization of metabolic adjustment (MOMA) algorithm was then used to predict the protein essentiality only in IDH2-high cells. The MOMA analysis predicted PHGDH, PSAT1, and S-formyl glutathione hydrolase (ESD) as essential proteins for IDH2-induced biomass production, thus forming SDL interactions with IDH2 (Fig. 4A). PHGDH is the first enzyme in the serine biosynthesis pathway; it diverts 3-phosphoglycerate (3-PG) from glycolytic pathway to 3-phospho-hydroxypyruvate (3-PHP) and PSAT1 transaminates 3-PHP to phosphoserine and subsequently to serine and glycine (Fig. 4B). ESD converts S-formyl-glutathione to glutathione and formate, which is further fed into the one-carbon metabolism pathway (Fig. 4B). Examination of the clinical significance of the SDL interactions using mRNA expression data from the METABRIC project showed better survival of patients with IDH2-high/PHGDH-low bbwdesire Zaloguj siД™ or PSAT1-low than patients with high PHGDH or PSAT (Fig. 4C). Weiterlesen

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