Serine Synthesis via PHGDH Is Essential for Heme Production in Endothelial Cells

Cell Metab. 2018 Oct 2;28(4):573-587.e13. doi: 10.1016/j.cmet.2018.06.009. Epub 2018 Jul 12.


The role of phosphoglycerate dehydrogenase (PHGDH), a key enzyme of the serine synthesis pathway (SSP), in endothelial cells (ECs) remains poorly characterized. We report that mouse neonates with EC-specific PHGDH deficiency suffer lethal vascular defects within days of gene inactivation, due to reduced EC proliferation and survival. In addition to nucleotide synthesis impairment, PHGDH knockdown (PHGDHKD) caused oxidative stress, due not only to decreased glutathione and NADPH synthesis but also to mitochondrial dysfunction. Electron transport chain (ETC) enzyme activities were compromised upon PHGDHKD because of insufficient heme production due to cellular serine depletion, not observed in other cell types. As a result of heme depletion, elevated reactive oxygen species levels caused EC demise. Supplementation of hemin in PHGDHKD ECs restored ETC function and rescued the apoptosis and angiogenesis defects. These data argue that ECs die upon PHGDH inhibition, even without external serine deprivation, illustrating an unusual importance of serine synthesis for ECs.

Keywords: PHGDH; angiogenesis; apoptosis; endothelial cell; heme biosynthesis; mitochondria; pyrimidine synthesis; serine metabolism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Carbohydrate Metabolism, Inborn Errors / metabolism
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival
  • Dietary Supplements
  • Endothelial Cells / metabolism*
  • Gene Knockdown Techniques
  • Heme / metabolism*
  • Hemin / metabolism
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Microcephaly / metabolism
  • Mitochondria / metabolism
  • Mitophagy
  • Neovascularization, Physiologic
  • Oxidative Stress
  • Phosphoglycerate Dehydrogenase / deficiency
  • Phosphoglycerate Dehydrogenase / genetics*
  • Phosphoglycerate Dehydrogenase / metabolism*
  • Protein Biosynthesis
  • Psychomotor Disorders / metabolism
  • Purines / metabolism
  • Reactive Oxygen Species / metabolism
  • Seizures / metabolism
  • Serine / metabolism*


  • Purines
  • Reactive Oxygen Species
  • Heme
  • Serine
  • Hemin
  • Phosphoglycerate Dehydrogenase
  • purine

Supplementary concepts

  • Phosphoglycerate Dehydrogenase Deficiency