Repurposing of glycine transport inhibitors for the treatment of erythropoietic protoporphyria

Cell Chem Biol. 2021 Aug 19;28(8):1221-1234.e6. doi: 10.1016/j.chembiol.2021.02.021. Epub 2021 Mar 22.


Erythropoietic protoporphyria (EPP) is a rare disease in which patients experience severe light sensitivity. It is caused by a deficiency of ferrochelatase (FECH), the last enzyme in heme biosynthesis (HBS). The lack of FECH causes accumulation of its photoreactive substrate protoporphyrin IX (PPIX) in patients' erythrocytes. Here, we explored an approach for the treatment of EPP by decreasing PPIX synthesis using small-molecule inhibitors directed to factors in the HBS pathway. We generated a FECH-knockout clone from K562 erythroleukemia cells, which accumulates PPIX and undergoes oxidative stress upon light exposure. We used these matched cell lines to screen a set of publicly available inhibitors of factors in the HBS pathway. Inhibitors of the glycine transporters GlyT1 and GlyT2 lowered levels of PPIX and markers of oxidative stress selectively in K56211B4 cells, and in primary erythroid cultures from an EPP patient. Our findings open the door to investigation of glycine transport inhibitors for HBS disorders.

Keywords: CRISPR-Cas9; drug repurposing; erythropoietic protoporphyria; glycine transporter 2; oxidative stress; photodamage; protoporphyrin IX.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Erythrocytes / drug effects
  • Erythrocytes / metabolism
  • Glycine Plasma Membrane Transport Proteins / antagonists & inhibitors*
  • Glycine Plasma Membrane Transport Proteins / metabolism
  • Humans
  • K562 Cells
  • Molecular Structure
  • Protoporphyria, Erythropoietic / drug therapy*
  • Protoporphyria, Erythropoietic / metabolism
  • Protoporphyrins / pharmacology*


  • Glycine Plasma Membrane Transport Proteins
  • Protoporphyrins
  • SLC6A5 protein, human
  • SLC6A9 protein, human
  • protoporphyrin IX