Blocking extracellular glycine uptake mediated by GlyT1 mitigates protoporphyria
Marc Liesa
Marc Liesa
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Commentary

Blocking extracellular glycine uptake mediated by GlyT1 mitigates protoporphyria

Abstract

Accumulation of the light-reactive heme precursor protoporphyrin IX (PPIX) in blood causes protoporphyria, a disease characterized by severe pain resulting from sunlight exposure, as well as by the occurrence of liver failure in some patients. Thus, decreasing PPIX biosynthesis is a promising strategy to treat protoporphyria. In this issue of the JCI, Ducamp et al. report that inhibition of the glycine plasma membrane transporter GLYT1 using bitopertin decreased PPIX accumulation and ameliorated liver disease using human in vitro and mouse in vivo models. Their findings support the ongoing development of bitopertin to treat protoporphyria, while concurrently pointing to underexplored roles of glycine in erythroid cells.

Authors

Marc Liesa

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Figure 1

EPP and XLPP induce PPIX accumulation by different mechanisms, but blocking glycine import with bitopertin can decrease PPIX accumulation in both forms.

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EPP and XLPP induce PPIX accumulation by different mechanisms, but block...
ALAS2 catalyzes glycine and succinyl-CoA into ALA in the first reaction of heme biosynthesis in erythroid cells, but not in hepatocytes. In a downstream reaction that occurs in both erythroid cells and hepatocytes, the enzyme FECH converts PPIX into heme. (A) Diminished FECH function in EPP is expected to induce a larger increase in PPIX in hepatocytes due to primary PPIX accumulation in both erythroid cells and hepatocytes. (B) However, in XLPP, ALAS2 gain of function leads to PPIX accumulation in erythroid cells only. (C) Illustration shows how bitopertin-mediated blockade of the glycine transporter limits glycine availability, preventing PPIX accumulation in both conditions. Notably, although limiting glycine availability and decreasing FECH in erythroid cells was predicted to be accompanied by decreased heme biosynthesis if PPIX were to decrease, this was not observed. This points to other mechanisms by which glycine contributes to heme homeostasis and by which erythroid cells can preserve heme content independently of FECH activity.