Extracellular glycine is necessary for optimal hemoglobinization of erythroid cells

• Published in: Haematologica (Roma) Vol. 102; no. 8; pp. 1314 - 1323
• Main Authors: Garcia-Santos, Daniel, Schranzhofer, Matthias, Bergeron, Richard, Sheftel, Alex D, Ponka, Prem
• Format: Journal Article
• Language: English
• Published: Italy Ferrata Storti Foundation 01.08.2017
• Subjects: Animals; Erythroid Cells - metabolism; Glycine - metabolism; Glycine Plasma Membrane Transport Proteins - deficiency; Glycine Plasma Membrane Transport Proteins - genetics; Heme - biosynthesis; Hemoglobins - biosynthesis; Hemoglobins - metabolism; Mice; Mice, Knockout
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.2016.155671

Vertebrate heme synthesis requires three substrates: succinyl-CoA, which regenerates in the tricarboxylic acid cycle, iron and glycine. For each heme molecule synthesized, one atom of iron and eight molecules of glycine are needed. Inadequate delivery of iron to immature erythroid cells leads to a decreased production of heme, but virtually nothing is known about the consequence of an insufficient supply of extracellular glycine on the process of hemoglobinization. To address this issue, we exploited mice in which the gene encoding glycine transporter 1 (GlyT1) was disrupted. Primary erythroid cells isolated from fetal livers of GlyT1 knockout (GlyT1 ) and GlyT1-haplodeficient (GlyT1 ) embryos had decreased cellular uptake of [2 C]glycine and heme synthesis as revealed by a considerable decrease in [2- C]glycine and Fe incorporation into heme. Since GlyT1 mice die during the first postnatal day, we analyzed blood parameters of newborn pups and found that GlyT1 animals develop hypochromic microcytic anemia. Our finding that Glyt1-deficiency causes decreased heme synthesis in erythroblasts is unexpected, since glycine is a non-essential amino acid. It also suggests that GlyT1 represents a limiting step in heme and, consequently, hemoglobin production.