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Haematologica. 2017 Aug;102(8):1314-1323. doi: 10.3324/haematol.2016.155671. Epub 2017 May 11.

Extracellular glycine is necessary for optimal hemoglobinization of erythroid cells.

Author information

1
Lady Davis Institute for Medical Research, Jewish General Hospital, and the Department of Physiology, McGill University, Montréal, Quebec, Canada.
2
Ottawa Hospital Research Institute, University of Ottawa, Ontario, Canada.
3
Spartan Bioscience Inc., Ottawa, Canada.
4
High Impact Editing, Ottawa, Ontario, Canada.
5
Lady Davis Institute for Medical Research, Jewish General Hospital, and the Department of Physiology, McGill University, Montréal, Quebec, Canada prem.ponka@mcgill.ca.

Abstract

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 [2-14C]glycine and heme synthesis as revealed by a considerable decrease in [2-14C]glycine and 59Fe 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.

PMID:
28495915
PMCID:
PMC5541866
DOI:
10.3324/haematol.2016.155671
[Indexed for MEDLINE]
Free PMC Article

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