Heme Biosynthesis and Iron Metabolism in Erythroid Cells

Haem is synthesised via eight enzymatic reactions that traverse the mitochondrial matrix and cytosol, beginning with the condensation of glycine and succinyl-CoA by 5-aminolevulinate synthase and culminating in ferrous iron insertion by ferrochelatase. Developing erythroid cells couple this pathway tightly to globin synthesis, ensuring that iron, imported as transferrin-bound Fe3+ and reduced to Fe2+, is delivered to the mitochondrion via specialised transporters such as mitoferrin and sideroflexins. Cytosolic iron levels are regulated by iron regulatory proteins and ferritin, while systemic iron homeostasis is governed by hepcidin-mediated ferroportin degradation. Interorganelle coordination, involving ATP-binding cassette transporters and mitochondrial protein complexes, underpins efficient porphyrin and haem trafficking. Emerging evidence highlights the role of erythropoietin-driven signalling and post-translational modifications, such as protein kinase A-mediated phosphorylation, in fine-tuning enzyme activity and coordinating haem synthesis with erythroid maturation. Dysregulation of any step may lead to sideroblastic anaemia, porphyrias or iron-overload syndromes, and advances in molecular understanding have illuminated targets for therapeutic modulation in congenital and acquired red-cell disorders.

Research from Nature Portfolio

Recent structural analysis of the erythroid 5-aminolevulinate synthase (ALAS2) enzyme has revealed an eukaryotic-specific C-terminal autoinhibitory extension that occludes the active site until conformational rearrangement permits substrate binding. This discovery explains how C-terminal deletions in X-linked protoporphyria alleviate autoinhibition and suggests strategies for developing small-molecule inhibitors that stabilise the inactive state and mitigate toxic porphyrin accumulation. In parallel, investigation of sideroflexin 4 in erythroid precursors has established its essential role in Fe–S cluster assembly, mitochondrial iron distribution and maintenance of ferrochelatase expression. Loss of sideroflexin 4 disrupts iron homeostasis, depresses haem output and impairs mitochondrial respiration, underscoring the interdependence of Fe–S cluster formation and haem biosynthetic flux in red-cell progenitors.

Heme Biosynthesis and Iron Metabolism in Erythroid Cells publication trend

The graph below shows the total number of articles in heme biosynthesis and iron metabolism in erythroid cells across all publications each year (not limited to Nature Index journals).

Technical terms

5-Aminolevulinate synthase (ALAS2): Enzyme catalysing the first step of haem biosynthesis in erythroid cells.

Ferrochelatase (FECH): Mitochondrial enzyme inserting ferrous iron into protoporphyrin IX.

Mitoferrin: Mitochondrial inner-membrane transporter of ferrous iron in erythroid precursors.

Sideroflexin 4 (SFXN4): Mitochondrial protein essential for Fe–S cluster assembly and iron homeostasis.

Protein kinase A (PKA): Serine/threonine kinase mediating post-translational regulation of haem synthetic enzymes.

FAM210B: Mitochondrial adaptor protein that enhances iron import and ferrochelatase activity during erythropoiesis.

ABCB10: Mitochondrial ATP-binding cassette transporter integral to erythroid haem synthesis signalling.

References

1. FAM210B is an erythropoietin target and regulates erythroid heme synthesis by controlling mitochondrial iron import and ferrochelatase activity. Journal of Biological Chemistry (2018).
2. Reductions in the mitochondrial ABC transporter Abcb10 affect the transcriptional profile of heme biosynthesis genes. Journal of Biological Chemistry (2017).
3. Molecular Expression and Characterization of Erythroid-Specific 5-Aminolevulinate Synthase Gain-of-Function Mutations Causing X-Linked Protoporphyria. Molecular Medicine (2013).
4. Erythropoietin signaling regulates heme biosynthesis. eLife (2017).
5. Sideroflexin 4 affects Fe-S cluster biogenesis, iron metabolism, mitochondrial respiration and heme biosynthetic enzymes. Scientific Reports (2019).
6. Human aminolevulinate synthase structure reveals a eukaryotic-specific autoinhibitory loop regulating substrate binding and product release. Nature Communications (2020).