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Measurement of Heme Synthesis Levels in Mammalian Cells
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A reversible feedback mechanism regulating mitochondrial heme synthesis.

Iva Chitrakar1, Alexis B Roberson1,2, Pedro H Ayres-Galhardo1

  • 1Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

Biorxiv : the Preprint Server for Biology
|September 18, 2025
PubMed
Summary

Heme binds to the mature human enzyme Aminolevulinic Acid Synthase 2 (ALAS2), inhibiting its activity. This reveals a crucial negative feedback loop in heme synthesis regulation within the mitochondrion.

Keywords:
aminolevulinic acidenzyme inhibitionerythropoiesishemeheme regulatory motifpyridoxal 5-phosphate

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cellular Metabolism

Background:

  • Heme biosynthesis is vital for cellular functions and its dysregulation is implicated in various human diseases.
  • Aminolevulinic Acid Synthase 2 (ALAS2) is the rate-limiting enzyme for erythroid heme production, located in mitochondria.
  • Regulation of mature mitochondrial ALAS2 remains poorly understood despite nuclear and cytoplasmic regulation studies.

Purpose of the Study:

  • To investigate the regulation of mature human ALAS2 within the mitochondrial matrix.
  • To elucidate the mechanism by which heme influences ALAS2 enzymatic activity.

Main Methods:

  • Biochemical assays to determine the interaction between heme and mature ALAS2.
  • Structure-based modeling to visualize the binding interface and conformational changes.
  • Enzyme kinetics studies to characterize the inhibition mechanism.

Main Results:

  • Heme binds to mature human ALAS2 with high affinity.
  • Heme acts as a reversible mixed inhibitor, reducing ALAS2 enzymatic activity.
  • Structure-based modeling shows heme binding to flexible regions, inducing an inactive conformation and occluding the active site.

Conclusions:

  • A novel negative feedback mechanism for heme synthesis is identified, mediated by heme binding to mature ALAS2.
  • This study provides insights into the spatial regulation of ALAS2 within the mitochondrion.
  • Understanding this mechanism is crucial for comprehending heme cofactor maturation and its role in cellular health.