Breann Brown

Heme is a critical biomolecule used by nearly all organisms, including humans where it serves as the oxygen-carrying cofactor of hemoglobin. The coordinated regulation of heme synthesis is necessary to maintain effective erythropoiesis. Thus, it is important to understand how heme production is controlled by the rate-limiting enzyme, mitochondrial Aminolevulinic Acid Synthase (ALAS2). Multiple studies report the regulation of ALAS2 at the nuclear and cytoplasmic levels, but little is known regarding how ALAS2 is modulated once inside the mitochondrial matrix. Using a combination of biophysical assays, enzymology, and structural modeling, we report that heme acts as an allosteric effector to alter ALAS2 structure and function in vitro. We present a model whereby this potential feedback mechanism may provide a rapid and reversible pathway to modulate metabolism in instances of heme stress. Future work will address how allosteric changes induced by heme alter protein assembly to modulate erythropoiesis.