A reversible feedback mechanism regulating mitochondrial heme synthesis

TL;DR

The paper explains how heme, a crucial molecule, inhibits its own production by binding to an enzyme in mitochondria, providing new insights into heme regulation.

Contribution

The study identifies a reversible feedback mechanism where heme inhibits its own synthesis by binding to ALAS2 in mitochondria.

Findings

Heme binds mature human ALAS2 with high affinity, acting as a reversible mixed inhibitor.

Structural modeling suggests heme binding locks ALAS2 in an inactive conformation.

This mechanism reveals spatial regulation of ALAS2 and heme cofactor maturation.

Abstract

Proper heme biosynthesis is essential for numerous cellular functions across nearly all life forms. In humans, dysregulated heme metabolism is linked to multiple blood diseases, neurodegeneration, cardiovascular disease, and metabolic disorders. Erythroid heme production begins with the rate-limiting enzyme aminolevulinic acid synthase 2 (ALAS2) in the mitochondrion. Although prior studies discuss the regulation of ALAS2 in the cytoplasm, its modulation as a mature mitochondrial matrix enzyme remains poorly understood. We report that heme binds mature human ALAS2 with high affinity, acting as a reversible mixed inhibitor that reduces enzymatic activity. Structural modeling supports the hypothesis that two flexible regions of ALAS2 interact with heme, locking the enzyme in an inactive conformation and occluding the active site. Our work reveals a negative feedback mechanism for heme synthesis, offering insights into the spatial regulation of ALAS2 and the maturation of the essential heme cofactor.

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