Dependence of heme biosynthesis on iron-sulfur cluster biogenesis: human ALAD is an unrecognized iron-sulfur protein

Abstract

<jats:title>Abstract</jats:title> <jats:p>Heme biosynthesis and iron-sulfur cluster (ISC) biogenesis are two major mammalian metabolic pathways that require iron. It has long been known that these two pathways interconnect, but the previously described interactions do not fully explain why heme biosynthesis depends on intact ISC biogenesis. Herein we have identified a previously unrecognized connection between these two pathways through our discovery that human aminolevulinic acid dehydratase (ALAD), which catalyzes the second step of heme biosynthesis, is an Fe-S protein. We found that several highly conserved cysteines and an Ala306-Phe307-Arg308 motif of human ALAD are important for [Fe<jats:sub>4</jats:sub>S<jats:sub>4</jats:sub>] cluster acquisition and coordination. The enzymatic activity of human ALAD was greatly reduced upon loss of its Fe-S cluster, which resulted in reduced heme biosynthesis in human cells. Our findings explain why heme biosynthesis depends on intact ISC biogenesis, as ALAD provides an early Fe-S-dependent checkpoint in the heme biosynthetic pathway.</jats:p>

Regulation of Heme Synthesis by Mitochondrial Homeostasis Proteins

“…A recent study reports that the cytosolic heme synthesis enzyme, ALAD, is an Fe-S binding enzyme which requires Fe-S to maintain its enzymatic activity. This study potentially provides a mechanism by which iron homeostasis and heme synthesis are coordinated in cells (Liu et al, 2020). The importance of Fe-S assembly as a link between iron availability and heme synthesis is also underscored by the importance of frataxin, a mitochondrial protein essential for Fe-S assembly.…”

Case Report: Lack of Response to Givosiran in a Case of ALAD Porphyria

“…Additional evaluation established a diagnosis of ADP due to two ALAD mutations (c.265G > A, p.Glu89Lys and c.394 T > C, p.Cys132Arg), one inherited from each parent (Akagi et al, 2006). Interestingly, Cys132 is likely involved in coordination of a recently discovered iron-sulfur cluster required for full ALAD activity (Liu et al, 2020). At that time other laboratory testing including ferritin, aminotransferases, amylase, lipase, creatinine, and platelets were normal (Akagi et al, 2006).…”