Heme biosynthesis depends on acquisition of iron-sulfur cofactor
In 2020, we can still discover a new cofactor for a well studied enzyme. That’s horrifying - how much the researchers have missed before?
Herein we identify 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 find that several highly conserved cysteines and an Ala306-Phe307-Arg308 motif of human ALAD are important for Fe4S4 cluster acquisition and coordination.
The enzymatic activity of human ALAD is greatly reduced upon loss of its Fe-S cluster, which results in reduced heme biosynthesis in human cells. As ALAD provides an early Fe-S-dependent checkpoint in the heme biosynthetic pathway, our findings help explain why heme biosynthesis depends on intact ISC biogenesis."