Heme biosynthesis depends on previously unrecognized acquisition of iron-sulfur cofactors in human amino-levulinic acid dehydratase

Gang Liu, Debangsu Sil, Nunziata Maio, Wing-Hang Tong, J. Martin Bollinger, Carsten Krebs () and Tracey Ann Rouault ()
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Gang Liu: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
Debangsu Sil: The Pennsylvania State University
Nunziata Maio: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
Wing-Hang Tong: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
J. Martin Bollinger: The Pennsylvania State University
Carsten Krebs: The Pennsylvania State University
Tracey Ann Rouault: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: Abstract 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 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.

Date: 2020
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DOI: 10.1038/s41467-020-20145-9

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