A mammalian siderophore synthesized by an enzyme with a bacterial homolog involved in enterobactin production.
Intracellular iron homeostasis is critical for survival and proliferation. Lipocalin 24p3 is an iron-trafficking protein that binds iron through association with a bacterial siderophore, such as enterobactin, or a postulated mammalian siderophore. Here, we show that the iron-binding moiety of the 24p3-associated mammalian siderophore is 2,5-dihydroxybenzoic acid (2,5-DHBA), which is similar to 2,3-DHBA, the iron-binding component of enterobactin. We find that the murine enzyme responsible for 2,5-DHBA synthesis, BDH2, is the homolog of bacterial EntA, which catalyzes 2,3-DHBA production during enterobactin biosynthesis. RNA interference-mediated knockdown of BDH2 results in siderophore depletion. Mammalian cells lacking the siderophore accumulate abnormally high amounts of cytoplasmic iron, resulting in elevated levels of reactive oxygen species, whereas the mitochondria are iron deficient. Siderophore-depleted mammalian cells and zebrafish embryos fail to synthesize heme, an iron-dependent mitochondrial process. Our results reveal features of intracellular iron homeostasis that are conserved from bacteria through humans.
Devireddy
Laxminarayana R
LR
Case Comprehensive Cancer Center and Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA. laxminarayana.devireddy@case.edu
Hart
Daniel O
DO
Goetz
David H
DH
Green
Michael R
MR
D000595:Amino Acid Sequence; D000818:Animals; D004758:Enterobactin / Q000378:metabolism*; D029968:Escherichia coli Proteins / Q000378:metabolism; D005841:Gentisates / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006884:Hydroxybutyrate Dehydrogenase / Q000737:chemistry / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D018384:Oxidative Stress; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000378:metabolism; D016415:Sequence Alignment; D017262:Siderophores / Q000378:metabolism*; D015027:Zebrafish
D029968:Escherichia coli Proteins; D005841:Gentisates; D017262:Siderophores; D004758:Enterobactin; D007501:Iron; D006884:Hydroxybutyrate Dehydrogenase; D044925:Oxidoreductases Acting on CH-CH Group Donors; C061899:entA protein, E coli; C010925:2,5-dihydroxybenzoic acid