Topologically Conserved Residues Direct Heme Transport in HRG-1-related Proteins

Yuan, Xian‐You; Protchenko, Olga; Philpott, Caroline C.; Hamza, Iqbal

doi:10.1074/jbc.m111.326785

Cited by 55 publications

(121 citation statements)

References 48 publications

Supporting

Mentioning

111

Contrasting

Order By: Relevance

“…A Leishmania heme response-1 (lhr-1) gene was later identified in Leishmania parasites, which shared homology to C. elegans hrg-4 (58). These HRG-related proteins are membrane-bound transporters with four transmembrane domains with their topologically conserved amino acid residues being critical for hemetransport functions (59). Bioinformatic searches for HRG-like proteins in Plasmodium spp.…”

Section: Discussionmentioning

confidence: 99%

The Heme Biosynthesis Pathway Is Essential for Plasmodium falciparum Development in Mosquito Stage but Not in Blood Stages

Sigala

Miura

et al. 2014

Journal of Biological Chemistry

138

161

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

The Heme Biosynthesis Pathway Is Essential for Plasmodium falciparum Development in Mosquito Stage but Not in Blood Stages

Sigala

Miura

et al. 2014

Journal of Biological Chemistry

138

161

View full text Add to dashboard Cite

“…Heterologous expression of this permease in yeast was shown to result in similar plasma membrane localization and import of exogenous heme into the cytosol (16). We tested whether the expression of HRG-4 in hem1⌬ and hem15⌬ cells would restore respiratory growth to these cells when cultured on medium containing supplemental heme.…”

Section: Supmentioning

confidence: 99%

The Plasma Membrane Protein Nce102 Implicated in Eisosome Formation Rescues a Heme Defect in Mitochondria

Kim

Jeong

Parnell

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

The cellular transport of the cofactor heme and its biosynthetic intermediates such as protoporphyrin IX is a complex and highly coordinated process. To investigate the molecular details of this trafficking pathway, we created a synthetic lesion in the heme biosynthetic pathway by deleting the gene HEM15 encoding the enzyme ferrochelatase in S. cerevisiae and performed a genetic suppressor screen. Cells lacking Hem15 are respiratory-defective because of an inefficient heme delivery to the mitochondria. Thus, the biogenesis of mitochondrial cytochromes is negatively affected. The suppressor screen resulted in the isolation of respiratory-competent colonies containing two distinct missense mutations in Nce102, a protein that localizes to plasma membrane invaginations designated as eisosomes. The presence of the Nce102 mutant alleles enabled formation of the mitochondrial respiratory complexes and respiratory growth in hem15⌬ cells cultured in supplemental hemin. Respiratory function in hem15⌬ cells can also be restored by the presence of a heterologous plasma membrane heme permease (HRG-4), but the mode of suppression mediated by the Nce102 mutant is more efficient. Attenuation of the endocytic pathway through deletion of the gene END3 impaired the Nce102-mediated rescue, suggesting that the Nce102 mutants lead to suppression through the yeast endocytic pathway.Heme is an essential cofactor in eukaryotes and bacteria and functions in a myriad of pathways including oxygen transport, nitric oxide and carbon monoxide sensing, oxygenase reactions, and electron transport reactions (1-3). The heme biosynthetic pathway in eukaryotes, including the yeast Saccharomyces cerevisiae, is a complex process involving eight enzymes (see Fig. 1A) (4). The process starts in the mitochondrial matrix with the condensation of glycine with succinyl-CoA to produce ∂-aminolevulinic acid (ALA) 3 by the enzyme 5-aminolevulinate synthase (Hem1 is the yeast designation) (2, 4). ALA is translocated across the mitochondrial membranes to the cytosol, where the next four enzymes in the pathway convert two ALA molecules to form the intermediate pyrrole porphobilinogen and subsequent formation of coproporphyrinogen III, which is transported back into the mitochondria for conversion to protoporphyrin IX (PPIX). Ferrous iron is inserted into PPIX by ferrochelatase (Hem15), tethered to the inner membrane and facing the matrix, to form the heme cofactor. A defect in any of heme biosynthetic enzymes leads to one of the porphyric disorders in humans, each with a unique phenotype resulting from a buildup of toxic intermediates (3).The mechanism of heme transport between cellular compartments remains poorly understood (4). Nevertheless, significant inroads have been recently made utilizing the heme auxotroph Caenorhabditis elegans, resulting in the identification of heme and porphyrin transporters, including the HRG-1-related heme transporters (4, 5). These transporters have mammalian homologs with similar function and specificity. Additionally, the fel...

show abstract

“…Furthermore, null alleles in BCRP in humans result in the "Junior" blood system group, which has no apparent clinical phenotype other than transfusion incompatibility (12). Using the heme auxotroph Caenorhabditis elegans, Hamza and colleagues identified a number of heme-responsive genes (HRGs) and their mammalian orthologs, including HRG1, which appears to transport heme with high affinity and specificity (13,14). Immunolocalization studies reveal that mammalian HRG1 localizes to endolysosomes and the phago lysosome of RES macrophages (13,15).…”

Section: A Mitochondrial Flvcr1 Isoformmentioning

confidence: 99%

Mitochondrial heme: an exit strategy at last

Fleming¹,

Hamza²

2012

J. Clin. Invest.

Self Cite

View full text Add to dashboard Cite

Topologically Conserved Residues Direct Heme Transport in HRG-1-related Proteins

Cited by 55 publications

References 48 publications

The Heme Biosynthesis Pathway Is Essential for Plasmodium falciparum Development in Mosquito Stage but Not in Blood Stages

The Heme Biosynthesis Pathway Is Essential for Plasmodium falciparum Development in Mosquito Stage but Not in Blood Stages

The Plasma Membrane Protein Nce102 Implicated in Eisosome Formation Rescues a Heme Defect in Mitochondria

Mitochondrial heme: an exit strategy at last

Contact Info

Product

Resources

About