Cellular sensing and transport of metal ions: implications in micronutrient homeostasis

Bird, Amanda J.

doi:10.1016/j.jnutbio.2015.08.002

Cited by 45 publications

(30 citation statements)

References 218 publications

(233 reference statements)

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“…Metal regulatory factors sense fluctuations in metal ion levels and, in response, alter gene expression via transcriptional, posttranscriptional and posttranslational mechanisms to maintain metal ion homeostasis [42]. Targeting these factors will enable the manipulation of transition metal homeostasis independent of metal ion sensing.…”

Section: Targeting Metal Homeostasis Through Metal Regulatory Proteinsmentioning

confidence: 99%

Developing drugs targeting transition metal homeostasis

Weekley

2017

Current Opinion in Chemical Biology

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Metal dyshomeostasis is involved in the pathogenesis and progression of diseases including cancer and neurodegenerative diseases. Metal chelators and ionophores are well known modulators of transition metal homeostasis, and a number of these molecules are in clinical trials. Metalbinding compounds are not the only drugs capable of targeting transition metal homeostasis. This review presents recent highlights in the development of chelators and ionophores for the treatment of cancer and neurodegenerative disease. Moreover, we discuss the development of small molecules that alter copper and iron homeostasis by inhibiting metal transport proteins. Finally, we consider the emergence of metal regulatory factor 1 as a drug target in diseases where it mediates zinc-induced signalling cascades leading to pathogenesis.

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Section: Targeting Metal Homeostasis Through Metal Regulatory Proteinsmentioning

confidence: 99%

Developing drugs targeting transition metal homeostasis

Weekley

2017

Current Opinion in Chemical Biology

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“…T ransition metals from manganese (Mn) to zinc (Zn) in the first row of the periodic table serve as essential cofactors in metalloenzymes that are required for many important cellular processes, including replication, regulation, and central metabolism, among all domains of life (1)(2)(3). Despite their importance, excess transition metals can impair bacterial growth.…”

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confidence: 99%

Functional Determinants of Metal Ion Transport and Selectivity in Paralogous Cation Diffusion Facilitator Transporters CzcD and MntE in Streptococcus pneumoniae

Martin

Giedroc

2016

J Bacteriol

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Cation diffusion facilitators (CDFs) are a large family of divalent metal transporters that collectively possess broad metal specificity and contribute to intracellular metal homeostasis and virulence in bacterial pathogens. Streptococcus pneumoniae expresses two homologous CDF efflux transporters, MntE and CzcD. Cells lacking mntE or czcD are sensitive to manganese (Mn) or zinc (Zn) toxicity, respectively, and specifically accumulate Mn or Zn, respectively, thus suggesting that MntE selectively transports Mn, while CzcD transports Zn. Here, we probe the origin of this metal specificity using a phenotypic growth analysis of pneumococcal variants. Structural homology to Escherichia coli YiiP predicts that both MntE and CzcD are dimeric and each protomer harbors four pairs of conserved metal-binding sites, termed the A site, the B site, and the C1/C2 binuclear site. We find that single amino acid mutations within both the transmembrane domain A site and the B site in both CDFs result in a cellular metal sensitivity similar to that of the corresponding null mutants. However, multiple mutations in the predicted cytoplasmic C1/C2 cluster of MntE have no impact on cellular Mn resistance, in contrast to the analogous substitutions in CzcD, which do have on impact on cellular Zn resistance. Deletion of the MntE-specific C-terminal tail, present only in Mn-specific bacterial CDFs, resulted in only a modest growth phenotype. Further analysis of MntE-CzcD functional chimeric transporters showed that Asn and Asp in the ND-DD A-site motif of MntE and the most N-terminal His in the HD-HD site A of CzcD (the specified amino acids are underlined) play key roles in transporter metal selectivity. IMPORTANCECation diffusion facilitator (CDF) proteins are divalent metal ion transporters that are conserved in organisms ranging from bacteria to humans and that play important roles in cellular physiology, from metal homeostasis and resistance to type I diabetes in vertebrates. The respiratory pathogen Streptococcus pneumoniae expresses two metal CDF transporters, CzcD and MntE. How CDFs achieve metal selectivity is unclear. We show here that CzcD and MntE are true paralogs, as CzcD transports zinc, while MntE selectively transports manganese. Through the use of an extensive collection of pneumococcal variants, we show that a primary determinant for metal selectivity is the A site within the transmembrane domain. This extends our understanding of how CDFs discriminate among transition metals. T ransition metals from manganese (Mn) to zinc (Zn) in the first row of the periodic table serve as essential cofactors in metalloenzymes that are required for many important cellular processes, including replication, regulation, and central metabolism, among all domains of life (1-3). Despite their importance, excess transition metals can impair bacterial growth. Excess iron (Fe) is harmful due to its participation in Fenton chemistry, which produces a highly reactive hydroxyl radical that can damage biomolecules (4-7). Other transition m...

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“…The subcellular homeostasis of Zn is tightly regulated through uptake, storage, re-distribution and efflux mechanisms that are, among other, mediated by Zn transporters of the ZnT and ZIP family (Bird, 2015). Seven members of the ZIP family and four members of the ZnT family have been identified in Dictyostelium (Dunn et al, 2017; Sunaga et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Think zinc: Role of zinc poisoning in the intraphagosomal killing of bacteria by the amoeba Dictyostelium

Barisch

Kalinina

et al. 2018

Preprint

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31Professional phagocytes have developed an extensive repertoire of autonomous immunity strategies 32 to ensure killing of bacteria. Besides phagosome acidification and the generation of reactive oxygen species, 33 deprivation of nutrients and the lumenal accumulation of toxic metals are essential to kill ingested bacteria or 34 inhibit growth of intracellular pathogens. We use the soil amoeba Dictyostelium discoideum, a professional 35 phagocyte that digests bacteria for nutritional purposes, to decipher the role of zinc poisoning during 36 phagocytosis of non-pathogenic bacteria and visualize the temporal and spatial dynamics of 37 compartmentalized, free zinc using fluorescent probes. Immediately after particle uptake, zinc is delivered to 38 phagosomes by fusion with "zincosomes" of endosomal origin, but also by the action of one or more zinc 39 transporters. We localize the four Dictyostelium ZnT transporters to endosomes, the contractile vacuole and 40 the Golgi apparatus, and study the impact of znt knockouts on zinc homeostasis. Finally, we show that zinc is 41 delivered into the lumen of Mycobacterium smegmatis-containing vacuoles, and that Escherichia coli 42 deficient in the zinc efflux P 1B -type ATPase ZntA is killed faster than wild type bacteria. 43

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Cellular sensing and transport of metal ions: implications in micronutrient homeostasis

Cited by 45 publications

References 218 publications

Developing drugs targeting transition metal homeostasis

Developing drugs targeting transition metal homeostasis

Functional Determinants of Metal Ion Transport and Selectivity in Paralogous Cation Diffusion Facilitator Transporters CzcD and MntE in Streptococcus pneumoniae

Think zinc: Role of zinc poisoning in the intraphagosomal killing of bacteria by the amoeba Dictyostelium

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