Metal Preferences and Metallation

Foster, Andrew W.; Osman, Deenah; Robinson, Nigel J.

doi:10.1074/jbc.r114.588145

Cited by 332 publications

(336 citation statements)

References 100 publications

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“…An alternative possibility not tested here is that the CTD physically interacts with an as yet unidentified accessory protein or metal chaperone to influence metal transport activity, as previously described for MamB (38). This is not unprecedented, as other metal transporters have been shown to employ similar mechanisms to regulate their activities (49,50). For example, the E. coli Mn transporter MntP may be inhibited by expression of the small protein MntS (8).…”

Section: Discussionmentioning

confidence: 97%

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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Section: Discussionmentioning

confidence: 97%

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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“…S8 in the supplemental material). Besides, while we determined an affinity of 8HQ for Cu in the nanomolar range (log K f ϭ 9.22; see Table S2 in the supplemental material), intracellular Curequiring proteins bind Cu ions with much greater affinities (69,70). These protein-bound Cu ions are therefore unlikely accessible to 8HQ.…”

Section: Discussionmentioning

confidence: 99%

8-Hydroxyquinolines Are Boosting Agents of Copper-Related Toxicity in Mycobacterium tuberculosis

Shah

Dalecki

Malalasekera

et al. 2016

Antimicrob Agents Chemother

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c Copper (Cu) ions are likely the most important immunological metal-related toxin utilized in controlling bacterial infections. Impairment of bacterial Cu resistance reduces viability within the host. Thus, pharmacological enhancement of Cu-mediated antibacterial toxicity may lead to novel strategies in drug discovery and development. Screening for Cu toxicity-enhancing antibacterial molecules identified 8-hydroxyquinoline (8HQ) to be a potent Cu-dependent bactericidal inhibitor of Mycobacterium tuberculosis. The MIC of 8HQ in the presence of Cu was 0.16 M for replicating and nonreplicating M. tuberculosis cells. We found 8HQ's activity to be dependent on the presence of extracellular Cu and to be related to an increase in cell-associated labile Cu ions. Both findings are consistent with 8HQ acting as a Cu ionophore. Accordingly, we identified the 1:1 complex of 8HQ and Cu to be its active form, with Zn, Fe, or Mn neither enhancing nor reducing its Cu-specific action. This is remarkable, considering that the respective metal complexes have nearly identical structures and geometries. Finally, we found 8HQ to kill M. tuberculosis selectively within infected primary macrophages. Given the stark Cu-dependent nature of 8HQ activity, this is the first piece of evidence that Cu ions within macrophages may bestow antibacterial properties to a Cu-dependent inhibitor of M. tuberculosis. In conclusion, our findings highlight the metal-binding ability of the 8-hydroxyquinoline scaffold to be a potential focus for future medicinal chemistry and highlight the potential of innate immunity-inspired screening platforms to reveal molecules with novel modes of action against M. tuberculosis.

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“…According to the Irving-Williams series of metal binding to proteins, Cu binds more strongly than both Fe and Mn ( 47 ). The high copper content in the protein sample could be due to either nonspecifi cally protein-bound Cu 2+ or specifi cally bound Cu 2+ at the active site.…”

Section: +mentioning

confidence: 99%

Manganese lipoxygenase of F. oxysporum and the structural basis for biosynthesis of distinct 11-hydroperoxy stereoisomers

Wennman

Magnuson

Hámberg

et al. 2015

Journal of Lipid Research

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This article is available online at http://www.jlr.org Lipoxygenases (LOXs) belong to a common gene family ( 1, 2 ). The catalytic domain is formed by ␣ -helices, which harbor fi ve metal ligands. The 3D structure is known for over 10 enzymes from plants, animals, and bacteria with 13 S -LOX of soybean LOX-1 (sLOX-1) and 8 R -LOX of Plexaura homomalla as old and new prototypes ( 3-5 ). The latter was recently crystallized with its substrate in the active site ( 5 ). Information on the active site and reaction mechanism has also been gained by site-directed mutagenesis and by analysis of various substrates, deuterated fatty acids, and LOX inhibitors ( 1, 6 ). With few exceptions, LOXs oxidize polyunsaturated fatty acids with one or more cis , cis-1,4-pentadiene units to hydroperoxides, which in many cases are precursors of biological mediators ( 1, 6, 7 ). Mammalian LOXs initiate biosynthesis of leukotrienes and epoxy alcohols, which are involved in allergic infl ammation, asthma, formation of the skin-water barrier, and cancer development ( 6,8 ). Plant LOXs form jasmonates and related oxylipins with functions in defense against pathogens and in wound healing ( 9,10 ).The N-terminal parts of mammalian and plant LOXs usually consist of ␤ -sheets with homology to polycystin-1/ LOX/ ␣ -toxin (PLAT) domains with regulatory functions. The N-terminal domains of fungal LOXs lack this homology, but they often contain a secretion signal ( 11, 12 ). Abbreviations: Af-MnLOX, Aspergillus fumigatus manganese lipoxygenase; Cg-MnLOX, Colletotrichum gloeosporioides manganese lipoxygenase; CP, chiral phase; EPR, electron paramagnetic resonance; FeLOX, iron lipoxygenase; Fo-MnLOX, Fusarium oxysporum manganese lipoxygenase; HPODE, hydroperoxyoctadecadienoic acid; 9 S -H(P)ODE, 9 S -hydro(pero) xy-10 E ,12 Z -octadecadienoic acid; 11 S -H(P)ODE, 11 S -hydro(pero)xy-9 Z ,12 Z -octadecadienoic acid; 13 R -H(P)ODE, 13 R -hydro(pero)xy-9 Z ,11 Eoctadecadienoic acid; HPOTrE, hydroperoxyoctadecatrienoic acid; 9 S -H(P)OTrE, 9 S -hydro(pero)xy-10 E ,12 Z ,15Z-octadecatrienoic acid; 11 R -H(P)OTrE, 11 R -hydro(pero)xy-9 Z ,12 Z ,15 Z -octadecatrienoic acid; 13 R -H(P)OTrE, 13 R -hydro(pero)xy-9 Z ,11 E ,15Z-octadecatrienoic acid; ICP-AES, inductively coupled plasma atomic emission spectroscopy; LOX, lipoxygenase; MnLOX, manganese lipoxygenase; Mo-MnLOX, Magnaporthe oryzae manganese lipoxygenase; RP, reversed phase; sLOX-1, soybean lipoxygenase-1; TPP, triphenylphosphine . Abstract The biosynthesis of jasmonates in plants is

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Metal Preferences and Metallation

Cited by 332 publications

References 100 publications

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

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

8-Hydroxyquinolines Are Boosting Agents of Copper-Related Toxicity in Mycobacterium tuberculosis

Manganese lipoxygenase of F. oxysporum and the structural basis for biosynthesis of distinct 11-hydroperoxy stereoisomers

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