This content will become publicly available on October 11, 2024
A dipyrrin-supported copper complex mediates C–H bond amination and aziridination of exogenous substrates using electron-deficient arylazides, proceeding through copper-nitrene adducts.
more » « less- NSF-PAR ID:
- 10471068
- Publisher / Repository:
- Royal Society of Chemistry
- Date Published:
- Journal Name:
- Chemical Science
- Volume:
- 14
- Issue:
- 39
- ISSN:
- 2041-6520
- Page Range / eLocation ID:
- 10847 to 10860
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
more » « less
Introduction: Heavy metal pollutants can have long lasting negative impacts on ecosystem health and can shape the evolution of species. The persistent and ubiquitous nature of heavy metal pollution provides an opportunity to characterize the genetic mechanisms that contribute to metal resistance in natural populations.Methods: We examined variation in resistance to copper, a common heavy metal contaminant, using wild collections of the model organismDrosophila melanogaster . Flies were collected from multiple sites that varied in copper contamination risk. We characterized phenotypic variation in copper resistance within and among populations using bulked segregant analysis to identify regions of the genome that contribute to copper resistance.Results and Discussion: Copper resistance varied among wild populations with a clear correspondence between resistance level and historical exposure to copper. We identified 288 SNPs distributed across the genome associated with copper resistance. Many SNPs had population-specific effects, but some had consistent effects on copper resistance in all populations. Significant SNPs map to several novel candidate genes involved in refolding disrupted proteins, energy production, and mitochondrial function. We also identified one SNP with consistent effects on copper resistance in all populations nearCG11825 , a gene involved in copper homeostasis and copper resistance. We compared the genetic signatures of copper resistance in the wild-derived populations to genetic control of copper resistance in theDrosophila Synthetic Population Resource (DSPR) and theDrosophila Genetic Reference Panel (DGRP), two copper-naïve laboratory populations. In addition toCG11825 , which was identified as a candidate gene in the wild-derived populations and previously in the DSPR, there was modest overlap of copper-associated SNPs between the wild-derived populations and laboratory populations. Thirty-one SNPs associated with copper resistance in wild-derived populations fell within regions of the genome that were associated with copper resistance in the DSPR in a prior study. Collectively, our results demonstrate that the genetic control of copper resistance is highly polygenic, and that several loci can be clearly linked to genes involved in heavy metal toxicity response. The mixture of parallel and population-specific SNPs points to a complex interplay between genetic background and the selection regime that modifies the effects of genetic variation on copper resistance. -
more » « less
Background and Aim: Copper is an essential trace metal serving as a cofactor in innate immunity, metabolism, and iron transport. We hypothesize that copper deficiency may influence survival in patients with cirrhosis through these pathways.
Methods: We performed a retrospective cohort study involving 183 consecutive patients with cirrhosis or portal hypertension. Copper from blood and liver tissues was measured using inductively coupled plasma mass spectrometry. Polar metabolites were measured using nuclear magnetic resonance spectroscopy. Copper deficiency was defined by serum or plasma copper below 80 µg/dL for women or 70 µg/dL for men.
Results: The prevalence of copper deficiency was 17% (N=31). Copper deficiency was associated with younger age, race, zinc and selenium deficiency, and higher infection rates (42% vs. 20%,
p =0.01). Serum copper correlated positively with albumin, ceruloplasmin, hepatic copper, and negatively with IL-1β. Levels of polar metabolites involved in amino acids catabolism, mitochondrial transport of fatty acids, and gut microbial metabolism differed significantly according to copper deficiency status. During a median follow-up of 396 days, mortality was 22.6% in patients with copper deficiency compared with 10.5% in patients without. Liver transplantation rates were similar (32% vs. 30%). Cause-specific competing risk analysis showed that copper deficiency was associated with a significantly higher risk of death before transplantation after adjusting for age, sex, MELD-Na, and Karnofsky score (HR: 3.40, 95% CI, 1.18–9.82,p =0.023).Conclusions: In advanced cirrhosis, copper deficiency is relatively common and is associated with an increased infection risk, a distinctive metabolic profile, and an increased risk of death before transplantation.
-
more » « less
Summary Cu+‐chaperones are a diverse group of proteins that allocate Cu+ions to specific copper proteins, creating different copper pools targeted to specific physiological processes.
Symbiotic nitrogen fixation carried out in legume root nodules indirectly requires relatively large amounts of copper, for example for energy delivery via respiration, for which targeted copper deliver systems would be required.
MtNCC1 is a nodule‐specific Cu+‐chaperone encoded in the
Medicago truncatula genome, with a N‐terminus Atx1‐like domain that can bind Cu+with picomolar affinities. MtNCC1 is able to interact with nodule‐specific Cu+‐importer MtCOPT1.MtNCC1 is expressed primarily from the late infection zone to the early fixation zone and is located in the cytosol, associated with plasma and symbiosome membranes, and within nuclei. Consistent with its key role in nitrogen fixation,ncc1 mutants have a severe reduction in nitrogenase activity and a 50% reduction in copper‐dependent cytochromec oxidase activity.A subset of the copper proteome is also affected in the
ncc1 mutant nodules. Many of these proteins can be pulled down when using a Cu+‐loaded N‐terminal MtNCC1 moiety as a bait, indicating a role in nodule copper homeostasis and in copper‐dependent physiological processes. Overall, these data suggest a pleiotropic role of MtNCC1 in copper delivery for symbiotic nitrogen fixation. -
more » « less
Abstract Warming environments can alter the outcome of host–parasite relationships with important consequences for biodiversity. Warming often increases disease risk, and interactions with other environmental factors can intensify impacts by modifying the underlying mechanisms, such as host immunity. In coastal ecosystems, metal pollution is a pervasive stressor that influences disease and immunity in many organisms. Despite the crisis facing coral reefs, which stems in part from warming‐associated disease outbreaks, the impacts of metal pollutants on scleractinian and octocoral disease are largely unknown. We investigated how warming oceans and copper pollution affect host immunity and disease risk for two diseases of the abundant Caribbean octocoral, the sea fan Gorgonia ventalina. Field surveys across a sediment copper concentration gradient in Puerto Rico, USA revealed that cellular immunity of sea fans increased by 12.6% at higher sediment copper concentrations, while recovery from multifocal purple spots disease (
MFPS ) tended to decrease.MFPS severity in the field increased at warmer sites. In a controlled laboratory experiment, sea fans were inoculated with live cultures of a labyrinthulid parasite to test the interactive effects of temperature and copper on immune activation. As in the field, higher copper induced greater immunity, but the factorial design of the experiment revealed that copper and temperature interacted to modulate the immune response to the parasite: immune cell densities increased with elevated temperature at lower copper concentrations, but not with high copper concentrations. Tissue damage was also greater in treatments with higher copper and warmer temperatures. Field and lab evidence confirm that elevated copper hinders sea fan immune defenses against damaging parasites. Temperature and copper influenced host–pathogen interactions in octocorals by modulating immunity, disease severity, and disease recovery. This is the first evidence that metal pollution affects processes influencing disease in octocorals and highlights the importance of immune mechanisms in environmentally mediated disease outbreaks. Although coral conservation efforts must include a focus on global factors, such as rapid warming, reducing copper and other pollutants that compromise coral health on a local scale may help corals fight disease in a warming ocean. -
more » « less
Abstract The continuous rise of multi-drug resistant pathogenic bacteria has become a significant challenge for the health care system. In particular, novel drugs to treat infections of methicillin-resistant Staphylococcus aureus strains (MRSA) are needed, but traditional drug discovery campaigns have largely failed to deliver clinically suitable antibiotics. More than simply new drugs, new drug discovery approaches are needed to combat bacterial resistance. The recently described phenomenon of copper-dependent inhibitors has galvanized research exploring the use of metal-coordinating molecules to harness copper’s natural antibacterial properties for therapeutic purposes. Here, we describe the results of the first concerted screening effort to identify copper-dependent inhibitors of Staphylococcus aureus. A standard library of 10 000 compounds was assayed for anti-staphylococcal activity, with hits defined as those compounds with a strict copper-dependent inhibitory activity. A total of 53 copper-dependent hit molecules were uncovered, similar to the copper independent hit rate of a traditionally executed campaign conducted in parallel on the same library. Most prominent was a hit family with an extended thiourea core structure, termed the NNSN motif. This motif resulted in copper-dependent and copper-specific S. aureus inhibition, while simultaneously being well tolerated by eukaryotic cells. Importantly, we could demonstrate that copper binding by the NNSN motif is highly unusual and likely responsible for the promising biological qualities of these compounds. A subsequent chemoinformatic meta-analysis of the ChEMBL chemical database confirmed the NNSNs as an unrecognized staphylococcal inhibitor, despite the family’s presence in many chemical screening libraries. Thus, our copper-biased screen has proven able to discover inhibitors within previously screened libraries, offering a mechanism to reinvigorate exhausted molecular collections.
