Elesclomol rescues mitochondrial copper deficiency in disease models without triggering cuproptosis DOI
Mohammad Zulkifli, Krishna P. Maremanda,

Adriana U. Okonkwo

et al.

Journal of Pharmacology and Experimental Therapeutics, Journal Year: 2024, Volume and Issue: 392(2), P. 100048 - 100048

Published: Nov. 30, 2024

Copper (Cu) is an essential cofactor for metalloenzymes such as cytochrome c oxidase (CcO), the terminal enzyme of mitochondrial electron transport chain. Mutations that directly or indirectly prevent Cu to mitochondria result in lethal pediatric diseases, Menkes disease. There no clinically approved treatment We recently discovered investigational chemotherapy drug, elesclomol (ES), when complexed with (ES-Cu), rescues deficiency, activates CcO, and prevents perinatal lethality a mouse model However, ES-Cu also has potential trigger cuproptosis, type Cu-dependent cell death. Therefore, develop therapeutic agent disease, it critical determine index Cu-deficient models. To this end, we used rat cardiomyocyte line mottled-brindled severe disease toxicity efficacy ES-Cu. Our culture studies demonstrated EC50 ∼50-fold lower than IC50. Moreover, biomarkers toxicity, including lipoylated proteins subset iron-sulfur cluster-containing mitochondria, are activated only at ∼10-fold 25-fold higher its EC50. Importantly, none these mice treated doses study shows can deliver CcO both vitro vivo without triggering finding could facilitate use deficiency disorders, SIGNIFICANCE STATEMENT: Genetic copper causes which lacks treatment. Recently, Cu-transporting chemotherapeutic been reported. Because risk Cu-induced from ES-Cu, crucial index. Here, models were measured demonstrate restore cuproenzymes biomarkers.

Language: Английский

Unveiling the promising anticancer effect of copper-based compounds: a comprehensive review DOI Creative Commons

Sara Abdolmaleki,

Alireza Aliabadi, Samad Khaksar

et al.

Journal of Cancer Research and Clinical Oncology, Journal Year: 2024, Volume and Issue: 150(4)

Published: April 25, 2024

Abstract Copper is a necessary micronutrient for maintaining the well-being of human body. The biological activity organic ligands, especially their anticancer activity, often enhanced when they coordinate with copper(I) and (II) ions. its compounds are capable inducing tumor cell death through various mechanisms action, including activation apoptosis signaling pathways by reactive oxygen species (ROS), inhibition angiogenesis, induction cuproptosis, paraptosis. Some copper complexes currently being evaluated in clinical trials ability to map hypoxia cancers, locally advanced rectal cancer bulky tumors. Several studies have shown that nanoparticles can be used as effective agents chemodynamic therapy, phototherapy, hyperthermia, immunotherapy. Despite promising copper-based compounds, use subject certain limitations. Elevated concentrations may promote growth, metastasis affecting cellular processes.

Language: Английский

Citations

26
Metals in Motion: Understanding Labile Metal Pools in Bacteria DOI Creative Commons
John D. Helmann

Biochemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 5, 2025

Metal ions are essential for all life. In microbial cells, potassium (K+) is the most abundant cation and plays a key role in maintaining osmotic balance. Magnesium (Mg2+) dominant divalent required nucleic acid structure as an enzyme cofactor. Microbes typically require transition metals manganese (Mn), iron (Fe), copper (Cu), zinc (Zn), although precise set of metal needed to sustain life variable. Intracellular pools can be conceptualized chemically complex mixture rapidly exchanging (labile) ions, complemented by those reservoirs that exchange slowly relative cell metabolism (sequestered). Labile buffered transient interactions with anionic metabolites macromolecules, ribosome playing major role. Sequestered include many metalloproteins, cofactors, storage depots, some redeployed upon depletion. Here, I review size, composition, dynamics intracellular highlight gaps understanding.

Language: Английский

Citations

3
NMR spectroscopic investigations of transition metal complexes in organometallic and bioinorganic chemistry DOI Creative Commons
Jeongcheol Shin, Mi Hee Lim, Jiyeon Han

et al.

Bulletin of the Korean Chemical Society, Journal Year: 2024, Volume and Issue: 45(7), P. 593 - 613

Published: May 28, 2024

Abstract The field of coordination chemistry has evolved to intersect with organic and biochemistry, giving rise the disciplines organometallic bioinorganic chemistry. Nuclear magnetic resonance (NMR) spectroscopy can be applied for characterizing transition metal complexes, spanning both diamagnetic paramagnetic complexes prevalent in compounds metalloproteins. This review offers a comprehensive overview wide variety characterization techniques, ranging from basic 1 H 13 C NMR advanced methods such as heteronuclear experiments, polarization transfer relaxometry, multidimensional spectroscopy. diverse array spectroscopic outlined here promises enhance our comprehension facilitating development innovative catalysts therapeutics.

Language: Английский

Citations

8
Exploring the Reaction Surface of Cu(I) Transfer from Atx1 to Ccc2a Protein: A Theoretical Study DOI Open Access

J. Vijaya Sundar,

M. Jacob Jesni,

V. Rajapandian

et al.

ChemistrySelect, Journal Year: 2025, Volume and Issue: 10(6)

Published: Feb. 1, 2025

Abstract In this study, a detailed mechanism for the copper transfer between yeast Atx1 and Ccc2a (P‐type‐ATPase) is proposed. To explore potential energy surface (PES) of reaction pathway, density functional theory (DFT)‐based B3LYP/6‐31+G** ∪ Lanl2DZ method was used active site model. The effect protein environment on pathway unraveled by Our own N‐layered Integrated molecular Orbital Mechanics (ONIOM model) using Lanl2DZ:UFF method. Results obtained from calculations unveil formation kinetically stable 3‐coordinated intermediate IM3(ONIOM). It also provides information irreversibility Cu(I) to domain. proposed enables us understand rate‐determining step activation barrier transfer, which 14.15 kcal/mol model 22.87 ONIOM evident NBO analysis that interaction K65‐Atx1 Cu(I)–S 3 unit mediated water molecule, responsible stabilization 3‐coordinate (IM3). These results provide new insight into in chaperones.

Language: Английский

Citations

0
Quantity of cu(II) ions in a copper pot by a DNAzyme-based fluorescent sensor DOI Creative Commons
Dazhi Jiang, Shijin Wang, Chang‐Hao Yang

et al.

Food Chemistry Molecular Sciences, Journal Year: 2025, Volume and Issue: 10, P. 100249 - 100249

Published: Feb. 18, 2025

Language: Английский

Citations

0
The Escherichia coli AZY operon links copper uptake to antibiotic resistance DOI Creative Commons

Christine Elizabeth Palmer,

Yara Ghnamah,

Nurit Livnat-Levanon

et al.

Communications Biology, Journal Year: 2025, Volume and Issue: 8(1)

Published: March 19, 2025

Copper import to the bacterial cytoplasm has been underinvestigated as cuproenzymes are extracytoplasmic. However, copper must access interact with metal-dependent transcription factors. In particular, multiple drug antibiotic resistance (mar) operon is induced by a signal, source of which not established. Here we show that Escherichia coli AZY operon, encodes copper-binding periplasmic proteins YobA and YebY putative importer YebZ, mediates uptake. uptake YebZ depends on two conserved histidine residues modulated YebY. Moreover, necessary for activation mar mediate antibiotics in copper-dependent fashion. AZY-like operons widespread gram-negative bacteria, suggesting this previously unknown link between general mechanism may offer an alternative therapeutic target multidrug resistance. The E. comprise copper-specific system required pathway, elucidating missing bacteria.

Language: Английский

Citations

0
Cu(I) chelators: Useful tools to reveal and control Cu(I) homeostasis and toxicity DOI Creative Commons
Charlène Esmieu, Sarah Hostachy, Christelle Hureau

et al.

Coordination Chemistry Reviews, Journal Year: 2025, Volume and Issue: 539, P. 216684 - 216684

Published: April 24, 2025

Language: Английский

Citations

0
Some Properties of the C. elegans Multicopper Oxidase F21D5.3, an Ortholog of Human Ceruloplasmin DOI Open Access
Polina D. Samuseva,

Aleksandra A. Mekhova-Caramalac,

Federico Catalano

et al.

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(10), P. 4776 - 4776

Published: May 16, 2025

This study identified an oxidase-positive protein in the plasma membrane fraction of C. elegans N2 strain. The with a molecular weight approximately 85 kDa reacted antibodies against human and mouse, but not rat, ceruloplasmin exhibited oxidase activity. Bioinformatic analysis revealed that F21D5.3 possesses four copper-binding sites, similar to those other multicopper oxidases (MCOs), plastocyanin-like domains characteristic MCOs. However, neither iron-binding domain nor ferroxidase activity, typical features MCOs, were detected through silico or in-gel assays. Despite absence these findings suggest may be product gene, ortholog MCOs elegans. Heat map indicated expression entero-rectal valve cells both anterior posterior intestines. Among genes associated copper transport, only cua-1 pattern. In cua-1H828Q strain, which mimics mutation ATP7B linked Wilson’s disease (WD), activity was also observed. Notably, strains showed reduced when cultured silver nanoparticles (AgNPs). These highlight potential strain as model for studying iron metabolism developing therapeutic strategies WD.

Language: Английский

Citations

0
Transcriptional regulation of ATOX1 by PRRX2 impacts the progression and cuproptosis of hepatocellular carcinoma DOI
Ling Tang, Bin Xie,

Xiankui Cao

et al.

Cellular Signalling, Journal Year: 2025, Volume and Issue: unknown, P. 111883 - 111883

Published: May 1, 2025

Language: Английский

Citations

0
Serum copper assessment in patients with polycystic ovary syndrome and tubal infertility: A retrospective 5‐year study DOI Creative Commons
Yanping Liu, Wei Zhang, Zhenxing Liu

et al.

Food Science & Nutrition, Journal Year: 2024, Volume and Issue: 12(8), P. 5979 - 5989

Published: June 10, 2024

Abstract The association between serum copper and polycystic ovary syndrome (PCOS) lacks definitive conclusions, the intricate interactions with in vitro fertilization (IVF) cycle characteristics infertility remain insufficiently explored. This retrospective study included 560 patients tubal (no‐PCOS) 266 PCOS undergoing IVF at Affiliated Suzhou Hospital of Nanjing Medical University from January 2018 to December 2022. Patients' basic characteristics, hormonal metabolic parameters, essential trace elements, were measured analyzed. results revealed a significantly elevated level group compared control [17.27 (15.54, 19.67) vs 15.4 (13.87, 17.35), μmol/L; p < .001]. Spearman correlation analyses significant positive concentration body mass index (BMI), fasting glucose (FG), triglyceride (TG), total cholesterol (TC), low‐density lipoprotein (LDL) no‐PCOS group. Additionally, notable negative high‐density (HDL) was observed ( r = −.184, .001). Within group, correlated BMI .198, .004) TG .214, .002). linear trend analysis indicated no relationship ovarian response as well preimplantation outcomes both groups after adjusting for confounding factors. Our provided evidence patients, closely associated lipid metabolism but showing outcomes. These findings provide valuable real‐world data, enriching our nuanced understanding role female fertility.

Language: Английский

Citations

2