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An Anticancer Rhenium Tricarbonyl Targets Fe-S Biogenesis in Ovarian Cancer Cells – Profiling

ABSTRACT: Target identification remains a critical challenge in inorganic drug discovery to deconvolute potential polypharmacology. Here, we describe an improved approach to prioritize candidate protein targets based on a combination of dose-dependent chemoproteomics and treatment effects in living cancer cells for the rhenium tricarbonyl compound TRIP. Chemoproteomics revealed 89 dose-dependent targets with competing concentrations between 0.1–32 µM despite the broad proteotoxic effects of TRIP. Target response networks revealed two highly probable targets of which the Fe-S cluster biogenesis factor NUBP2 was competed by free TRIP at nanomolar concentrations. Importantly, TRIP treatment led to a down-regulation of Fe-S cluster-containing proteins and upregulated ferritin. Fe-S cluster depletion was further verified by assessing mitochondrial bioenergetics. Consequently, TRIP emerges as a first-in-class modulator of the scaffold protein NUBP2, which disturbs Fe-S cluster biogenesis at sub-cytotoxic concentrations in ovarian cancer cells.

INSTRUMENT(S): timsTOF Pro

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Epithelial Ovarian Cancer Cell

SUBMITTER: Christopher Gerner

LAB HEAD: Christopher Gerner

PROVIDER: PXD034472 | Pride | 2025-04-22

REPOSITORIES: Pride

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			Action	DRS
	20-Prot-1275_GA1_1_2091.d.rar	Other
	20-Prot-1276_GA2_1_2092.d.rar	Other
	20-Prot-1277_GA3_1_2093.d.rar	Other
	20-Prot-1278_GA4_1_2095.d.rar	Other
	20-Prot-1279_GA5_1_2096.d.rar	Other

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Similar Datasets

An Anticancer Rhenium Tricarbonyl Targets Fe-S Biogenesis in Ovarian Cancer Cells – Pull-Down

Project description:Target identification remains a critical challenge in inorganic drug discovery to deconvolute potential polypharmacology. Here, we describe an improved approach to prioritize candidate protein targets based on a combination of dose-dependent chemoproteomics and treatment effects in living cancer cells for the rhenium tricarbonyl compound TRIP. Chemoproteomics revealed 89 dose-dependent targets with competing concentrations between 0.1–32 µM despite the broad proteotoxic effects of TRIP. Target response networks revealed two highly probable targets of which the Fe-S cluster biogenesis factor NUBP2 was competed by free TRIP at nanomolar concentrations. Importantly, TRIP treatment led to a down-regulation of Fe-S cluster-containing proteins and upregulated ferritin. Fe-S cluster depletion was further verified by assessing mitochondrial bioenergetics. Consequently, TRIP emerges as a first-in-class modulator of the scaffold protein NUBP2, which disturbs Fe-S cluster biogenesis at sub-cytotoxic concentrations in ovarian cancer cells.

2025-04-22 | PXD034466 | Pride

METTL17 is an Fe-S cluster checkpoint for mitochondrial translation

Project description:Friedreich’s ataxia (FA) is the most common monogenic mitochondrial disease. FA is caused by a depletion of the mitochondrial protein frataxin (FXN), an iron-sulfur (Fe-S) cluster biogenesis factor. To better understand the cellular consequences of FA, we performed quantitative proteome profiling of human cells depleted for FXN. Nearly every known Fe-S cluster-containing protein was depleted in the absence of FXN, indicating that as a rule, cluster binding confers stability to Fe-S proteins. Proteomic and genetic interaction mapping identified impaired mitochondrial translation downstream of FXN loss, and specifically highlighted the methyltransferase-like protein METTL17 as a candidate effector. Using comparative sequence analysis, mutagenesis, biochemistry and cryogenic electron microscopy we show that METTL17 binds to the mitoribosomal small subunit during late assembly and harbors a previously unrecognized [Fe4S4]2+ cluster required for its stability on the mitoribosome. Notably, METTL17 overexpression rescued the mitochondrial translation and bioenergetic defects, but not the cellular growth, of FXN depleted cells. Our data suggest that METTL17 serves as an Fe-S cluster checkpoint: promoting the translation and assembly of Fe-S cluster rich OXPHOS proteins only when Fe-S cluster levels are replete.

2023-12-27 | PXD045443 | Pride

E. coli monothiol glutaredoxin GrxD replenishes Fe-S clusters to the essential ErpA A-type carrier under low iron stress  

Project description:Iron-sulfur (Fe-S) clusters are required for essential biological pathways, including respiration and isoprenoid biosynthesis. Complex Fe-S cluster biogenesis systems have evolved to maintain an adequate supply of this critical protein cofactor. In Escherichia coli, two Fe-S biosynthetic systems, the “housekeeping” Isc and “stress responsive” Suf pathways, interface with a network of cluster trafficking proteins, such as ErpA, IscA, SufA, and NfuA. GrxD, a Fe-S cluster-binding monothiol glutaredoxin, also participates in Fe-S protein biogenesis in both prokaryotes and eukaryotes. Previous studies in E. coli showed that the ∆grxD mutation causes sensitivity to iron depletion, spotlighting a critical role for GrxD under conditions that disrupt Fe-S homeostasis. Here, we utilized a global chemoproteomic mass spectrometry (MS) approach to analyse the contribution of GrxD to the Fe-S proteome. Our results demonstrate that 1) GrxD is required for biogenesis of a specific subset of Fe-S proteins under iron-depleted conditions, 2) GrxD is required for cluster delivery to ErpA under iron limitation, 3) GrxD is functionally distinct from other Fe-S trafficking proteins and, 4) GrxD Fe-S cluster binding is responsive to iron limitation. All these results lead to the proposal that GrxD is required to maintain Fe-S cluster delivery to the essential trafficking protein ErpA during iron limitation conditions.

2024-07-13 | PXD053317 | Pride

A pathogenic role for histone H3 copper reductase activity in a yeast model of Friedreich’s Ataxia

Project description:Disruptions to iron-sulfur (Fe-S) clusters, essential cofactors for a broad range of proteins, cause widespread cellular defects resulting in human disease. An underappreciated source of damage to Fe-S clusters are cuprous (Cu1+) ions. Since histone H3 enzymatically produces Cu1+ to support copper-dependent functions, we asked whether this activity could become detrimental to Fe-S clusters. Here, we report that histone H3-mediated Cu1+ toxicity is a major determinant of cellular functional pool of Fe-S clusters. Inadequate Fe-S cluster supply, either due to diminished assembly as occurs in Friedreich’s Ataxia or defective distribution, causes severe metabolic and growth defects in S. cerevisiae. Decreasing Cu1+ abundance, through attenuation of histone cupric reductase activity or depletion of total cellular copper, restored Fe-S cluster-dependent metabolism and growth. Our findings reveal a novel interplay between chromatin and mitochondria in Fe-S cluster homeostasis, and a potential pathogenic role for histone enzyme activity and Cu1+ in diseases with Fe-S cluster dysfunction.

2021-10-21 | ST001954 | MetabolomicsWorkbench

Human Mitochondrial NFS1-FXN XL LS-MS/MS

Project description:Frataxin (FXN) is involved in mitochondrial iron-sulfur (Fe-S) cluster biogenesis and serves to accelerate Fe-S cluster formation. FXN deficiency is associated with Friedreich ataxia, a neurodegenerative disease. Using chemical cross-linking (XL) accompanied with LC-MS/MS, we studied the the interaction between the core complexes Acp-ISD11-NFS1 (AIN) and AIN-ISCU (AINU) with FXN.

2018-07-11 | PXD006928 | Pride

Human Mitochondria NFS1-ISCU-FXN XL-MS

2018-07-11 | PXD006938 | Pride

NFU3 is an Fe-S cluster carrier protein that is implicated in photosystem I maturation (PsaA, PsaB, PsaC). Label free proteomic approach on nfu3-2 mutant allow the discovery of new potential client proteins

Project description:NFU3 is a Fe-S cluster carrier protein of Arabidopsis that allow the maturation of Fe-S cluster proteins in chloroplast. proteomic Label free experiment was carried out to monitored wich Fe-S cluster proteins are affected in nfu3-2 mutant background

2021-09-09 | PXD020228 | Pride

Transcription profiling of yeast mutants Gal-YAH1, Gal-ATM1 and Gal-NBP35 to investigate responses to defects in cellular Fe-S protein maturation

Project description:The biogenesis of iron-sulfur proteins in eukaryotes is an essential process involving the mitochondrial iron-sulfur cluster (ISC) assembly and export machineries and the cytosolic Fe/S protein assembly (CIA) apparatus. To define the integration of Fe/S protein biogenesis into cellular homeostasis, we compared the global transcriptional responses to defects in the three biogenesis systems in S. cerevisiae using DNA microarrays. Microarray analyses were carried out with regulatable yeast mutants in which representatives of each of the three biosynthetic systems could be depleted. In particular, we used the mutants Gal-YAH1, Gal-ATM1 and Gal-NBP35.

2007-12-14 | E-MEXP-1215 | biostudies-arrayexpress

RNA sequencing of Mtb H37Rv, MtbΔsufR and sufR complemented mycobacterium tuberculosis strains upon treatment with 0.5 mM DETA-NO.

Project description:Fe-S cluster proteins are involved in fundamental processes such as electron transfer, gene regulation, and DNA repair in diverse bacteria. Since Fe-S clusters are susceptible to damage by oxidative and nitrosative stress conditions, bacteria harbour systems such as ISC (iron-sulfur cluster assembly) and SUF (sulfur mobilization) to regulate Fe-S homeostasis. Fe-S cluster production is tightly regulated so as to promote Fe-S formation when the necessity for clusters is heightened (e.g., ROI/RNI/iron limitation) and to limit unnecessary production when the demand is low (e.g., hypoxia). Deregulation of Fe-S cluster biogenesis can lead to the accumulation of metabolic poisons such as polysulfides and reactive oxygen species. The human pathogen, Mycobacterium tuberculosis (Mtb) exploits several Fe-S containing proteins to maintain cellular homeostasis and survival in an antagonistic host environment. The Mtb genome encodes an atypical Suf system (Rv1460-Rv1466;sufRBDCSUT) as the only complete Fe-S cluster biogenesis machinery. Expression of sufR and the complete operon was shown to be upregulated upon exposure to nitrosative stresses. Thus, we did transcriptomic study of sufR deleted strain upon exposure to 0.5 mM DETA-NO to study comprehensively the suf regulon in response to ROI/RNI stress and what are the underlying regulatory mechanisms.

2021-07-15 | GSE154169 | GEO

Effects of Fe(II) on anammox community activity and functional genes expression

Project description:Four Fe(II) concentrations (0.03, 0.09, 0.12 & 0.75 mM) were tested to investigate the stimulation and inhibition effects of ferrous iron on anammox bacterial activity. RNAs were extracted from the cultures, and the synthesized cDNAs by reverse transcription were used to carry out GeoChip analysis, by which the functional communities and expression level differences in functional genes under different Fe(II) concentrations conditions were obtained, and the response of anammox bacteria to Fe(II) stimulation and inhibition are speculated.

2020-08-28 | GSE120704 | GEO

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