Biosynthesis of fluopsin C, a copper-containing antibiotic from
            <i>Pseudomonas aeruginosa</i>

Patteson, Jon B.; Putz, Andrew T.; Tao, Lizhi; Simke, William C.; Bryant, L. Henry; Britt, R. David; Li, Bo

doi:10.1126/science.abj6749

Cited by 64 publications

(67 citation statements)

References 75 publications

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“…Our study explains the relationship between mitochondrial metabolism and the sensitivity to copper-mediated cell death: Respiring, TCA-cycle active cells have increased levels of lipoylated TCA enzymes (in particular, the PDH complex), and the lipoyl moiety serves as a direct copper binder, resulting in lipoylated protein aggregation, loss of Fe-S cluster-containing proteins, and induction of HSP70, reflective of acute proteotoxic stress. The targets of copper-induced toxicity that we describe here in human cancer cells (lipoylation and Fe-S cluster proteins) are evolutionarily conserved from bacteria to humans, suggesting that copper-induced cell death might be also used by microorganisms where copper ionophores are naturally synthesized and exhibit antimicrobial activity (48,49).…”

Section: Discussionmentioning

confidence: 93%

Copper induces cell death by targeting lipoylated TCA cycle proteins

Tsvetkov

Coy

Petrova

et al. 2022

Science

2,397

3,213

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Copper is an essential cofactor for all organisms, and yet it becomes toxic if concentrations exceed a threshold maintained by evolutionarily conserved homeostatic mechanisms. How excess copper induces cell death, however, is unknown. Here, we show in human cells that copper-dependent, regulated cell death is distinct from known death mechanisms and is dependent on mitochondrial respiration. We show that copper-dependent death occurs by means of direct binding of copper to lipoylated components of the tricarboxylic acid (TCA) cycle. This results in lipoylated protein aggregation and subsequent iron-sulfur cluster protein loss, which leads to proteotoxic stress and ultimately cell death. These findings may explain the need for ancient copper homeostatic mechanisms.

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Section: Discussionmentioning

confidence: 93%

Copper induces cell death by targeting lipoylated TCA cycle proteins

Tsvetkov

Coy

Petrova

et al. 2022

Science

2,397

3,213

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“…Our results demonstrate that BesC utilizes a coupled dinuclear iron cofactor to perform the oxidative carbon–carbon bond cleavage of 4-chloro- l -lysine to generate 4-chloro- l -allylglycine. Mössbauer and optical spectroscopy confirms its position as a new member of the emerging and expanding heme-oxygenase-like subfamily of diiron oxidases (HDOs) that activate dioxygen for diverse transformations . By analogy to the C–C-cleaving HDO UndA, it would be tempting to speculate that BesC would activate dioxygen to ultimately generate a high-valent intermediate to mediate this transformation.…”

Section: Discussionmentioning

confidence: 99%

“…Mossbauer and optical spectroscopy confirms its position as a new member of the emerging and expanding heme-oxygenaselike subfamily of diiron oxidases (HDOs) that activate dioxygen for diverse transformations. 46 By analogy to the C− C-cleaving HDO UndA, it would be tempting to speculate that BesC would activate dioxygen to ultimately generate a highvalent intermediate to mediate this transformation. Although BesC indeed activates O 2 to form a diferric-peroxo intermediate (BesC-P), the decay kinetics for this species are clearly modulated by the strength of the C4−H bond, a scenario that is best rationalized by a mechanism in which the diferric-peroxo, rather than a high-valent intermediate, directly performs HAT to initiate C−C bond cleavage.…”

Section: ■ Conclusionmentioning

confidence: 99%

BesC Initiates C–C Cleavage through a Substrate-Triggered and Reactive Diferric-Peroxo Intermediate

et al. 2021

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BesC catalyzes the iron- and O2-dependent cleavage of 4-chloro-l-lysine to form 4-chloro-l-allylglycine, formaldehyde, and ammonia. This process is a critical step for a biosynthetic pathway that generates a terminal alkyne amino acid which can be leveraged as a useful bio-orthogonal handle for protein labeling. As a member of an emerging family of diiron enzymes that are typified by their heme oxygenase-like fold and a very similar set of coordinating ligands, recently termed HDOs, BesC performs an unusual type of carbon–carbon cleavage reaction that is a significant departure from reactions catalyzed by canonical dinuclear-iron enzymes. Here, we show that BesC activates O2 in a substrate-gated manner to generate a diferric-peroxo intermediate. Examination of the reactivity of the peroxo intermediate with a series of lysine derivatives demonstrates that BesC initiates this unique reaction trajectory via cleavage of the C4–H bond; this process represents the rate-limiting step in a single turnover reaction. The observed reactivity of BesC represents the first example of a dinuclear-iron enzyme that utilizes a diferric-peroxo intermediate to capably cleave a C–H bond as part of its native function, thus circumventing the formation of a high-valent intermediate more commonly associated with substrate monooxygenations.

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“…Cuproptosis is a newly described mechanism that mediates cell death and has been associated with mitochondrial metabolism ( Tsvetkov et al, 2022 ). Cuproptosis may have important functions in microorganisms, as targets of copper-induced toxicity have been identified in various organisms, from bacteria to humans ( Patteson et al, 2021 ). Antibacterial activity may therefore be liked to cuproptosis ( Raffa et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

A Cuproptosis-Related Gene Model For Predicting the Prognosis of Clear Cell Renal Cell Carcinoma

et al. 2022

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Despite advances in its treatment, patients diagnosed with clear cell renal cell carcinoma (ccRCC) have a poor prognosis. The mechanism of cuproptosis has been found to differ from other mechanisms that regulate cell death, including apoptosis, iron poisoning, pyrophosphate poisoning, and necrosis. Cuproptosis is an essential component in the regulation of a wide variety of biological processes, such as cell wall remodeling and oxidative stress responses. However, cuproptosis-related genes’ expression in ccRCC patients and their association with the patient’s prognosis remain ambiguous. Evaluation of The Cancer Genome Atlas (TCGA) identified 11 genes associated with cuproptosis that were differently expressed in ccRCC and nearby nontumor tissue. To construct a multigene prognostic model, the prognostic value of 11 genes was assessed and quantified. A signature was constructed by least absolute shrinkage and selection operator (LASSO) Cox regression analysis, and this signature was used to separate ccRCC patients into different risk clusters, with low-risk patients having a much better prognosis. This five-gene signature, when combined with patients’ clinical characteristics, might serve as one independent predictor of overall survival (OS) in ccRCC patients. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis demonstrated that cuproptosis-related genes were enriched in patients with ccRCC. Then, quantitative real-time PCR (qPCR) was employed to verify these genes’ expression. Generally, research has indicated that cuproptosis-related genes are important in tumor immunity and can predict OS of ccRCC patients.

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Biosynthesis of fluopsin C, a copper-containing antibiotic from Pseudomonas aeruginosa

Cited by 64 publications

References 75 publications

Copper induces cell death by targeting lipoylated TCA cycle proteins

Copper induces cell death by targeting lipoylated TCA cycle proteins

BesC Initiates C–C Cleavage through a Substrate-Triggered and Reactive Diferric-Peroxo Intermediate

A Cuproptosis-Related Gene Model For Predicting the Prognosis of Clear Cell Renal Cell Carcinoma

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