Iron–Sulfur Clusters toward Stresses: Implication for Understanding and Fighting Tuberculosis

Elchennawi, Ingie; Choudens, Sandrine Ollagnier de

doi:10.3390/inorganics10100174

Cited by 7 publications

(12 citation statements)

References 175 publications

(234 reference statements)

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“…Recently, some genes in the suf operon were shown to be vulnerable [11], identifying the Mtb SUF system as an interesting target in the fight against tuberculosis [12]. Over the last two decades, the Escherichia coli and Bacillus subtilis SUF systems have been intensively investigated.…”

Section: Introductionmentioning

confidence: 99%

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Structural and Biochemical Characterization of Mycobacterium tuberculosis Zinc SufU-SufS Complex

et al. 2023

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Iron–sulfur (Fe–S) clusters are inorganic prosthetic groups in proteins composed exclusively of iron and inorganic sulfide. These cofactors are required in a wide range of critical cellular pathways. Iron–sulfur clusters do not form spontaneously in vivo; several proteins are required to mobilize sulfur and iron, assemble and traffic-nascent clusters. Bacteria have developed several Fe–S assembly systems, such as the ISC, NIF, and SUF systems. Interestingly, in Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), the SUF machinery is the primary Fe–S biogenesis system. This operon is essential for the viability of Mtb under normal growth conditions, and the genes it contains are known to be vulnerable, revealing the Mtb SUF system as an interesting target in the fight against tuberculosis. In the present study, two proteins of the Mtb SUF system were characterized for the first time: Rv1464(sufS) and Rv1465(sufU). The results presented reveal how these two proteins work together and thus provide insights into Fe–S biogenesis/metabolism by this pathogen. Combining biochemistry and structural approaches, we showed that Rv1464 is a type II cysteine–desulfurase enzyme and that Rv1465 is a zinc-dependent protein interacting with Rv1464. Endowed with a sulfurtransferase activity, Rv1465 significantly enhances the cysteine–desulfurase activity of Rv1464 by transferring the sulfur atom from persulfide on Rv1464 to its conserved Cys40 residue. The zinc ion is important for the sulfur transfer reaction between SufS and SufU, and His354 in SufS plays an essential role in this reaction. Finally, we showed that Mtb SufS-SufU is more resistant to oxidative stress than E. coli SufS–SufE and that the presence of zinc in SufU is likely responsible for this improved resistance. This study on Rv1464 and Rv1465 will help guide the design of future anti-tuberculosis agents.

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Section: Introductionmentioning

confidence: 99%

“…Third, the SufA protein is an Fe-S transporter, transferring the cluster from the SufBC2D complex to cellular targets [17,20]. Recently, some genes in the suf operon were shown to be vulnerable [11], identifying the Mtb SUF system as an interesting target in the fight against tuberculosis [12].…”

Section: Introductionmentioning

confidence: 99%

Structural and Biochemical Characterization of Mycobacterium tuberculosis Zinc SufU-SufS Complex

et al. 2023

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“…1A). ROS-scavenging enzymes, along with Fe-S cluster biogenesis systems, protect cells from the adverse consequences of oxidative radicals and maintains redox homeostasis in diverse organisms (2,5,(19)(20)(21). Therefore, we asked whether IscS is required to maintain redox balance under aerobic growth conditions in Mtb.…”

Section: Iscs Is Required To Maintain Redox Homeostasis In Mtbmentioning

confidence: 99%

“…Iron-sulfur (Fe-S) clusters, which are the most ancient protein prosthetic groups, are sensitive targets for ROS and RNS, and their biogenesis is adversely affected by iron starvation ( 2 , 3 ). Mtb contains more than 50 Fe-S cluster proteins that carry out diverse functions within central metabolism, gene regulation, drug resistance, and persistence (table S1) ( 4 , 5 ). Therefore, knowledge of the biogenesis and repair of Fe-S clusters is critical to understanding the basis of persistence for this human pathogen.…”

Section: Introductionmentioning

confidence: 99%

Cysteine desulfurase (IscS)–mediated fine-tuning of bioenergetics and SUF expression prevents Mycobacterium tuberculosis hypervirulence

Das,

Sreedharan,

Shee

et al. 2023

Sci. Adv.

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Iron-sulfur (Fe-S) biogenesis requires multiprotein assembly systems, SUF and ISC, in most prokaryotes. M. tuberculosis ( Mtb ) encodes a complete SUF system, the depletion of which was bactericidal. The ISC operon is truncated to a single gene iscS (cysteine desulfurase), whose function remains uncertain. Here, we show that Mtb Δ iscS is bioenergetically deficient and hypersensitive to oxidative stress, antibiotics, and hypoxia. Mtb Δ iscS resisted killing by nitric oxide (NO). RNA sequencing indicates that IscS is important for expressing regulons of DosR and Fe-S–containing transcription factors, WhiB3 and SufR. Unlike wild-type Mtb , Mtb Δ iscS could not enter a stable persistent state, continued replicating in mice, and showed hypervirulence. The suf operon was overexpressed in Mtb Δ iscS during infection in a NO-dependent manner. Suppressing suf expression in Mtb Δ iscS either by CRISPR interference or upon infection in inducible NO-deficient mice arrests hypervirulence. Together, Mtb redesigned the ISC system to “fine-tune” the expression of SUF machinery for establishing persistence without causing detrimental disease in the host.

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“…However, it maintains redox balance to survive under stress and defend themselves against drugs ( Pacl et al, 2018 ). In response to this stress iron–sulfur cluster assembly pathway is activated which is not only responsible for assembling and maintaining Fe–S clusters but also play a protective role by ensuring the controlled and proper utilization of iron ions ( Elchennawi and Choudens, 2022 ). Intracellular resistance of Mtb to oxidative and nitrosative stress is due to the upregulation of genes involved in Fe–S cluster assembly ( Voskuil et al, 2011 ).…”

Section: Introductionmentioning

confidence: 99%

Genome mining of Mycobacterium tuberculosis: targeting SufD as a novel drug candidate through in silico characterization and inhibitor screening

Gorityala,

Baidya,

Sagurthi

2024

Front. Microbiol.

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Tuberculosis (TB) stands as the second most fatal infectious disease globally, causing 1.3 million deaths in 2022. The resurgence of TB and the alarming rise of antibiotic resistance demand urgent call to develop novel antituberculosis drugs. Despite concerted efforts to control TB, the disease persists and spreads rapidly on a global scale. Targeting stress response pathways in Mycobacterium tuberculosis (Mtb) has become imperative to achieve complete eradication. This study employs subtractive genomics to identify and prioritize potential drug targets among the hypothetical proteins of Mtb, focusing on indispensable pathways. Amongst 177 essential hypothetical proteins, 152 were nonhomologous to human. These proteins participated in 34 pathways, and a 20-fold enrichment of SUF pathway genes led to its selection as a target pathway. Fe–S clusters are fundamental, widely distributed protein cofactors involved in vital cellular processes. The survival of Mtb in a hypoxic environment relies on the iron–sulfur (Fe–S) cluster biogenesis pathway for the repair of damaged Fe–S clusters. It also protects pathogen against drugs, ensuring controlled iron utilization and contributing to drug resistance. In Mtb, six proteins of Fe–S cluster assembly pathway are encoded by the suf operon. The present study was focused on SufD because of its role in iron acquisition and prevention of Fenton reaction. The research further delves into the in silico characterization of SufD, utilizing bioinformatics tools for sequence and structure based analysis. The protein’s structural features, including the identification of conserved regions, motifs, and 3D structure prediction enhanced functional annotation. Target based virtual screening of compounds from the ChEMBL database resulted in 12 inhibitors with best binding affinities. Drug likeness and ADMET profiling of potential inhibitors identified promising compounds with favorable drug-like properties. The study also involved cloning in SUMO-pRSF-Duet1 expression vector, overexpression, and purification of recombinant SufD from E. coli BL21 (DE3) cells. Optimization of expression conditions resulted in soluble production, and subsequent purification highlighting the efficacy of the SUMO fusion system for challenging Mtb proteins in E. coli. These findings provide valuable insights into pharmacological targets for future experimental studies, holding promise for the development of targeted therapy against Mtb.

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Iron–Sulfur Clusters toward Stresses: Implication for Understanding and Fighting Tuberculosis

Cited by 7 publications

References 175 publications

Structural and Biochemical Characterization of Mycobacterium tuberculosis Zinc SufU-SufS Complex

Structural and Biochemical Characterization of Mycobacterium tuberculosis Zinc SufU-SufS Complex

Cysteine desulfurase (IscS)–mediated fine-tuning of bioenergetics and SUF expression prevents Mycobacterium tuberculosis hypervirulence

Genome mining of Mycobacterium tuberculosis: targeting SufD as a novel drug candidate through in silico characterization and inhibitor screening

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