Why cells need iron: a compendium of iron utilisation

Trends in Endocrinology and Metabolism, Год журнала: 2024, Номер unknown

Опубликована: Май 1, 2024

Iron deficiency is globally prevalent, causing an array of developmental, haematological, immunological, neurological, and cardiometabolic impairments, associated with symptoms ranging from chronic fatigue to hair loss. Within cells, iron utilised in a variety ways by hundreds different proteins. Here, we review links between molecular activities regulated the pathophysiological effects deficiency. We identify specific enzyme groups, biochemical pathways, cellular functions, cell lineages that are particularly dependent. provide examples how deprivation influences multiple key systems tissues, including immunity, hormone synthesis, cholesterol metabolism. propose greater mechanistic understanding physiological processes may lead new therapeutic opportunities across range diseases.

Язык: Английский

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Iron-sulfur protein odyssey: exploring their cluster functional versatility and challenging identification

Metallomics, Год журнала: 2024, Номер 16(5)

Опубликована: Май 1, 2024

Abstract Iron-sulfur (Fe-S) clusters are an essential and ubiquitous class of protein-bound prosthetic centers that involved in a broad range biological processes (e.g. respiration, photosynthesis, DNA replication repair gene regulation) performing wide functions including electron transfer, enzyme catalysis, sensing. In general manner, Fe-S can gain or lose electrons through redox reactions, highly sensitive to oxidation, notably by small molecules such as oxygen nitric oxide. The [2Fe-2S] [4Fe-4S] clusters, the most common cofactors, typically coordinated four amino acid side chains from protein, usually cysteine thiolates, but other residues histidine, aspartic acid) also be found. While diversity cluster coordination ensures functional variety lack conserved motifs makes new protein identification challenging especially when is shared between two proteins observed several dimeric transcriptional regulators mitoribosome. Thanks recent development cellulo, vitro, silico approaches, still regularly identified, highlighting this proteins. review, we will present three main explain difficulties encountered identify methods have been employed overcome these issues.

Язык: Английский

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Classification, replication, and transcription of Nidovirales

Frontiers in Microbiology, Год журнала: 2024, Номер 14

Опубликована: Янв. 24, 2024

Nidovirales is one order of RNA virus, with the largest single-stranded positive sense genome enwrapped membrane envelope. It comprises four families ( Arterividae, Mesoniviridae, Roniviridae, and Coronaviridae ) has been circulating in humans animals for almost century, posing great threat to livestock poultry，as well as public health. shares similar life cycle: attachment cell surface, entry, primary translation replicases, viral replication cytoplasm, proteins, virion assembly, budding, release. The synthesis critical step during infection, including genomic (gRNA) subgenomic mRNAs (sg mRNAs) transcription. gRNA requires a negative full-length intermediate, while sg transcription involves nested set intermediates by discontinuous strategy. This process mediated replication/transcription complex (RTC), which consists several enzymatic replicases derived from polyprotein 1a 1ab cellular proteins. These host factors represent optimal potential therapeutic targets. Hereby, we summarize classification, associated diseases, “replication organelle,” mechanisms, related regulatory factors.

Язык: Английский

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The Coronavirus helicase in replication

Virus Research, Год журнала: 2024, Номер 346, С. 199401 - 199401

Опубликована: Май 31, 2024

The coronavirus nonstructural protein (nsp) 13 encodes an RNA helicase (nsp13-HEL) with multiple enzymatic functions, including unwinding and nucleoside phosphatase (NTPase) activities. Attempts for inactivation have defined the nsp13-HEL as a critical enzyme viral replication high-priority target antiviral development. Helicases been shown to play numerous roles beyond their canonical ATPase activities, though these functions are just beginning be explored in biology. Recent genetic biochemical studies, well work structurally-related helicases, provided evidence that supports new hypotheses helicase's potential role replication. Here, we review several aspects of nsp13-HEL, its reported proposed highlight fundamental areas research may aid development inhibitors.

Язык: Английский

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A Repurposed Drug Interferes with Nucleic Acid to Inhibit the Dual Activities of Coronavirus Nsp13

ACS Chemical Biology, Год журнала: 2024, Номер 19(7), С. 1593 - 1603

Опубликована: Июль 9, 2024

The recent pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) highlighted a critical need to discover more effective antivirals. While therapeutics for SARS-CoV-2 exist, its nonstructural protein 13 (Nsp13) remains clinically untapped target. Nsp13 is helicase responsible unwinding double-stranded RNA during viral replication and essential propagation. Like other helicases, has two active sites: nucleotide binding site that hydrolyzes nucleoside triphosphates (NTPs) nucleic acid channel unwinds or DNA. Targeting helicases with small molecules, as well the identification of ligand pockets, have been ongoing challenges, partly due flexible nature these proteins. Here, we use virtual screen identify ligands from collection used drugs. We find known ion inhibitor, IOWH-032, inhibits dual ATPase activities at low micromolar concentrations. Kinetic assays, along computational mutational analyses, indicate IOWH-032 interacts interface, leading displacement substrate, but not bound ATP. Evaluation microbial superfamilies reveals it selective Nsp13. Furthermore, against mutants representative observed variants. Overall, this work provides new inhibitor rationale observation lowers loads in human cells, setting stage discovery potent modulators.

Язык: Английский

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A Comparison of Conserved Features in the Human Coronavirus Family Shows That Studies of Viruses Less Pathogenic than SARS-CoV-2, Such as HCoV-OC43, Are Good Model Systems for Elucidating Basic Mechanisms of Infection and Replication in Standard Laboratories

Viruses, Год журнала: 2025, Номер 17(2), С. 256 - 256

Опубликована: Фев. 13, 2025

In 2021, at the height of COVID-19 pandemic, coronavirus research spiked, with over 83,000 original articles related to word "coronavirus" added online resource PubMed. Just 2 years later, in 2023, only 30,900 were added. While, irrefutably, funding drastically decreased, a possible explanation for decrease interest is that projects on SARS-CoV-2, causative agent COVID-19, halted due challenge establishing good cellular or animal model system. Most laboratories do not have capabilities culture SARS-CoV-2 'in house' as this requires Biosafety Level (BSL) 3 laboratory. Until recently, BSL laboratory endemic coronaviruses was arduous low cytopathic effect isolated cell infection models and lack means quantify viral loads. The purpose review article compare human provide an assessment latest techniques use coronaviruses-HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1-as lower-biosafety-risk more pathogenic coronaviruses-SARS-CoV-2, SARS-CoV, MERS-CoV.

Язык: Английский

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Two opposite abilities of the infectious bronchitis virus helicase Nsp13: separating the duplex and promoting the annealing of single-stranded nucleic acid

Frontiers in Veterinary Science, Год журнала: 2025, Номер 12

Опубликована: Март 17, 2025

Genome replication is a key step in the coronavirus life cycle and requires involvement of range virally encoded non-structural proteins. The protein 13 (Nsp13) coronaviruses highly conserved helicase considered an ideal drug target. However, activity characteristics Nsp13 infectious bronchitis virus (IBV) remain unclear. In this study, we expressed biochemically characterized purified recombinant IBV found that was able to unwind duplex substrates 5'-to-3' direction by using energy from hydrolysis all nucleotide triphosphate (NTP) deoxyribonucleoside (dNTP). We also explored substrate selectivity influencing factors unwinding Nsp13. nucleic acid continuity loading strand essential for substrates. addition, first demonstrated had annealing promote two single-stranded acids form double-stranded acid. Biochemical analysis activities helpful deeply revealing mechanism development antiviral drugs.

Язык: Английский

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Regulatory and Sensing Iron–Sulfur Clusters: New Insights and Unanswered Questions

Inorganics, Год журнала: 2024, Номер 12(4), С. 101 - 101

Опубликована: Март 30, 2024

Iron is an essential nutrient and necessary for biological functions from DNA replication repair to transcriptional regulation, mitochondrial respiration, electron transfer, oxygen transport, photosynthesis, enzymatic catalysis, nitrogen fixation. However, due iron’s propensity generate toxic radicals which can cause damage DNA, proteins, lipids, multiple processes regulate the uptake distribution of iron in living systems. Understanding how intracellular metabolism optimized utilized other important our overall understanding a multitude processes. One tools that cell utilizes ligation iron–sulfur (Fe-S) cluster cofactor. Fe-S clusters comprised inorganic sulfur are ancient components matter on earth integral physiological function all domains life. FeS as sensors have been implicated diverse group life mammals bacteria, fungi, plants, archaea. Here, we will explore ways cells organisms utilize sense changes their environment restore equilibrium.

Язык: Английский

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Structure of human MUTYH and functional profiling of cancer-associated variants reveal an allosteric network between its [4Fe-4S] cluster cofactor and active site required for DNA repair

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Апрель 15, 2025

Abstract MUTYH is a clinically important DNA glycosylase that thwarts mutations by initiating base-excision repair at 8-oxoguanine (OG):A lesions. The roles for its [4Fe-4S] cofactor in remain enigmatic. Functional profiling of cancer-associated variants near the reveals most variations abrogate both retention and enzyme activity. Surprisingly, R241Q N238S retained metal cluster bound substrate tightly, but were completely inactive. We determine crystal structure human to transition state mimic this shows Arg241 Asn238 build an H-bond network connecting catalytic Asp236 mediates base excision. bacterial MutY variant R149Q, along with molecular dynamics simulations enzyme, support model which functions position activate Asp. These results suggest allosteric cross-talk between binding excision site regulate function.

Язык: Английский

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Tip of the Iceberg: A New Wave of Iron–Sulfur Cluster Proteins Found in Viruses

Inorganics, Год журнала: 2024, Номер 12(1), С. 34 - 34

Опубликована: Янв. 18, 2024

Viruses rely on host cells to replicate their genomes and assemble new viral particles. Thus, they have evolved intricate mechanisms exploit factors. Host cells, in turn, developed strategies inhibit viruses, resulting a nuanced interplay of co-evolution between virus host. This dynamic often involves competition for resources crucial both cell survival replication. Iron iron-containing cofactors, including iron–sulfur clusters, are known be heavily fought resource during bacterial infections, where control over iron can tug the war favor pathogen or It is logical assume that viruses also engage this competition. Surprisingly, our knowledge about how utilize (Fe) (FeS) clusters remains limited. The handful reviews topic primarily emphasize significance supporting immune response against infections. aim review, however, organize current understanding proteins FeS give perspectives what questions ask next propose important avenues future investigations.

Язык: Английский

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