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Iron-Sulfur Clusters: Assembly and Biological Roles

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A special issue of Inorganics (ISSN 2304-6740). This special issue belongs to the section "Bioinorganic Chemistry".

Deadline for manuscript submissions: closed (20 March 2024) | Viewed by 10363

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Special Issue Editor

Dr. Nunziata Maio

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Guest Editor

Metals Biology and Molecular Medicine Group, Section on Human Iron Metabolism, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bldg 35A/2D908, Bethesda, MD 20892, USA
Interests: iron metabolism; iron-sulfur clusters; chaperones; haem; iron cofactors; metal coordination chemistry; biochemistry of redox cofactors; metalloenzymes

Special Issue Information

Dear Colleagues,

Iron-sulfur (Fe-S) clusters are versatile prosthetic groups that enable their associated proteins to perform an impressive array of functions in numerous essential biological processes, ranging from electron transport to substrate coordination, ribosome biogenesis, DNA replication and repair, biosynthesis of heme and other essential cofactors. Despite being pervasive throughout all three kingdoms of life, Fe-S proteins did not become a focus of research until the late 1950’s, when spectroscopic techniques advanced the field by enabling the elucidation of features that were unique to Fe-S clusters. Furthermore, Fe-S centers are often destabilized upon exposure to oxygen, which explains why discovery of Fe-S proteins lagged behind the characterization of other iron containing proteins, such as haemoproteins. Therefore, working with Fe-S proteins requires special equipment, such as anaerobic chambers to preserve the integrity of these cofactors, and electron paramagnetic resonance (EPR) and Mössbauer spectrometers to enable their characterization. Additional challenges are presented to researchers in the field by the understanding and dissection of the several steps involved in the assembly of these cofactors, carried out by complex multi-protein machineries, and by the elucidation of the several pathways that lead to their insertion into subsets of recipient Fe-S apoproteins. Studies originally performed in bacterial model systems have enlightened basic mechanisms of Fe-S cluster biogenesis that are conserved in all the kingdoms of life. Moreover, it has become apparent that defects in the assembly process cause several rare human conditions. As a result, a growing need for interdisciplinary communication has emerged and biomedical researchers and basic scientists have made efforts to bridge the gap between the physics and chemistry of Fe-S clusters and the important biological questions associated with their functions.

In this Special Issue, we wish to make the subject of Fe-S proteins accessible to a broad audience and to uncover aspects of the unique chemistry of Fe-S clusters, techniques required for the biochemical characterization of Fe-S proteins along with articles focusing on Fe-S cluster assembly, delivery to recipient proteins and involvement of Fe-S proteins in numerous sensing and regulatory pathways essential to human physiology.

Dr. Nunziata Maio
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

iron-sulfur clusters
metallocofactors
chaperones
multiple mitochondrial dysfunctions syndromes
Friedreich’s ataxia
myopathy
sideroblastic anemia

Published Papers (7 papers)

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Research

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19 pages, 4662 KiB

Open AccessArticle

E. coli MnmA Is an Fe-S Cluster-Independent 2-Thiouridylase

by Moses Ogunkola, Lennart Wolff, Eric Asare Fenteng, Benjamin R. Duffus and Silke Leimkühler

Inorganics 2024, 12(3), 67; https://doi.org/10.3390/inorganics12030067 - 23 Feb 2024

Viewed by 1284

Abstract

All kingdoms of life have more than 150 different forms of RNA alterations, with tRNA accounting for around 80% of them. These chemical alterations include, among others, methylation, sulfuration, hydroxylation, and acetylation. These changes are necessary for the proper codon recognition and stability of tRNA. In Escherichia coli, sulfur modification at the wobble uridine (34) of lysine, glutamic acid, and glutamine is essential for codon and anticodon binding and prevents frameshifting during translation. Two important proteins that are involved in this thiolation modification are the L-cysteine desulfurase IscS, the initial sulfur donor, and tRNA-specific 2-thiouridylase MnmA, which adenylates and finally transfers the sulfur from IscS to the tRNA. tRNA-specific 2-thiouridylases are iron–sulfur clusters (Fe-S), either dependent or independent depending on the organism. Here, we dissect the controversy of whether the E. coli MnmA protein is an Fe-S cluster-dependent or independent protein. We show that when Fe-S clusters are bound to MnmA, tRNA thiolation is inhibited, making MnmA an Fe-S cluster-independent protein. We further show that 2-thiouridylase only binds to tRNA from its own organism. Full article

(This article belongs to the Special Issue Iron-Sulfur Clusters: Assembly and Biological Roles)

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18 pages, 6318 KiB

Open AccessArticle

Probing the Reactivity of [4Fe-4S] Fumarate and Nitrate Reduction (FNR) Regulator with O₂ and NO: Increased O₂ Resistance and Relative Specificity for NO of the [4Fe-4S] L28H FNR Cluster

by Jason C. Crack, Patricia Amara, Eve de Rosny, Claudine Darnault, Melanie R. Stapleton, Jeffrey Green, Anne Volbeda, Juan C. Fontecilla-Camps and Nick E. Le Brun

Inorganics 2023, 11(12), 450; https://doi.org/10.3390/inorganics11120450 - 21 Nov 2023

Cited by 1 | Viewed by 1344

Abstract

The Escherichia coli fumarate and nitrate reduction (FNR) regulator acts as the cell’s master switch for the transition between anaerobic and aerobic respiration, controlling the expression of >300 genes in response to O₂ availability. Oxygen is perceived through a reaction with FNR’s [4Fe-4S] cluster cofactor. In addition to its primary O₂ signal, the FNR [4Fe-4S] cluster also reacts with nitric oxide (NO). In response to physiological concentrations of NO, FNR de-represses the transcription of hmp, which encodes a principal NO-detoxifying enzyme, and fails to activate the expression of the nitrate reductase (nar) operon, a significant source of endogenous cellular NO. Here, we show that the L28H variant of FNR, which is much less reactive towards O₂ than wild-type FNR, remains highly reactive towards NO. A high resolution structure and molecular dynamics (MD) simulations of the closely related L28H-FNR from Aliivibrio fischeri revealed decreased conformational flexibility of the Cys20-Cys29 cluster-binding loop that is suggested to inhibit outer-sphere O₂ reactivity, but only partially impair inner-sphere NO reactivity. Our data provide new insights into the mechanistic basis for how iron–sulfur cluster regulators can distinguish between O₂ and NO. Full article

(This article belongs to the Special Issue Iron-Sulfur Clusters: Assembly and Biological Roles)

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Review

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21 pages, 2005 KiB

Open AccessReview

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

by Anna M. SantaMaria and Tracey A. Rouault

Inorganics 2024, 12(4), 101; https://doi.org/10.3390/inorganics12040101 - 30 Mar 2024

Viewed by 748

Abstract

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

(This article belongs to the Special Issue Iron-Sulfur Clusters: Assembly and Biological Roles)

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24 pages, 5563 KiB

Open AccessReview

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

by Audrey L. Heffner and Nunziata Maio

Inorganics 2024, 12(1), 34; https://doi.org/10.3390/inorganics12010034 - 18 Jan 2024

Cited by 1 | Viewed by 1622

Abstract

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

(This article belongs to the Special Issue Iron-Sulfur Clusters: Assembly and Biological Roles)

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20 pages, 6442 KiB

Open AccessReview

Investigating Iron-Sulfur Proteins in Infectious Diseases: A Review of Characterization Techniques

by Md Kausar Raza, Vivian Robert Jeyachandran and Sania Bashir

Inorganics 2024, 12(1), 25; https://doi.org/10.3390/inorganics12010025 - 07 Jan 2024

Viewed by 1975

Abstract

Iron-sulfur [Fe-S] clusters, comprising coordinated iron and sulfur atoms arranged in diverse configurations, play a pivotal role in redox reactions and various biological processes. Diverse structural variants of [Fe-S] clusters exist, each possessing distinct attributes and functions. Recent discovery of [Fe-S] clusters in infectious pathogens, such as Mycobacterium tuberculosis, and in viruses, such as rotavirus, polyomavirus, hepatitis virus, mimivirus, and coronavirus, have sparked interest in them being a potential therapeutics target. Recent findings have associated these [Fe-S] cluster proteins playing a critical role in structural and host protein activity. However, for a very long time, metalloenzymes containing iron-sulfur clusters have been prone to destabilization in the presence of oxygen, which led to a delayed understanding of [Fe-S] proteins compared to other non-heme iron-containing proteins. Consequently, working with [Fe-S] proteins require specialized equipment, such as anaerobic chambers to maintain cofactor integrity, and tools like ultraviolet visible (UV-Vis) spectroscopy, mass spectrometry, X-ray crystallography, nuclear magnetic resonance (NMR), electron paramagnetic resonance (EPR), Mössbauer spectroscopy and electrochemical characterization. Many of these [Fe-S] cluster proteins have been misannotated as Zinc-binding proteins when purified aerobically. Moreover, the assembly of these iron-sulfur cluster cofactors have not been fully understood since it is a multi-step assembly process. Additionally, disruptions in this assembly process have been linked to human diseases. With rapid advancements in anaerobic gloveboxes and spectroscopic techniques, characterization of these [Fe-S] cluster-containing proteins that are essential for the pathogens can open up new avenues for diagnostics and therapeutics. Full article

(This article belongs to the Special Issue Iron-Sulfur Clusters: Assembly and Biological Roles)

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21 pages, 2619 KiB

Open AccessReview

The Cryptic Nature of Fe-S Clusters: A Case Study of the Hepatitis B HBx Oncoprotein

by Trent Quist, Jiahua Chen, Alex MacNeil and Maria-Eirini Pandelia

Inorganics 2023, 11(12), 475; https://doi.org/10.3390/inorganics11120475 - 06 Dec 2023

Viewed by 1669

Abstract

Fe-S clusters are ubiquitous inorganic cofactors found in proteins across all domains of life, including viruses. Their prevalence stems from their unique redox and structural plasticity that supports functions ranging from electron transfer and catalysis to stabilization of protein structure. Although the ability of Fe-S clusters to exchange electrons is often functionally crucial, it can also act as an Achilles heel when these cofactors are exposed to oxidizing conditions, often leading to their degradation. This O₂ sensitivity has rendered certain Fe-S clusters untraceable, particularly when the nascent proteins are isolated under ambient conditions. As a consequence of this O₂ sensitivity, a growing number of proteins with roles in viral infection have been found to harbor Fe-S clusters rather than the annotated Zn²⁺ cofactor. The enigmatic protein X (HBx) of the Hepatitis B Virus is a multifunctional protein essential for viral replication and development of liver disease. Although HBx has defied biochemical characterization for over forty years, it has been shown to coordinate a redox-active Fe-S cluster that represents a significant feature for establishing its molecular function. The present review narrates the approaches to validate the HBx metallocofactor that can be broadly applied as a guide for uncovering the presence of Fe-S clusters in proteins with non-canonical sequence motifs. Full article

(This article belongs to the Special Issue Iron-Sulfur Clusters: Assembly and Biological Roles)

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14 pages, 1708 KiB

Open AccessReview

Mrp and SufT, Two Bacterial Homologs of Eukaryotic CIA Factors Involved in Fe-S Clusters Biogenesis

by Corinne Aubert, Pierre Mandin and Béatrice Py

Inorganics 2023, 11(11), 431; https://doi.org/10.3390/inorganics11110431 - 03 Nov 2023

Cited by 1 | Viewed by 1073

Abstract

Fe-S clusters are essential cofactors for the activity of a large variety of metalloproteins that play important roles in respiration, photosynthesis, nitrogen fixation, regulation of gene expression, and numerous metabolic pathways, including biosynthesis of other protein cofactors. Assembly of iron and sulfur atoms into a cluster, followed by its insertion into the polypeptide chain, is a complex process ensured by multiproteic systems. Through evolution, eukaryotes have acquired two Fe-S protein biogenesis systems by endosymbiosis from bacteria. These systems, ISC and SUF, are compartmentalized in mitochondria and plastids, respectively. The eukaryotic Fe-S protein biogenesis system (CIA) is dedicated to the biogenesis of cytosolic and nuclear Fe-S proteins. While the CIA system is absent in bacteria, at least two of its components share homologies with bacterial Fe-S protein biogenesis factors, Mrp and SufT. Here, we provide an overview of the role of Mrp and SufT in Fe-S protein biogenesis in bacteria, aiming to put forward specific but also common features with their eukaryotic CIA counterparts. Full article

(This article belongs to the Special Issue Iron-Sulfur Clusters: Assembly and Biological Roles)

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