Iron-sulfur Cluster Metabolism in Mycobacterium Tuberculosis PDF Download
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Author: Stephanie Stuteley
Publisher:
ISBN:
Category : Antitubercular agents
Languages : en
Pages : 158
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Book Description
Tuberculosis (TB) infects up to one third of the world’s population and, as one of the leading killers of humans, it is imperative to understand its pathogenic mechanisms. Key to the success of the causative agent, Mycobacterium tuberculosis (Mtb), is its ability to transition into an undetectable latent state that it may remain in for decades. Fe-S clusters are an essential component in Mtb metabolism and have been identified as playing a role in sensing and responding to the harsh environmental conditions, such as the oxidative and nitrosative stress and iron starvation, imposed on Mtb by the host immune system. While the regulation of Fe-S biogenesis in Gram-negative bacteria is well understood, less is known about this process in Mtb. Research in our laboratory has identified a putative transcriptional regulator of Fe-S cluster biogenesis in Mtb, SufR, which is the main subject of my research. This protein is highly expressed in both patient derivedsamples and infection models, leading us to believe that the regulation of Fe-S cluster biogenesis plays an important role in TB pathogenesis. During this research, I showed that SufR potentially binds [4Fe-4S] clusters and identified a DNA binding element that SufR preferentially binds in the presence of the intact clusters. This binding sequence is located within the putative coding region of SufR, suggesting that the original SufR open reading frame may be misannotated. Intriguingly, Mtb-SufR is a monomer in solution and dimerises upon DNA binding, potentially adding another level of control via protein association. While crystallisation experiments yielded promising brown coloured crystals of SufR in the presence of regulatory DNA, they did not diffract to a resolution useful for structural determination. One of the significant uses of Fe-S clusters in Mtb is in the formation of the catalytic chromophore (F0)of F420, a cofactor which has been shown to have protective antioxidant properties. Biosynthesis of F0is carried out by the enzyme FbiC which contains two [4Fe-4S] radical SAM active sites. While a reaction mechanism has been proposed based on the investigation of homologues from other species, this research reports the first soluble production of FbiC from mycobacteria.
Author: Stephanie Stuteley
Publisher:
ISBN:
Category : Antitubercular agents
Languages : en
Pages : 158
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Book Description
Tuberculosis (TB) infects up to one third of the world’s population and, as one of the leading killers of humans, it is imperative to understand its pathogenic mechanisms. Key to the success of the causative agent, Mycobacterium tuberculosis (Mtb), is its ability to transition into an undetectable latent state that it may remain in for decades. Fe-S clusters are an essential component in Mtb metabolism and have been identified as playing a role in sensing and responding to the harsh environmental conditions, such as the oxidative and nitrosative stress and iron starvation, imposed on Mtb by the host immune system. While the regulation of Fe-S biogenesis in Gram-negative bacteria is well understood, less is known about this process in Mtb. Research in our laboratory has identified a putative transcriptional regulator of Fe-S cluster biogenesis in Mtb, SufR, which is the main subject of my research. This protein is highly expressed in both patient derivedsamples and infection models, leading us to believe that the regulation of Fe-S cluster biogenesis plays an important role in TB pathogenesis. During this research, I showed that SufR potentially binds [4Fe-4S] clusters and identified a DNA binding element that SufR preferentially binds in the presence of the intact clusters. This binding sequence is located within the putative coding region of SufR, suggesting that the original SufR open reading frame may be misannotated. Intriguingly, Mtb-SufR is a monomer in solution and dimerises upon DNA binding, potentially adding another level of control via protein association. While crystallisation experiments yielded promising brown coloured crystals of SufR in the presence of regulatory DNA, they did not diffract to a resolution useful for structural determination. One of the significant uses of Fe-S clusters in Mtb is in the formation of the catalytic chromophore (F0)of F420, a cofactor which has been shown to have protective antioxidant properties. Biosynthesis of F0is carried out by the enzyme FbiC which contains two [4Fe-4S] radical SAM active sites. While a reaction mechanism has been proposed based on the investigation of homologues from other species, this research reports the first soluble production of FbiC from mycobacteria.
Author: B. Rowe Byers
Publisher: Springer Science & Business Media
ISBN: 3319003038
Category : Science
Languages : en
Pages : 96
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Book Description
Iron Acquisition by the Genus Mycobacterium summarizes the early evidence for the necessity of iron in mycobacteria and the discovery of the mycobacterial siderophores mycobactin, carboxymycobactin, and exochelin. The structural characterization of the mycobacterial siderophores is described. The genes so far identified as essential for iron acquisition and maintenance of an infection by pathogenic mycobacteria are discussed. The potential role of siderocalin in iron gathering by M. tuberculosis is featured. Because new drugs for M. tuberculosis are needed, this brief also emphasizes the design of antibiotics that interfere with siderophore biosynthesis and the use of siderophore analogs and/or conjugates.
Author: Benjamin Scott Gold
Publisher:
ISBN:
Category :
Languages : en
Pages : 284
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Book Description
Author: Jacob Philip Bitoun
Publisher:
ISBN:
Category :
Languages : en
Pages :
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Author: Lisa Marie McMath
Publisher:
ISBN: 9781267089571
Category :
Languages : en
Pages : 137
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Book Description
Tuberculosis is the deadly disease caused by Mycobacterium tuberculosis (Mtb). Like most pathogens, iron metabolism is critical for survival. Because of the poor solubility of iron in physiological conditions, bacteria have evolved elaborate iron acquisition systems to steal the essential metal from the host. Ferritins evolved to store iron and keep it bioavailable. The Mtb genome encodes for two ferritin homologs: a heme-containing bacterioferritin (BfrA) and a non-heme ferritin (BfrB). Both are structurally conserved and share nearly identical architectures. The main structural difference is that bacterioferritins contain a heme in a pocket created by the interface between two subunits of a dimer related by a non-crystallographic twofold axis. Both Mtb BfrA and Mtb BfrB were crystallized and solved by X-ray crystallography, and the typical ferritin fold was observed for each. Additionally, analysis of the Mtb BfrB crystal structure combined with sequence alignments with other structurally characterized bacterial ferritins revealed the presence of an unstructured 17-residue C-terminal extension. By protein pull-down experiments, we showed that BfrB interacts with a newly described protein nanocompartment, encapsulin, and we have shown that this extension is the BfrB anchor peptide for the interaction. However, BfrA has no such extension and does not exhibit an interaction with encapsulin. Hence, in an effort to gain a better understanding of Mtb iron metabolism, we report the structural and functional characterization of the Mtb BfrA and BfrB assemblies, as well as a description of a novel association with encapsulin. Additionally, we have shown that Mtb has a novel heme uptake system, and have identified the genomic region responsible. Found encoded within this genomic region is a secreted protein that binds heme tightly, which we propose to be a hemophore, and its crystal structure without heme bound has been solved. This protein transfers heme to two predicted transmembrane heme transporters, MmpL11 and MmpL3. We also observed that non-pathogenic Mycobacterium bovis BCG (BCG) has an attenuated system in comparison with Mtb. By sequence alignment, the homologous BCG hemophore is identical to the Mtb hemophore, except for lysine 87 substituted with threonine, and this substitution may contribute to the attenuation seen in the BCG system. In an effort to define the heme binding site and consequences of the K87T mutation, attempts were made to crystallize both proteins with and without heme bound.
Author: Patricia C. dos Santos
Publisher:
ISBN: 9781071616055
Category : Proteins
Languages : en
Pages : 351
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Book Description
This volume explores current technologies used to investigate the formation, insertion, and function of metalloclusters associated with proteins. Chapters describe relevant topics about Fe-S cluster metabolism are explored through genetic, biochemical, spectroscopic methods. Written in the highly successful Methods in Molecular Biology series format, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Authoritative and cutting-edge, Fe-S Proteins: Methods and Protocols aims to be a useful practical guide to researchers to help further their study in this field.
Author: Tracey Rouault
Publisher: Walter de Gruyter GmbH & Co KG
ISBN: 3110478552
Category : Science
Languages : en
Pages : 547
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Book Description
This volume on iron-sulfur proteins includes chapters that describe the initial discovery of iron-sulfur proteins in the 1960s to elucidation of the roles of iron sulfur clusters as prosthetic groups of enzymes, such as the citric acid cycle enzyme, aconitase, and numerous other proteins, ranging from nitrogenase to DNA repair proteins. The capacity of iron sulfur clusters to accept and delocalize single electrons is explained by basic chemical principles, which illustrate why iron sulfur proteins are uniquely suitable for electron transport and other activities. Techniques used for detection and stabilization of iron-sulfur clusters, including EPR and Mossbauer spectroscopies, are discussed because they are important for characterizing unrecognized and elusive iron sulfur proteins. Recent insights into how nitrogenase works have arisen from multiple advances, described here, including studies of high-resolution crystal structures.
Author: Tracey Rouault
Publisher: Walter de Gruyter GmbH & Co KG
ISBN: 3110308428
Category : Science
Languages : en
Pages : 672
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Book Description
This volume on iron-sulfur proteins includes chapters that describe the initial discovery of iron-sulfur proteins in the 1960s to elucidation of the roles of iron sulfur clusters as prosthetic groups of enzymes, such as the citric acid cycle enzyme, aconitase, and numerous other proteins, ranging from nitrogenase to DNA repair proteins. The capacity of iron sulfur clusters to accept and delocalize single electrons is explained by basic chemical principles, which illustrate why iron sulfur proteins are uniquely suitable for electron transport and other activities. Techniques used for detection and stabilization of iron-sulfur clusters, including EPR and Mossbauer spectroscopies, are discussed because they are important for characterizing unrecognized and elusive iron sulfur proteins. Recent insights into how nitrogenase works have arisen from multiple advances, described here, including studies of high-resolution crystal structures. Numerous chapters discuss how microbes, plants, and animals synthesize these complex prosthetic groups, and why it is important to understand the chemistry and biogenesis of iron sulfur proteins. In addition to their vital importance in mitochondrial respiration, numerous iron sulfur proteins are important in maintenance of DNA integrity. Multiple rare human diseases with different clinical presentations are caused by mutations of genes in the iron sulfur cluster biogenesis pathway. Understanding iron sulfur proteins is important for understanding a rapidly expanding group of metabolic pathways important in all kingdoms of life, and for understanding processes ranging from nitrogen fixation to human disease.
Author: P. Gütlich
Publisher: Springer Science & Business Media
ISBN: 3662125455
Category : Science
Languages : en
Pages : 292
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Book Description
Two decades have passed since the original discovery of recoilless nuclear gamma resonance by Rudolf Mossbauer; the spectroscopic method based on this resonance effect - referred to as Mossbauer spectroscopy - has developed into a powerful tool in solid-state research. The users are chemists, physicists, biologists, geologists, and scientists from other disciplines, and the spectrum of problems amenable to this method has become extraordinarily broad. In the present volume we have confined ourselves to applications of Mossbauer spectroscopy to the area of transition elements. We hope that the book will be useful not only to non-Mossbauer special ists with problem-Oriented activities in the chemistry and physics of transition elements, but also to those actively working in the field of Mossbauer spectroscopy on systems (compounds as well as alloys) of transition elements. The first five chapters are directed to introducing the reader who is not familiar with the technique to the principles of the recoilless nuclear resonance effect, the hyperfme interactions between nuclei and electronic properties such as electric and magnetic fields, some essential aspects about measurements, and the evaluation of Moss bauer spectra. Chapter 6 deals with the interpretation of Mossbauer parameters of iron compounds. Here we have placed emphasis on the information about the electronic structure, in correlation with quantum chemical methods, because of its importance for chemical bonding and magnetic properties.
Author: Graham F. Hatfull
Publisher: John Wiley & Sons
ISBN: 1555818846
Category : Science
Languages : en
Pages : 832
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Book Description
A comprehensive collection of perspectives by experts in mycobacterial molecular biology Mycobacterium tuberculosis causes one in four avoidable deaths in the developing world and kills more adults than malaria, AIDS, and all tropical diseases combined. Tuberculosis was named a global health emergency by the World Health Organization, a distinction no other disease has received. Although the study of mycobacterial genetics has expanded dramatically, with new investigations into mycobacterial growth, replication, metabolism, physiology, drug susceptibility, and virulence, most of the problems in tuberculosis control that existed in 2000 remain today. Advances in our understanding of mycobacterial genetics have been reflected in exciting recent developments. New diagnostic approaches can identify drug resistance within a few hours, promising new drugs are progressing through the pipeline and into the clinic, and a range of newly developed vaccines are being evaluated. It is an exciting time as the fruits of 30 years of intensive genetic investigation are finally beginning to emerge. Written by leading experts in the field, Molecular Genetics of Mycobacteria, Second Edition, Discusses key areas of current research in mycobacterial genetics Explains the genetics of the physiology, metabolism, and drug sensitivities of M. tuberculosis Presents genetic approaches for manipulating M. tuberculosis This book is an invaluable resource for anyone interested in the molecular genetics and molecular biology of mycobacteria.
