iron metabolism in tb

IsdG-type enzymes catalyze the non-canonical degradation of heme to iron, staphylobilin (SB), and formaldehyde (HCHO), presumably by binding heme in an unusually distorted conformation. Their unique mechanism has been elucidated for MhuD from Mycobacterium tuberculosis, revealing an unusual ring-opening of hydroxyheme by dioxygenation. A similar mechanism has been postulated for other IsdG enzymes; however, MhuD, which is special as an IsdG-type enzyme, retains a formyl group in the linearized tetrapyrrole...

The chemistry of metal ions with human pathogens is essential for their survival, energy generation, redox signaling, and niche dominance. To regulate and manipulate the metal ions, various enzymes and metal chelators are present in pathogenic bacteria. Metalloenzymes incorporate transition metal such as iron, zinc, cobalt, and copper in their reaction centers to perform essential metabolic functions; however, iron and copper have gained more importance. Multicopper oxidases have the ability to perform redox reaction on phenolic substrates with the help of copper ions...

The self-assembled ferritin nanocages, nature's solution to iron toxicity and its low solubility, scavenge free iron to synthesize hydrated ferric oxyhydroxide mineral inside their central cavity by protein-mediated ferroxidase and hydrolytic/nucleation reactions. These complex processes in ferritin commence with the rapid influx of Fe2+ ions via the inter-subunit contact points (i.e., pores/channels). Investigation of these pores as Fe2+ uptake routes in ferritins remains a subject of intense research, in iron metabolism, toxicity, and bacterial pathogenesis, which are yet to be established in the bacterioferritin (BfrA) from Mycobacterium tuberculosis ( Mtb )...

[This corrects the article DOI: 10.3389/fmicb.2022.956602.].

OBJECTIVE: With the deepening of magnetic biomedical effects and electromagnetic technology, some medical instruments based on static magnetic field (SMF) have been used in orthopedic-related diseases treatment. Studies have shown SMF could combat osteoporosis by regulating the differentiation of mesenchymal stem cells (MSCs), osteoblast and osteoclast. With the development of nanotechnology, iron oxide nanoparticles (IONPs) have been reported to regulate the process of bone anabolism...

BACKGROUND: Description of the condition Malaria, an infectious disease transmitted by the bite of female mosquitoes from several Anopheles species, occurs in 87 countries with ongoing transmission (WHO 2020). The World Health Organization (WHO) estimated that, in 2019, approximately 229 million cases of malaria occurred worldwide, with 94% occurring in the WHO's African region (WHO 2020). Of these malaria cases, an estimated 409,000 deaths occurred globally, with 67% occurring in children under five years of age (WHO 2020)...

The establishment of Mycobacterium tuberculosis (Mtb) long-term infection in vivo depends on several factors, one of which is the availability of key nutrients such as iron (Fe). The relation between Fe deprivation inside and outside the granuloma, and the capacity of Mtb to accumulate lipids and persist in the absence of growth is not well understood. In this context, current knowledge of how Mtb modifies its lipid composition in response to growth arrest, depending on iron availability, is scarce. To shed light on these matters, in this work we compare genome-wide transcriptomic and lipidomic profiles of Mtb at exponential and stationary growth phases using cultures with glycerol as a carbon source, in the presence or absence of iron...

Macrophages are the host cells and the frontline defense against Mycobacterium tuberculosis (Mtb) infection, and the form of death of infected macrophages plays a pivotal role in the outcome of Mtb infections. Ferroptosis, a programmed necrotic cell death induced by overwhelming lipid peroxidation, was confirmed as one of the mechanisms of Mtb spread following infection and the pathogenesis of tuberculosis (TB). However, the mechanism underlying the macrophage ferroptosis induced by Mtb infection has not yet been fully understood...

Mycobacterium tuberculosis (Mtb), the cause of the human pulmonary disease tuberculosis (TB), contributes to approximately 1.5 million deaths every year. Prior work has established that lipids are actively catabolized by Mtb in vivo and fulfill major roles in Mtb physiology and pathogenesis. We conducted a high-throughput screen to identify inhibitors of Mtb survival in its host macrophage. One of the hit compounds identified in this screen, sAEL057, demonstrates highest activity on Mtb growth in conditions where cholesterol was the primary carbon source...

The redox property of iron makes it an essential cofactor for numerous enzymes involved in various metabolic processes. In vertebrates, iron is attached to either heme molecules or with other circulatory proteins, making its accessibility restricted for bacterial pathogens residing inside the host. Due to this importance, there is always an ongoing battle between the host system and pathogens, known as nutritional immunity. To capture the bound iron from the human hosts, intracellular pathogens like Mycobacterium tuberculosis secrete siderophore molecules which are ultimately uptaken by versatile transport machinery such as ATP-binding cassette (ABC) transporters...

Iron-sulfur (Fe-S) cluster proteins carry out essential cellular functions in diverse organisms, including the human pathogen Mycobacterium tuberculosis (Mtb). The mechanisms underlying Fe-S cluster biogenesis are poorly defined in Mtb. Here, we show that Mtb SufT (Rv1466), a DUF59 domain-containing essential protein, is required for the Fe-S cluster maturation. Mtb SufT homodimerizes and interacts with Fe-S cluster biogenesis proteins; SufS and SufU. SufT also interacts with the 4Fe-4S cluster containing proteins; aconitase and SufR...

New complexes of zinc(ii) and copper(ii) with 2-furoic acid (Hfur), acetic acids and N-donor ligands with the compositions [Zn2 (fur)4 ] n (1), [Zn2 (fur)4 (NH2 py)2 ] (2, NH2 py = 3-aminopyridine), [Zn(fur)2 (neoc)] (3, neoc = 2,9-dimethyl-1,10-phenantroline), [Zn(OAc)2 (neoc)] (4, OAc = acetat-anion), and [Cu(fur)2 (neoc)(H2 O)] (5) were synthesized. The structures of the compounds were established by single crystal X-ray diffraction analysis. Complexes 1 and 2 are binuclear; whereas 3-5 are mononuclear. The stabilization of supramolecular architectures in crystals for compounds 1-5 occurs due to π-π-bonding between heterocycles and hydrogen interactions that provide good solubility in aqueous solutions...

Reactive nitrogen species (RNS) are secreted by human cells in response to infection by Mycobacterium tuberculosis (Mtb). Although RNS can kill Mtb under some circumstances, Mtb can adapt and survive in the presence of RNS by a process that involves modulation of gene expression. Previous studies focused primarily on stress-related changes in the Mtb transcriptome. This study unveils changes in the Mtb proteome in response to a sub-lethal dose of nitric oxide (NO) over several hours of exposure. Proteins were identified using liquid chromatography coupled with electrospray ionization mass spectrometry (LC-MS/MS)...

Defense against oxidative stress is crucial for Mycobacterium tuberculosis to survive and replicate within macrophages. Mycobacteria have evolved multilayer antioxidant systems, including scavenging enzymes, iron homeostasis, repair pathways and metabolic adaptation, for coping with oxidative stress. How these systems are coordinated to enable the physiological adaptation to different intensities of oxidative stress, however, remains unclear. To address this, we investigated the expression kinetics of the well-characterized antioxidant genes at bacteriostatic H2 O2 concentrations ranging from 1 mM to 10 mM employing Mycolicibacterium smegmatis as a model...

The crucial transmission phase of tuberculosis (TB) relies on infectious sputum and yet cannot easily be modeled. We applied one-step RNA sequencing (RNA-Seq) to sputum from infectious TB patients to investigate the host and microbial environments underlying transmission of Mycobacterium tuberculosis. In such TB sputa, compared to non-TB controls, transcriptional upregulation of inflammatory responses, including an interferon-driven proinflammatory response and a metabolic shift toward glycolysis, was observed in the host...

Mycobacterial diseases are a major public health challenge. Their causative agents include, in order of impact, members of the Mycobacterium tuberculosis complex (causing tuberculosis), Mycobacterium leprae (causing leprosy), and non-tuberculous mycobacterial pathogens including Mycobacterium ulcerans. Macrophages are mycobacterial targets and they play an essential role in the host immune response to mycobacteria. This review aims to provide a comprehensive understanding of the immune-metabolic adaptations of the macrophage to mycobacterial infections...

BACKGROUND: During pregnancy metabolic disorders that affect differently the fetus, are known. These could be early or late disorders. OBJECTIVES: To analyze different biochemical parameters in umbilical cord blood (UCB) of healthy and pathological newborns from mothers with metabolic disorders. MATERIALS AND METHODS: Samples from UCB (121) were analyzed of newborn from mothers with metabolic disorders who attended at Obstetrics Division. Patients were consecutive, prospective and transversally studied...

Tuberculosis (TB), caused by the Mycobacterium tuberculosis complex bacteria, is one of the most pressing health problems. The development of new drugs and new therapeutic regimens effective against the pathogen is one of the greatest challenges in the way of tuberculosis control. Imidazo[1,2- b ][1,2,4,5]tetrazines have shown promising activity against M. tuberculosis and M. smegmatis strains. Mutations in MSMEG_1380 lead to mmpS5-mmpL5 operon overexpression, which provides M. smegmatis with efflux-mediated resistance to imidazo[1,2- b ][1,2,4,5]tetrazines, but the exact mechanism of action of these compounds remains unknown...

The persistence of Mycobacterium tuberculosis (Mtb) is a major problem in managing tuberculosis (TB). Host-generated nitric oxide (NO) is perceived as one of the signals by Mtb to reprogram metabolism and respiration for persistence. However, the mechanisms involved in NO sensing and reorganizing Mtb's physiology are not fully understood. Since NO damages iron-sulfur (Fe-S) clusters of essential enzymes, the mechanism(s) involved in regulating Fe-S cluster biogenesis could help Mtb persist in host tissues. Here, we show that a transcription factor SufR (Rv1460) senses NO via its 4Fe-4S cluster and promotes persistence of Mtb by mobilizing the Fe-S cluster biogenesis system; suf operon (Rv1460-Rv1466)...

Lipoic acid is an essential sulfur-containing cofactor used by several multienzyme complexes involved in energy metabolism and the breakdown of certain amino acids. It is composed of n-octanoic acid with sulfur atoms appended at C6 and C8. Lipoic acid is biosynthesized de novo in its cofactor form, in which it is covalently bound in an amide linkage to a target lysyl residue on a lipoyl carrier protein (LCP). The n-octanoyl moiety of the cofactor is derived from type 2 fatty acid biosynthesis and is transferred to an LCP to afford an octanoyllysyl amino acid...