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Redox Biology May 2020Ferroptosis is a newly discovered form of non-apoptotic regulated cell death and is characterized by iron-dependent and lipid peroxidation. Due to the enhanced...
Ferroptosis is a newly discovered form of non-apoptotic regulated cell death and is characterized by iron-dependent and lipid peroxidation. Due to the enhanced dependence on iron in cancer cells, induction of ferroptosis is becoming a promising therapeutic strategy. However, the precise underlying molecular mechanism and regulation process of ferroptosis remains largely unknown. In the present study, we demonstrate that the protein Frataxin (FXN) is a key regulator of ferroptosis by modulating iron homeostasis and mitochondrial function. Suppression of FXN expression specifically repressed the proliferation, destroyed mitochondrial morphology, impeded Fe-S cluster assembly and activated iron starvation stress. Moreover, suppression of FXN expression significantly enhanced erastin-induced cell death through accelerating free iron accumulation, lipid peroxidation and resulted in dramatic mitochondria morphological damage including enhanced fragmentation and vanished cristae. In addition, this type of cell death was confirmed to be ferroptosis, since it could be pharmacologically restored by ferroptotic inhibitor Fer-1 or GSH, but not by inhibitors of apoptosis, necrosis. Vice versa, enforced expression of FXN blocked iron starvation response and erastin-induced ferroptosis. More importantly, pharmacological or genetic blocking the signal of iron starvation could completely restore the resistance to ferroptosis in FXN knockdown cells and xenograft graft in vivo. This paper suggests that FXN is a novel ferroptosis modulator, as well as a potential provided target to improve the antitumor activity based on ferroptosis.
Topics: Ferroptosis; Iron-Binding Proteins; Lipid Peroxidation; Mitochondria; Frataxin
PubMed: 32169822
DOI: 10.1016/j.redox.2020.101483 -
Comprehensive Physiology Sep 2018Iron and copper have similar physiochemical properties; thus, physiologically relevant interactions seem likely. Indeed, points of intersection between these two... (Review)
Review
Iron and copper have similar physiochemical properties; thus, physiologically relevant interactions seem likely. Indeed, points of intersection between these two essential trace minerals have been recognized for many decades, but mechanistic details have been lacking. Investigations in recent years have revealed that copper may positively influence iron homeostasis, and also that iron may antagonize copper metabolism. For example, when body iron stores are low, copper is apparently redistributed to tissues important for regulating iron balance, including enterocytes of upper small bowel, the liver, and blood. Copper in enterocytes may positively influence iron transport, and hepatic copper may enhance biosynthesis of a circulating ferroxidase, ceruloplasmin, which potentiates iron release from stores. Moreover, many intestinal genes related to iron absorption are transactivated by a hypoxia-inducible transcription factor, hypoxia-inducible factor-2α (HIF2α), during iron deficiency. Interestingly, copper influences the DNA-binding activity of the HIF factors, thus further exemplifying how copper may modulate intestinal iron homeostasis. Copper may also alter the activity of the iron-regulatory hormone hepcidin. Furthermore, copper depletion has been noted in iron-loading disorders, such as hereditary hemochromatosis. Copper depletion may also be caused by high-dose iron supplementation, raising concerns particularly in pregnancy when iron supplementation is widely recommended. This review will cover the basic physiology of intestinal iron and copper absorption as well as the metabolism of these minerals in the liver. Also considered in detail will be current experimental work in this field, with a focus on molecular aspects of intestinal and hepatic iron-copper interplay and how this relates to various disease states. © 2018 American Physiological Society. Compr Physiol 8:1433-1461, 2018.
Topics: Animals; Copper; Humans; Intestinal Absorption; Intestinal Mucosa; Iron; Liver; Metalloproteins
PubMed: 30215866
DOI: 10.1002/cphy.c170045 -
Molecules (Basel, Switzerland) Jul 2020Trace metals are inorganic elements that are required for all organisms in very low quantities. They serve as cofactors and activators of metalloproteins involved in a... (Review)
Review
Trace metals are inorganic elements that are required for all organisms in very low quantities. They serve as cofactors and activators of metalloproteins involved in a variety of key cellular processes. While substantial effort has been made in experimental characterization of metalloproteins and their functions, the application of bioinformatics in the research of metalloproteins and metalloproteomes is still limited. In the last few years, computational prediction and comparative genomics of metalloprotein genes have arisen, which provide significant insights into their distribution, function, and evolution in nature. This review aims to offer an overview of recent advances in bioinformatic analysis of metalloproteins, mainly focusing on metalloprotein prediction and the use of different metals across the tree of life. We describe current computational approaches for the identification of metalloprotein genes and metal-binding sites/patterns in proteins, and then introduce a set of related databases. Furthermore, we discuss the latest research progress in comparative genomics of several important metals in both prokaryotes and eukaryotes, which demonstrates divergent and dynamic evolutionary patterns of different metalloprotein families and metalloproteomes. Overall, bioinformatic studies of metalloproteins provide a foundation for systematic understanding of trace metal utilization in all three domains of life.
Topics: Animals; Binding Sites; Computational Biology; Eukaryota; Genomics; Humans; Metalloproteins; Prokaryotic Cells; Proteome; Trace Elements
PubMed: 32722260
DOI: 10.3390/molecules25153366 -
Chembiochem : a European Journal of... Jun 2020The nitrogenase superfamily comprises homologous enzyme systems that carry out fundamentally important processes, including the reduction of N and CO, and the...
The nitrogenase superfamily comprises homologous enzyme systems that carry out fundamentally important processes, including the reduction of N and CO, and the biosynthesis of bacteriochlorophyll and coenzyme F430. This special issue provides a cross-disciplinary overview of the ongoing research in this highly diverse and unique research area of metalloprotein biochemistry.
Topics: Metalloproteins; Nitrogenase; Oxidation-Reduction
PubMed: 32426925
DOI: 10.1002/cbic.202000279 -
Chemical Reviews Jun 2020Nitrogenase harbors three distinct metal prosthetic groups that are required for its activity. The simplest one is a [4Fe-4S] cluster located at the Fe protein... (Review)
Review
Nitrogenase harbors three distinct metal prosthetic groups that are required for its activity. The simplest one is a [4Fe-4S] cluster located at the Fe protein nitrogenase component. The MoFe protein component carries an [8Fe-7S] group called P-cluster and a [7Fe-9S-C-Mo--homocitrate] group called FeMo-co. Formation of nitrogenase metalloclusters requires the participation of the structural nitrogenase components and many accessory proteins, and occurs both , for the P-cluster, and in external assembly sites for FeMo-co. The biosynthesis of FeMo-co is performed stepwise and involves molecular scaffolds, metallochaperones, radical chemistry, and novel and unique biosynthetic intermediates. This review provides a critical overview of discoveries on nitrogenase cofactor structure, function, and activity over the last four decades.
Topics: Iron-Sulfur Proteins; Models, Molecular; Molybdoferredoxin
PubMed: 31975585
DOI: 10.1021/acs.chemrev.9b00489 -
Methods in Molecular Biology (Clifton,... 2019An overview of modern methods used in the preparation and characterization of molybdenum-containing enzymes is presented, with an emphasis on those methods that have...
An overview of modern methods used in the preparation and characterization of molybdenum-containing enzymes is presented, with an emphasis on those methods that have been developed over the past decade to address specific difficulties frequently encountered in studies of these enzymes.
Topics: Anaerobiosis; Metalloproteins; Molybdenum; Oxygen
PubMed: 30317474
DOI: 10.1007/978-1-4939-8864-8_4 -
Molecules (Basel, Switzerland) Oct 2022Molybdenum cofactor (Moco) deficiency (MoCD) is characterized by neonatal-onset myoclonic epileptic encephalopathy and dystonia with cerebral MRI changes similar to... (Review)
Review
Molybdenum cofactor (Moco) deficiency (MoCD) is characterized by neonatal-onset myoclonic epileptic encephalopathy and dystonia with cerebral MRI changes similar to hypoxic-ischemic lesions. The molecular cause of the disease is the loss of sulfite oxidase (SOX) activity, one of four Moco-dependent enzymes in men. Accumulating toxic sulfite causes a secondary increase of metabolites such as S-sulfocysteine and thiosulfate as well as a decrease in cysteine and its oxidized form, cystine. Moco is synthesized by a three-step biosynthetic pathway that involves the gene products of , and . Depending on which synthetic step is impaired, MoCD is classified as type A, B, or C. This distinction is relevant for patient management because the metabolic block in MoCD type A can be circumvented by administering cyclic pyranopterin monophosphate (cPMP). Substitution therapy with cPMP is highly effective in reducing sulfite toxicity and restoring biochemical homeostasis, while the clinical outcome critically depends on the degree of brain injury prior to the start of treatment. In the absence of a specific treatment for MoCD type B/C and SOX deficiency, we summarize recent progress in our understanding of the underlying metabolic changes in cysteine homeostasis and propose novel therapeutic interventions to circumvent those pathological changes.
Topics: Male; Infant, Newborn; Humans; Cysteine; Thiosulfates; Cystine; Coenzymes; Metalloproteins; Sulfite Oxidase; Brain Diseases; Sulfites; Molybdenum Cofactors; Molybdenum
PubMed: 36296488
DOI: 10.3390/molecules27206896 -
Molecules (Basel, Switzerland) Oct 2022The molybdenum cofactor (Moco) is the active site prosthetic group found in numerous vitally important enzymes (Mo-enzymes), which predominantly catalyze 2 electron... (Review)
Review
The molybdenum cofactor (Moco) is the active site prosthetic group found in numerous vitally important enzymes (Mo-enzymes), which predominantly catalyze 2 electron transfer reactions. Moco is synthesized by an evolutionary old and highly conserved multi-step pathway, whereby the metal insertion reaction is the ultimate reaction step here. Moco and its intermediates are highly sensitive towards oxidative damage and considering this, they are believed to be permanently protein bound during synthesis and also after Moco maturation. In plants, a cellular Moco transfer and storage system was identified, which comprises proteins that are capable of Moco binding and release but do not possess a Moco-dependent enzymatic activity. The first protein described that exhibited these properties was the Moco carrier protein (MCP) from the green alga . However, MCPs and similar proteins have meanwhile been described in various plant species. This review will summarize the current knowledge of the cellular Moco distribution system.
Topics: Carrier Proteins; Catalytic Domain; Chlamydomonas reinhardtii; Coenzymes; Metalloproteins; Molybdenum; Molybdenum Cofactors; Plants
PubMed: 36235107
DOI: 10.3390/molecules27196571 -
Biochimica Et Biophysica Acta.... Jan 2021The molybdenum cofactor (Moco) represents an ancient metal‑sulfur cofactor, which participates as catalyst in carbon, nitrogen and sulfur cycles, both on individual... (Review)
Review
The molybdenum cofactor (Moco) represents an ancient metal‑sulfur cofactor, which participates as catalyst in carbon, nitrogen and sulfur cycles, both on individual and global scale. Given the diversity of biological processes dependent on Moco and their evolutionary age, Moco is traced back to the last universal common ancestor (LUCA), while Moco biosynthetic genes underwent significant changes through evolution and acquired additional functions. In this review, focused on eukaryotic Moco biology, we elucidate the benefits of gene fusions on Moco biosynthesis and beyond. While originally the gene fusions were driven by biosynthetic advantages such as coordinated expression of functionally related proteins and product/substrate channeling, they also served as origin for the development of novel functions. Today, Moco biosynthetic genes are involved in a multitude of cellular processes and loss of the according gene products result in severe disorders, both related to Moco biosynthesis and secondary enzyme functions.
Topics: Coenzymes; Eukaryota; Gene Fusion; Humans; Metalloproteins; Molybdenum; Molybdenum Cofactors; Pteridines; Substrate Specificity
PubMed: 33017596
DOI: 10.1016/j.bbamcr.2020.118883 -
Molecules (Basel, Switzerland) Feb 2022Metalloproteins are a family of proteins characterized by metal ion binding, whereby the presence of these ions confers key catalytic and ligand-binding properties. Due... (Review)
Review
Metalloproteins are a family of proteins characterized by metal ion binding, whereby the presence of these ions confers key catalytic and ligand-binding properties. Due to their ubiquity among biological systems, researchers have made immense efforts to predict the structural and functional roles of metalloproteins. Ultimately, having a comprehensive understanding of metalloproteins will lead to tangible applications, such as designing potent inhibitors in drug discovery. Recently, there has been an acceleration in the number of studies applying machine learning to predict metalloprotein properties, primarily driven by the advent of more sophisticated machine learning algorithms. This review covers how machine learning tools have consolidated and expanded our comprehension of various aspects of metalloproteins (structure, function, stability, ligand-binding interactions, and inhibitors). Future avenues of exploration are also discussed.
Topics: Amino Acid Sequence; Binding Sites; Drug Design; Machine Learning; Metalloproteins; Models, Molecular; Protein Binding; Protein Stability; Proteolysis; Structure-Activity Relationship
PubMed: 35209064
DOI: 10.3390/molecules27041277