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Cell Reports Jan 2023Endoplasmic reticulum (ER) homeostasis requires molecular regulators that tailor mitochondrial bioenergetics to the needs of protein folding. For instance, calnexin...
Endoplasmic reticulum (ER) homeostasis requires molecular regulators that tailor mitochondrial bioenergetics to the needs of protein folding. For instance, calnexin maintains mitochondria metabolism and mitochondria-ER contacts (MERCs) through reactive oxygen species (ROS) from NADPH oxidase 4 (NOX4). However, induction of ER stress requires a quick molecular rewiring of mitochondria to adapt to new energy needs. This machinery is not characterized. We now show that the oxidoreductase ERO1⍺ covalently interacts with protein kinase RNA-like ER kinase (PERK) upon treatment with tunicamycin. The PERK-ERO1⍺ interaction requires the C-terminal active site of ERO1⍺ and cysteine 216 of PERK. Moreover, we show that the PERK-ERO1⍺ complex promotes oxidization of MERC proteins and controls mitochondrial dynamics. Using proteinaceous probes, we determined that these functions improve ER-mitochondria Ca flux to maintain bioenergetics in both organelles, while limiting oxidative stress. Therefore, the PERK-ERO1⍺ complex is a key molecular machinery that allows quick metabolic adaptation to ER stress.
Topics: Oxidoreductases; Mitochondria; Endoplasmic Reticulum Stress; Endoplasmic Reticulum; Oxidative Stress
PubMed: 36586409
DOI: 10.1016/j.celrep.2022.111899 -
Metal Ions in Life Sciences 2014Dimethylsulfide (DMS) is a naturally occurring chemical that is part of the biogeochemical sulfur cycle and has been implicated in climate-relevant atmospheric... (Review)
Review
Dimethylsulfide (DMS) is a naturally occurring chemical that is part of the biogeochemical sulfur cycle and has been implicated in climate-relevant atmospheric processes. In addition, DMS occurs in soil environments as well as in food stuff as a flavor compound and it can also be associated with disease states such as halitosis. A major environmental source of DMS is the marine algal osmoprotectant dimethylsulfoniopropionate (DMSP). A variety of bacterial enzyme systems lead either to the production of DMS from DMSP or dimethylsulfoxide (DMSO) or its oxidation to, e.g., DMSO. The interconversion of DMS and DMSO is catalyzed by molybdenum-containing metalloenzymes that have been very well studied, and recently another enzyme system, an NADH-dependent, flavin-containing monooxygenase, that produces formaldehyde and methanethiol from DMS has also been described.DMS conversions are not limited to a specialized group of bacteria - evidence for DMS-based metabolism exists for heterotrophic, autotrophic and phototrophic bacteria and there is also evidence for the occurrence of this type of sulfur compound conversion in Archaea.
Topics: Aerobiosis; Anaerobiosis; Bacteria, Aerobic; Bacteria, Anaerobic; Biotransformation; Iron-Sulfur Proteins; Oxidation-Reduction; Oxidoreductases; Phylogeny; Sulfides
PubMed: 25416398
DOI: 10.1007/978-94-017-9269-1_11 -
Biotechnology Advances Nov 2017Fungi produce heme-containing peroxidases and peroxygenases, flavin-containing oxidases and dehydrogenases, and different copper-containing oxidoreductases involved in... (Review)
Review
Fungi produce heme-containing peroxidases and peroxygenases, flavin-containing oxidases and dehydrogenases, and different copper-containing oxidoreductases involved in the biodegradation of lignin and other recalcitrant compounds. Heme peroxidases comprise the classical ligninolytic peroxidases and the new dye-decolorizing peroxidases, while heme peroxygenases belong to a still largely unexplored superfamily of heme-thiolate proteins. Nevertheless, basidiomycete unspecific peroxygenases have the highest biotechnological interest due to their ability to catalyze a variety of regio- and stereo-selective monooxygenation reactions with HO as the source of oxygen and final electron acceptor. Flavo-oxidases are involved in both lignin and cellulose decay generating HO that activates peroxidases and generates hydroxyl radical. The group of copper oxidoreductases also includes other HO generating enzymes - copper-radical oxidases - together with classical laccases that are the oxidoreductases with the largest number of reported applications to date. However, the recently described lytic polysaccharide monooxygenases have attracted the highest attention among copper oxidoreductases, since they are capable of oxidatively breaking down crystalline cellulose, the disintegration of which is still a major bottleneck in lignocellulose biorefineries, along with lignin degradation. Interestingly, some flavin-containing dehydrogenases also play a key role in cellulose breakdown by directly/indirectly "fueling" electrons for polysaccharide monooxygenase activation. Many of the above oxidoreductases have been engineered, combining rational and computational design with directed evolution, to attain the selectivity, catalytic efficiency and stability properties required for their industrial utilization. Indeed, using ad hoc software and current computational capabilities, it is now possible to predict substrate access to the active site in biophysical simulations, and electron transfer efficiency in biochemical simulations, reducing in orders of magnitude the time of experimental work in oxidoreductase screening and engineering. What has been set out above is illustrated by a series of remarkable oxyfunctionalization and oxidation reactions developed in the frame of an intersectorial and multidisciplinary European RTD project. The optimized reactions include enzymatic synthesis of 1-naphthol, 25-hydroxyvitamin D, drug metabolites, furandicarboxylic acid, indigo and other dyes, and conductive polyaniline, terminal oxygenation of alkanes, biomass delignification and lignin oxidation, among others. These successful case stories demonstrate the unexploited potential of oxidoreductases in medium and large-scale biotransformations.
Topics: Biotransformation; Dinitrocresols; Fungi; Heme; Laccase; Lignin; Oxidation-Reduction; Oxidoreductases; Peroxidases
PubMed: 28624475
DOI: 10.1016/j.biotechadv.2017.06.003 -
International Journal of Molecular... Apr 2023Ovarian cancer is one of the most dangerous gynecologic malignancies showing a high fatality rate because of late diagnosis and relapse occurrence due to chemoresistance... (Review)
Review
Ovarian cancer is one of the most dangerous gynecologic malignancies showing a high fatality rate because of late diagnosis and relapse occurrence due to chemoresistance onset. Several researchers reported that oxidative stress plays a key role in ovarian cancer occurrence, growth and development. The NAD(P)H:quinone oxidoreductase 1 (NQO1) is an antioxidant enzyme that, using NADH or NADPH as substrates to reduce quinones to hydroquinones, avoids the formation of the highly reactive semiquinones, then protecting cells against oxidative stress. In this review, we report evidence from the literature describing the effect of NQO1 on ovarian cancer onset and progression.
Topics: Female; Humans; NAD(P)H Dehydrogenase (Quinone); Neoplasm Recurrence, Local; Antioxidants; NADH, NADPH Oxidoreductases; Quinones; Ovarian Neoplasms
PubMed: 37175546
DOI: 10.3390/ijms24097839 -
Journal of Molecular Medicine (Berlin,... Dec 2022WW domain-containing oxidoreductase (WWOX) spans the common fragile site FRA16D. There is evidence that translocations and deletions affecting WWOX accompanied by loss... (Review)
Review
WW domain-containing oxidoreductase (WWOX) spans the common fragile site FRA16D. There is evidence that translocations and deletions affecting WWOX accompanied by loss of expression are frequent in many cancers and often correlate with a worse prognosis. Additionally, WWOX germline mutations were also found to be the cause of pathologies of brain development. Because WWOX binds to some transcription factors, it is a modulator of many cellular processes, including metabolic processes. Recently, studies have linked WWOX to familial dyslipidemias, osteopenia, metabolic syndrome, and gestational diabetes, confirming its role as a regulator of steroid, cholesterol, glucose, and normal bone metabolism. The WW domain of WWOX is directly engaged in the control of the activity of transcription factors such as HIF1α and RUNX2; therefore, WWOX gene alterations are associated with some metabolic abnormalities. Presently, most interest is devoted to the associations between WWOX and glucose and basic energy metabolism disturbances. In particular, its involvement in the initiation of the Warburg effect in cancer or gestational diabetes and type II diabetes is of interest. This review is aimed at systematically and comprehensively presenting the current state of knowledge about the participation of WWOX in the metabolism of healthy and diseased organisms.
Topics: Female; Pregnancy; Humans; Diabetes Mellitus, Type 2; Diabetes, Gestational; Oxidoreductases; Neoplasms; Transcription Factors; Glucose; WW Domain-Containing Oxidoreductase; Tumor Suppressor Proteins
PubMed: 36271927
DOI: 10.1007/s00109-022-02265-5 -
Archives of Toxicology Aug 2022This is an overview of the metabolic reactions of drugs, natural products, physiological compounds, and other (general) chemicals catalyzed by flavin monooxygenase... (Review)
Review
This is an overview of the metabolic reactions of drugs, natural products, physiological compounds, and other (general) chemicals catalyzed by flavin monooxygenase (FMO), monoamine oxidase (MAO), NAD(P)H quinone oxidoreductase (NQO), and molybdenum hydroxylase enzymes (aldehyde oxidase (AOX) and xanthine oxidoreductase (XOR)), including roles as substrates, inducers, and inhibitors of the enzymes. The metabolism and bioactivation of selected examples of each group (i.e., drugs, "general chemicals," natural products, and physiological compounds) are discussed. We identified a higher fraction of bioactivation reactions for FMO enzymes compared to other enzymes, predominately involving drugs and general chemicals. With MAO enzymes, physiological compounds predominate as substrates, and some products lead to unwanted side effects or illness. AOX and XOR enzymes are molybdenum hydroxylases that catalyze the oxidation of various heteroaromatic rings and aldehydes and the reduction of a number of different functional groups. While neither of these two enzymes contributes substantially to the metabolism of currently marketed drugs, AOX has become a frequently encountered route of metabolism among drug discovery programs in the past 10-15 years. XOR has even less of a role in the metabolism of clinical drugs and preclinical drug candidates than AOX, likely due to narrower substrate specificity.
Topics: Aldehyde Oxidase; Biological Products; Humans; Molybdenum; Monoamine Oxidase; Oxidoreductases
PubMed: 35648190
DOI: 10.1007/s00204-022-03304-3 -
Experimental Biology and Medicine... Mar 2015Interactions mediated by short linear motifs in proteins play major roles in regulation of cellular homeostasis since their transient nature allows for easy modulation.... (Review)
Review
Interactions mediated by short linear motifs in proteins play major roles in regulation of cellular homeostasis since their transient nature allows for easy modulation. We are still far from a full understanding and appreciation of the complex regulation patterns that can be, and are, achieved by this type of interaction. The fact that many linear-motif-binding domains occur in tandem repeats in proteins indicates that their mutual communication is used extensively to obtain complex integration of information toward regulatory decisions. This review is an attempt to overview, and classify, different ways by which two and more tandem repeats cooperate in binding to their targets, in the well-characterized family of WW domains and their corresponding polyproline ligands.
Topics: Cell Proliferation; Humans; Oxidoreductases; Protein Interaction Domains and Motifs; Protein Structure, Tertiary; Signal Transduction; Tandem Repeat Sequences; Tumor Suppressor Proteins; WW Domain-Containing Oxidoreductase
PubMed: 25710931
DOI: 10.1177/1535370214566558 -
The Journal of Clinical Endocrinology... Jan 2012Disorders of steroidogenesis have been instrumental in delineating human steroidogenic pathways. Each genetic disorder seemed to correspond to a different steroidogenic... (Review)
Review
CONTEXT
Disorders of steroidogenesis have been instrumental in delineating human steroidogenic pathways. Each genetic disorder seemed to correspond to a different steroidogenic activity, helping to identify several enzymes. Beginning in 1972, several patients have been reported as having "17,20 lyase deficiency," but there have been inconsistent genetic findings.
OBJECTIVE
This manuscript reviews the biochemistry, genetics, and clinical disorders of 17,20 lyase activity, which converts 21-carbon precursors of glucocorticoids to 19-carbon precursors of sex steroids.
FINDINGS
A single enzyme, cytochrome P450c17, catalyzes both 17α-hydroxylase activity and 17,20 lyase activity. The 17,20 lyase activity is especially sensitive to the activities of the accessory proteins P450 oxidoreductase and cytochrome b(5). The first cases of genetically and biochemically proven 17,20 lyase deficiency were reported in 1997, in which specific P450c17 mutations were identified that lost 17,20 lyase activity but not 17α-hydroxylase activity when assayed in vitro. Subsequent work identified other P450c17 mutations and mutations in the genes encoding P450 oxidoreductase and cytochrome b(5). Recently, the initially reported cases from 1972 were found to carry mutations in two aldo-keto reductases, AKR1C2 and AKR1C4. These AKR1C isozymes catalyze 3α-hydroxysteroid dehydrogenase activity in the so-called "backdoor pathway" by which the fetal testis produces dihydrotestosterone without the intermediacy of testosterone.
CONCLUSIONS
17,20 Lyase deficiency should be considered a syndrome with multiple causes, and not a single disease. Study of this very rare disorder has substantially advanced our understanding of the pathways, mechanisms, and control of androgen synthesis. Mutations in other, as-yet unidentified genes may also cause this phenotype.
Topics: Adrenal Hyperplasia, Congenital; Cytochromes b5; Humans; Hydroxysteroid Dehydrogenases; Models, Biological; Mutation; Oxidoreductases; Steroid 17-alpha-Hydroxylase; Syndrome
PubMed: 22072737
DOI: 10.1210/jc.2011-2161 -
International Journal of Molecular... Aug 2021Nitroaromatic compounds (ArNO) maintain their importance in relation to industrial processes, environmental pollution, and pharmaceutical application. The manifestation... (Review)
Review
Nitroaromatic compounds (ArNO) maintain their importance in relation to industrial processes, environmental pollution, and pharmaceutical application. The manifestation of toxicity/therapeutic action of nitroaromatics may involve their single- or two-electron reduction performed by various flavoenzymes and/or their physiological redox partners, metalloproteins. The pivotal and still incompletely resolved questions in this area are the identification and characterization of the specific enzymes that are involved in the bioreduction of ArNO and the establishment of their contribution to cytotoxic/therapeutic action of nitroaromatics. This review addresses the following topics: (i) the intrinsic redox properties of ArNO, in particular, the energetics of their single- and two-electron reduction in aqueous medium; (ii) the mechanisms and structure-activity relationships of reduction in ArNO by flavoenzymes of different groups, dehydrogenases-electrontransferases (NADPH:cytochrome P-450 reductase, ferredoxin:NADP(H) oxidoreductase and their analogs), mammalian NAD(P)H:quinone oxidoreductase, bacterial nitroreductases, and disulfide reductases of different origin (glutathione, trypanothione, and thioredoxin reductases, lipoamide dehydrogenase), and (iii) the relationships between the enzymatic reactivity of compounds and their activity in mammalian cells, bacteria, and parasites.
Topics: Animals; Bacteria; Bacterial Proteins; Cytotoxins; Electrons; Flavoproteins; Humans; Nitro Compounds; Oxidation-Reduction; Oxidoreductases
PubMed: 34445240
DOI: 10.3390/ijms22168534 -
Oncotarget Dec 2014The human and mouse WWOX/Wwox gene encodes a candidate tumor suppressor WW domain-containing oxidoreductase protein. This gene is located on a common fragile site... (Review)
Review
The human and mouse WWOX/Wwox gene encodes a candidate tumor suppressor WW domain-containing oxidoreductase protein. This gene is located on a common fragile site FRA16D. WWOX participates in a variety of cellular events and acts as a transducer in the many signal pathways, including TNF, chemotherapeutic drugs, UV irradiation, Wnt, TGF-β, C1q, Hyal-2, sex steroid hormones, and others. While transiently overexpressed WWOX restricts relocation of transcription factors to the nucleus for suppressing cancer survival, physiological relevance of this regard in vivo has not been confirmed. Unlike many tumor suppressor genes, mutation of WWOX is rare, raising a question whether WWOX is a driver for cancer initiation. WWOX/Wwox was initially shown to play a crucial role in neural development and in the pathogenesis of Alzheimer's disease and neuronal injury. Later on, WWOX/Wwox was shown to participate in the development of epilepsy, mental retardation, and brain developmental defects in mice, rats and humans. Up to date, most of the research and review articles have focused on the involvement of WWOX in cancer. Here, we review the role of WWOX in neural injury and neurological diseases, and provide perspectives for the WWOX-regulated neurodegeneration.
Topics: Animals; Humans; Mice; Nervous System Diseases; Oxidoreductases; Tumor Suppressor Proteins; WW Domain-Containing Oxidoreductase
PubMed: 25537520
DOI: 10.18632/oncotarget.2961