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Nature Communications Nov 2023Organohalide-respiring bacteria are key organisms for the bioremediation of soils and aquifers contaminated with halogenated organic compounds. The major players in this...
Organohalide-respiring bacteria are key organisms for the bioremediation of soils and aquifers contaminated with halogenated organic compounds. The major players in this process are respiratory reductive dehalogenases, corrinoid enzymes that use organohalides as substrates and contribute to energy conservation. Here, we present the structure of a menaquinol:organohalide oxidoreductase obtained by cryo-EM. The membrane-bound protein was isolated from Desulfitobacterium hafniense strain TCE1 as a PceAB complex catalysing the dechlorination of tetrachloroethene. Two catalytic PceA subunits are anchored to the membrane by two small integral membrane PceB subunits. The structure reveals two menaquinone molecules bound at the interface of the two different subunits, which are the starting point of a chain of redox cofactors for electron transfer to the active site. In this work, the structure elucidates how energy is conserved during organohalide respiration in menaquinone-dependent organohalide-respiring bacteria.
Topics: Oxidoreductases; Vitamin K 2; Oxidation-Reduction; Electron Transport; Bacteria; Biodegradation, Environmental
PubMed: 37923808
DOI: 10.1038/s41467-023-42927-7 -
Current Opinion in Structural Biology Dec 20162-Oxoacid:ferredoxin oxidoreductases (OFORs) are essential enzymes in microbial one-carbon metabolism. They use thiamine pyrophosphate to reversibly cleave carbon-carbon... (Review)
Review
2-Oxoacid:ferredoxin oxidoreductases (OFORs) are essential enzymes in microbial one-carbon metabolism. They use thiamine pyrophosphate to reversibly cleave carbon-carbon bonds, generating low potential (∼-500mV) electrons. Crystallographic analysis of a recently discovered OFOR, an oxalate oxidoreductase (OOR), has provided a second view of OFOR architecture and active site composition. Using these recent structural data along with the previously determined structures of pyruvate:ferredoxin oxidoreductase, structure-function relationships in this superfamily have been expanded and re-evaluated. Additionally, structural motifs have been defined that better serve to distinguish one OFOR subfamily from another and potentially uncover novel OFORs.
Topics: Coenzymes; Humans; Keto Acids; Oxidoreductases; Phylogeny
PubMed: 27315560
DOI: 10.1016/j.sbi.2016.05.011 -
Experimental Biology and Medicine... Mar 2015The WW domain-containing oxidoreductase (WWOX) encodes a tumor suppressor that is frequently altered in cancer. WWOX binds several proteins and thus is postulated to be... (Review)
Review
The WW domain-containing oxidoreductase (WWOX) encodes a tumor suppressor that is frequently altered in cancer. WWOX binds several proteins and thus is postulated to be involved in a variety of cellular processes. Interestingly, Wwox-knockout mice develop normally in utero but succumb to hypoglycemia and other metabolic defects early in life resulting in their death by 3-4 weeks of age. Cumulative evidence has linked WWOX with cellular metabolism including steroid metabolism, high-density lipoprotein cholesterol (HDL-C) metabolism, bone metabolism and, more recently, glucose metabolism. In this review, we discuss these evolving functions for WWOX and how its deletion affects cellular metabolism and neoplastic progression.
Topics: Animals; Bone and Bones; Cells; Cholesterol, HDL; Disease Models, Animal; Disease Progression; Glucose; Humans; Mice; Mice, Knockout; Neoplasms; Oxidoreductases; Steroids; Tumor Suppressor Proteins; WW Domain-Containing Oxidoreductase
PubMed: 25491415
DOI: 10.1177/1535370214561956 -
The Journal of Biological Chemistry Mar 2024The bacterial envelope is an essential compartment involved in metabolism and metabolites transport, virulence, and stress defense. Its roles become more evident when... (Review)
Review
The bacterial envelope is an essential compartment involved in metabolism and metabolites transport, virulence, and stress defense. Its roles become more evident when homeostasis is challenged during host-pathogen interactions. In particular, the presence of free radical groups and excess copper in the periplasm causes noxious reactions, such as sulfhydryl group oxidation leading to enzymatic inactivation and protein denaturation. In response to this, canonical and accessory oxidoreductase systems are induced, performing quality control of thiol groups, and therefore contributing to restoring homeostasis and preserving survival under these conditions. Here, we examine recent advances in the characterization of the Dsb-like, Salmonella-specific Scs system. This system includes the ScsC/ScsB pair of Cu-binding proteins with thiol-oxidoreductase activity, an alternative ScsB-partner, the membrane-linked ScsD, and a likely associated protein, ScsA, with a role in peroxide resistance. We discuss the acquisition of the scsABCD locus and its integration into a global regulatory pathway directing envelope response to Cu stress during the evolution of pathogens that also harbor the canonical Dsb systems. The evidence suggests that the canonical Dsb systems cannot satisfy the extra demands that the host-pathogen interface imposes to preserve functional thiol groups. This resulted in the acquisition of the Scs system by Salmonella. We propose that the ScsABCD complex evolved to connect Cu and redox stress responses in this pathogen as well as in other bacterial pathogens.
Topics: Bacterial Proteins; Copper; Homeostasis; Oxidation-Reduction; Oxidoreductases; Salmonella; Sulfhydryl Compounds; Carrier Proteins
PubMed: 38309504
DOI: 10.1016/j.jbc.2024.105710 -
Microbial Biotechnology Nov 2017The most efficient means of generating cellular energy is through aerobic respiration. Under anaerobic conditions, several prokaryotes can replace oxygen by nitrate as... (Review)
Review
The most efficient means of generating cellular energy is through aerobic respiration. Under anaerobic conditions, several prokaryotes can replace oxygen by nitrate as final electron acceptor. During denitrification, nitrate is reduced via nitrite, NO and N O to molecular nitrogen (N ) by four membrane-localized reductases with the simultaneous formation of an ion gradient for ATP synthesis. These four multisubunit enzyme complexes are coupled in four electron transport chains to electron donating primary dehydrogenases and intermediate electron transfer proteins. Many components require membrane transport and insertion, complex assembly and cofactor incorporation. All these processes are mediated by fine-tuned stable and transient protein-protein interactions. Recently, an interactomic approach was used to determine the exact protein-protein interactions involved in the assembly of the denitrification apparatus of Pseudomonas aeruginosa. Both subunits of the NO reductase NorBC, combined with the flavoprotein NosR, serve as a membrane-localized assembly platform for the attachment of the nitrate reductase NarGHI, the periplasmic nitrite reductase NirS via its maturation factor NirF and the N O reductase NosZ through NosR. A nitrate transporter (NarK2), the corresponding regulatory system NarXL, various nitrite (NirEJMNQ) and N O reductase (NosFL) maturation proteins are also part of the complex. Primary dehydrogenases, ATP synthase, most enzymes of the TCA cycle, and the SEC protein export system, as well as a number of other proteins, were found to interact with the denitrification complex. Finally, a protein complex composed of the flagella protein FliC, nitrite reductase NirS and the chaperone DnaK required for flagella formation was found in the periplasm of P. aeruginosa. This work demonstrated that the interactomic approach allows for the identification and characterization of stable and transient protein-protein complexes and interactions involved in the assembly and function of multi-enzyme complexes.
Topics: Bacterial Proteins; Denitrification; Gene Expression Regulation, Bacterial; Nitrate Reductase; Nitrite Reductases; Oxidoreductases; Periplasmic Proteins; Protein Binding; Pseudomonas aeruginosa
PubMed: 28857512
DOI: 10.1111/1751-7915.12851 -
Molecules (Basel, Switzerland) Feb 2024Enzymes play an important role in numerous natural processes and are increasingly being utilized as environmentally friendly substitutes and alternatives to many common... (Review)
Review
Enzymes play an important role in numerous natural processes and are increasingly being utilized as environmentally friendly substitutes and alternatives to many common catalysts. Their essential advantages are high catalytic efficiency, substrate specificity, minimal formation of byproducts, and low energy demand. All of these benefits make enzymes highly desirable targets of academic research and industrial development. This review has the modest aim of briefly overviewing the classification, mechanism of action, basic kinetics and reaction condition effects that are common across all six enzyme classes. Special attention is devoted to immobilization strategies as the main tools to improve the resistance to environmental stress factors (temperature, pH and solvents) and prolong the catalytic lifecycle of these biocatalysts. The advantages and drawbacks of methods such as macromolecular crosslinking, solid scaffold carriers, entrapment, and surface modification (covalent and physical) are discussed and illustrated using numerous examples. Among the hundreds and possibly thousands of known and recently discovered enzymes, hydrolases and oxidoreductases are distinguished by their relative availability, stability, and wide use in synthetic applications, which include pharmaceutics, food and beverage treatments, environmental clean-up, and polymerizations. Two representatives of those groups-laccase (an oxidoreductase) and lipase (a hydrolase)-are discussed at length, including their structure, catalytic mechanism, and diverse usage. Objective representation of the current status and emerging trends are provided in the main conclusions.
Topics: Lipase; Laccase; Enzymes, Immobilized; Catalysis; Macromolecular Substances
PubMed: 38474502
DOI: 10.3390/molecules29050989 -
Scientific Reports Dec 2022Nonalcoholic steatohepatitis (NASH)-induced hepatocellular carcinoma (HCC) and its precursor, nonalcoholic fatty liver disease (NAFLD) are an unmet health issue due to...
Nonalcoholic steatohepatitis (NASH)-induced hepatocellular carcinoma (HCC) and its precursor, nonalcoholic fatty liver disease (NAFLD) are an unmet health issue due to widespread obesity. We assessed copy number changes of genes associated with hepatocarcinogenesis and oxidative pathways at a single-cell level. Eleven patients with NASH-HCC and 11 patients with NAFLD were included. Eight probes were analyzed using multiplex interphase fluorescence in situ hybridization (miFISH), single-cell imaging and phylogenetic tree modelling: Telomerase reverse transcriptase (TERT), C-Myc (MYC), hepatocyte growth factor receptor tyrosine kinase (MET), tumor protein 53 (TP53), cyclin D1 (CCND1), human epidermal growth factor receptor 2 (HER2), the fragile histidine triad gene (FHIT) and FRA16D oxidoreductase (WWOX). Each NASH-HCC tumor had up to 14 distinct clonal signal patterns indicating multiclonality, which correlated with high tumor grade. Changes frequently observed were TP53 losses, 45%; MYC gains, 36%; WWOX losses, 36%; and HER2 gains, 18%. Whole-genome duplications were frequent (82%) with aberrant tetraploid cells evolving from diploid ancestors. Non-tumorous NAFLD/NASH biopsies did not harbor clonal copy number changes. Fine mapping of NASH-HCC using single-cell multiplex FISH shows that branched tumor evolution involves genome duplication and that multiclonality increases with tumor grade. The loss of oxidoreductase WWOX and HER2 gains could be potentially associated with NASH-induced hepatocellular carcinoma.
Topics: Humans; Carcinoma, Hepatocellular; Non-alcoholic Fatty Liver Disease; Liver Neoplasms; In Situ Hybridization, Fluorescence; Phylogeny; Chromosome Aberrations; Neoplasm Proteins; Ploidies; Oxidoreductases
PubMed: 36587184
DOI: 10.1038/s41598-022-27173-z -
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 -
Journal of Biological Inorganic... Dec 2022Five tungstopterin-containing oxidoreductases were characterized from the hyperthermophile Pyrococcus furiosus. Each enzyme catalyzes the reversible conversion of one or...
Five tungstopterin-containing oxidoreductases were characterized from the hyperthermophile Pyrococcus furiosus. Each enzyme catalyzes the reversible conversion of one or more aldehydes to the corresponding carboxylic acid, but they have different specificities. The physiological functions of only two of these enzymes are known: one, termed GAPOR, is a glycolytic enzyme that oxidizes glyceraldehyde-3-phosphate, while the other, termed AOR, oxidizes multiple aldehydes generated during peptide fermentation. Two of the enzymes have known structures (AOR and FOR). Herein, we focus on WOR5, the fifth tungstopterin enzyme to be discovered in P. furiosus. Expression of WOR5 was previously shown to be increased during cold shock (growth at 72 ℃), although the physiological substrate is not known. To gain insight into WOR5 function, we sought to determine both its structure and identify its intracellular substrate. Crystallization experiments were performed with a concentrated cytoplasmic extract of P. furiosus grown at 72 ℃ and the structure of WOR5 was deduced from the crystals that were obtained. In contrast to a previous report, WOR5 is heterodimeric containing an additional polyferredoxin-like subunit with four [4Fe-4S] clusters. The active site structure of WOR5 is substantially different from that of AOR and FOR and the significant electron density observed adjacent to the tungsten cofactor of WOR5 was modeled as an aliphatic sulfonate. Biochemical assays and product analysis confirmed that WOR5 is an aliphatic sulfonate ferredoxin oxidoreductase (ASOR). A catalytic mechanism for ASOR is proposed based on the structural information and the potential role of ASOR in the cold-shock response is discussed.
Topics: Tungsten; Oxidoreductases; Aldehyde Oxidoreductases; Pyrococcus furiosus; Aldehydes
PubMed: 36269456
DOI: 10.1007/s00775-022-01965-0 -
Experimental Biology and Medicine... Mar 2015Breast cancer is one of the most common malignancies, often with complicated etiology and poor clinical outcome. In recent years, a critical role has emerged for the WW... (Review)
Review
Breast cancer is one of the most common malignancies, often with complicated etiology and poor clinical outcome. In recent years, a critical role has emerged for the WW domain-containing oxidoreductase (WWOX) in breast cancer. WWOX is a tumor suppressor; it is deleted or attenuated in 29-63.2% of breast cancer tissues and is associated with a poor prognosis of breast cancer patients. WWOX heterozygous knockout mice show a higher incidence of mammary tumors and impaired branching morphogenesis. At the molecular level, WWOX interacts with AP2γ, ErbB4, SMAD3, and WBP2 suppressing their transcription activities in breast cancer cell lines. This review provides comprehensive insights into the current knowledge of WWOX activities in the pathogenesis and endocrine therapy of breast cancer.
Topics: Animals; Antineoplastic Agents, Hormonal; Biomarkers, Tumor; Breast Neoplasms; Carcinogenesis; Disease Models, Animal; Disease Progression; Female; Humans; Mice; Oxidoreductases; Prognosis; Selective Estrogen Receptor Modulators; Tamoxifen; Tumor Suppressor Proteins; WW Domain-Containing Oxidoreductase
PubMed: 25476151
DOI: 10.1177/1535370214561587