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Biochemical Society Transactions Jun 2012The study of natural enzymes is complicated by the fact that only the most recent evolutionary progression can be observed. In particular, natural oxidoreductases stand... (Review)
Review
The study of natural enzymes is complicated by the fact that only the most recent evolutionary progression can be observed. In particular, natural oxidoreductases stand out as profoundly complex proteins in which the molecular roots of function, structure and biological integration are collectively intertwined and individually obscured. In the present paper, we describe our experimental approach that removes many of these often bewildering complexities to identify in simple terms the necessary and sufficient requirements for oxidoreductase function. Ours is a synthetic biology approach that focuses on from-scratch construction of protein maquettes designed principally to promote or suppress biologically relevant oxidations and reductions. The approach avoids mimicry and divorces the commonly made and almost certainly false ascription of atomistically detailed functionally unique roles to a particular protein primary sequence, to gain a new freedom to explore protein-based enzyme function. Maquette design and construction methods make use of iterative steps, retraceable when necessary, to successfully develop a protein family of sturdy and versatile single-chain three- and four-α-helical structural platforms readily expressible in bacteria. Internally, they prove malleable enough to incorporate in prescribed positions most natural redox cofactors and many more simplified synthetic analogues. External polarity, charge-patterning and chemical linkers direct maquettes to functional assembly in membranes, on nanostructured titania, and to organize on selected planar surfaces and materials. These protein maquettes engage in light harvesting and energy transfer, in photochemical charge separation and electron transfer, in stable dioxygen binding and in simple oxidative chemistry that is the basis of multi-electron oxidative and reductive catalysis.
Topics: Oxidation-Reduction; Oxidoreductases; Protein Engineering; Recombinant Proteins; Synthetic Biology
PubMed: 22616867
DOI: 10.1042/BST20120067 -
Experimental Biology and Medicine... Mar 2015WWOX is a gene that spans an extremely large chromosomal region. It is derived from within chromosomal band 16q23.2 which is a region with frequent deletions and other... (Review)
Review
WWOX is a gene that spans an extremely large chromosomal region. It is derived from within chromosomal band 16q23.2 which is a region with frequent deletions and other alterations in a variety of different cancers. This chromosomal band also contains the FRA16D common fragile site (CFS). CFSs are chromosomal regions found in all individuals which are highly unstable. WWOX has also been demonstrated to function as a tumor suppressor that is involved in the development of many cancers. Two other highly unstable CFSs, FRA3B (3p14.2) and FRA6E (6q26), also span extremely large genes, FHIT and PARK2, respectively, and these two genes are also found to be important tumor suppressors. There are a number of interesting similarities between these three large CFS genes. In spite of the fact that they are derived from some of the most unstable chromosomal regions in the genome, they are found to be highly evolutionarily conserved and the chromosomal region spanning the mouse homologs of both WWOX and FHIT are also CFSs in mice. Many of the other CFSs also span extremely large genes and many of these are very attractive tumor suppressor candidates. WWOX is therefore a member of a very interesting family of very large CFS genes.
Topics: Animals; Carcinogenesis; Chromosome Fragile Sites; Disease Models, Animal; Genomic Instability; Humans; Mice; Neoplasms; Oxidoreductases; Signal Transduction; Tumor Suppressor Proteins; WW Domain-Containing Oxidoreductase
PubMed: 25595185
DOI: 10.1177/1535370214565992 -
Experimental Biology and Medicine... Mar 2015Human fragile WWOX gene encodes a tumor suppressor WW domain-containing oxidoreductase (named WWOX, FOR, or WOX1). Functional suppression of WWOX prevents apoptotic cell... (Review)
Review
Human fragile WWOX gene encodes a tumor suppressor WW domain-containing oxidoreductase (named WWOX, FOR, or WOX1). Functional suppression of WWOX prevents apoptotic cell death induced by a variety of stress stimuli, such as tumor necrosis factor, UV radiation, and chemotherapeutic drug treatment. Loss of WWOX gene expression due to gene deletions, loss of heterozygosity, chromosomal translocations, or epigenetic silencing is frequently observed in human malignant cancer cells. Acquisition of chemoresistance in squamous cell carcinoma, osteosarcoma, and breast cancer cells is associated with WWOX deficiency. WWOX protein physically interacts with many signaling molecules and exerts its regulatory effects on gene transcription and protein stability and subcellular localization to control cell survival, proliferation, differentiation, autophagy, and metabolism. In this review, we provide an overview of the recent advances in understanding the molecular mechanisms by which WWOX regulates cellular functions and stress responses. A potential scenario is that activation of WWOX by anticancer drugs is needed to overcome chemoresistance and trigger cancer cell death, suggesting that WWOX can be regarded as a prognostic marker and a candidate molecule for targeted cancer therapies.
Topics: Apoptosis; Drug Resistance, Neoplasm; Humans; Neoplasms; Oxidoreductases; Signal Transduction; Stress, Physiological; Tumor Suppressor Protein p53; Tumor Suppressor Proteins; WW Domain-Containing Oxidoreductase
PubMed: 25595191
DOI: 10.1177/1535370214566747 -
Experimental Biology and Medicine... Mar 2015WWOX was cloned as a tumor suppressor gene mapping to chromosomal fragile site FRA16D. Loss of WWOX is closely related to tumorigenesis, cancer progression, and therapy... (Review)
Review
WWOX was cloned as a tumor suppressor gene mapping to chromosomal fragile site FRA16D. Loss of WWOX is closely related to tumorigenesis, cancer progression, and therapy resistance. Recent studies demonstrate the growing role of WWOX gene in other human pathologies such as metabolic and nervous system-related conditions. The neurologic phenotype of WWOX mutation includes seizures, ataxia, developmental delay, and spasticity of variable severity. WWOX is a ubiquitous protein with high expression in many tissues including brain, cerebellum, brain stem, and spinal cord. WWOX is highly expressed in different brain regions during murine fetal development and remained unchanged in the cortex and the corpus callosum in adult mice. The mechanism or the putative role of WWOX in the nervous system is still unclear but may include abnormal signaling protein, disruption of neuronal pathways, neuronal differentiation, mitochondrial dysfunction, or apoptosis. Homozygous mutations affecting WWOX in humans are likely to be more described in the future using exome sequencing. The described findings highlight that WWOX plays a critical role in normal central nervous system development and disease. The aim of this review is to summarize the roles of WWOX in the developing brain.
Topics: Animals; Brain; Brain Diseases; Chromosome Fragile Sites; Disease Models, Animal; Gene Expression Regulation, Developmental; Humans; Mice; Mutation; Oxidoreductases; Phenotype; Rats; Tumor Suppressor Proteins; WW Domain-Containing Oxidoreductase
PubMed: 25416187
DOI: 10.1177/1535370214561952 -
Biochimica Et Biophysica Acta Jan 2002An overview of the present knowledge about succinate:quinone oxidoreductase in Paracoccus denitrificans and Bacillus subtilis is presented. P. denitrificans contains a... (Comparative Study)
Comparative Study Review
An overview of the present knowledge about succinate:quinone oxidoreductase in Paracoccus denitrificans and Bacillus subtilis is presented. P. denitrificans contains a monoheme succinate:ubiquinone oxidoreductase that is similar to that of mammalian mitochondria with respect to composition and sensitivity to carboxin. Results obtained with carboxin-resistant P. denitrificans mutants provide information about quinone-binding sites on the enzyme and the molecular basis for the resistance. B. subtilis contains a diheme succinate:menaquinone oxidoreductase whose activity is dependent on the electrochemical gradient across the cytoplasmic membrane. Data from studies of mutant variants of the B. subtilis enzyme combined with available crystal structures of a similar enzyme, Wolinella succinogenes fumarate reductase, substantiate a proposed explanation for the mechanism of coupling between quinone reductase activity and transmembrane potential.
Topics: Amino Acid Sequence; Bacillus subtilis; Bacterial Proteins; Carboxin; Drug Resistance, Microbial; Electron Transport Complex II; Enzyme Inhibitors; Hydroxyquinolines; Intracellular Membranes; Membrane Potentials; Membrane Proteins; Molecular Sequence Data; Multienzyme Complexes; Oxidoreductases; Paracoccus denitrificans; Quinone Reductases; Sequence Alignment; Succinate Dehydrogenase
PubMed: 11803018
DOI: 10.1016/s0005-2728(01)00231-6 -
Biomolecular Concepts Sep 2017Protein folding and assembly into macromolecule complexes within the living cell are complex processes requiring intimate coordination. The biogenesis of complex iron... (Review)
Review
Protein folding and assembly into macromolecule complexes within the living cell are complex processes requiring intimate coordination. The biogenesis of complex iron sulfur molybdoenzymes (CISM) requires use of a system specific chaperone - a redox enzyme maturation protein (REMP) - to help mediate final folding and assembly. The CISM dimethyl sulfoxide (DMSO) reductase is a bacterial oxidoreductase that utilizes DMSO as a final electron acceptor for anaerobic respiration. The REMP DmsD strongly interacts with DMSO reductase to facilitate folding, cofactor-insertion, subunit assembly and targeting of the multi-subunit enzyme prior to membrane translocation and final assembly and maturation into a bioenergetic catalytic unit. In this article, we discuss the biogenesis of DMSO reductase as an example of the participant network for bacterial CISM maturation pathways.
Topics: Bacterial Proteins; Iron-Sulfur Proteins; Models, Molecular; Molecular Chaperones; Oxidoreductases; Protein Folding; Protein Interaction Maps; Protein Transport
PubMed: 28688222
DOI: 10.1515/bmc-2017-0011 -
Biochimica Et Biophysica Acta. Reviews... Jan 2024Endoplasmic reticulum oxidoreductin 1 (ERO1) alpha (ERO1A) is an endoplasmic reticulum (ER)-localized protein disulfide oxidoreductase, involved in the disulfide bond... (Review)
Review
Endoplasmic reticulum oxidoreductin 1 (ERO1) alpha (ERO1A) is an endoplasmic reticulum (ER)-localized protein disulfide oxidoreductase, involved in the disulfide bond formation of proteins. ERO1's activity in oxidative protein folding is redundant in higher eukaryotes and its loss is well compensated. Although it is dispensable in non-cancer cells, high ERO1 levels are seen with different cancers and predict their malignant phenotype. ERO1 fosters tumor aggressiveness and the response to drug therapy in hypoxic and highly metastatic tumors. It regulates vascular endothelial growth factor (VEGF) levels, oxidative folding and N-glycosylation in hypoxic conditions, boosting tumor fitness and angiogenesis on multiple levels. In addition, ERO1 regulates protein death ligand-1 (PD-L1) on tumors, interfering with the related immune surveillance mechanism, hence acting on the tumors' response to immune check-point inhibitors (ICI). This all points to inhibition of ERO1 as an effective pharmacological tool, selectively targeting tumors while sparing non-cancer cells from cytotoxicity. The critical discussion here closely examines the molecular basis for ERO1's involvement in tumors and ERO1 inhibition strategies for their treatment.
Topics: Humans; Vascular Endothelial Growth Factor A; Oxidoreductases; Neoplasms; Endoplasmic Reticulum; Disulfides
PubMed: 38007054
DOI: 10.1016/j.bbcan.2023.189027 -
Hormone Research 2008P450 oxidoreductase (POR) deficiency is an autosomal recessive disorder of steroidogenesis with multiple clinical manifestations. POR is the electron donor for all... (Review)
Review
P450 oxidoreductase (POR) deficiency is an autosomal recessive disorder of steroidogenesis with multiple clinical manifestations. POR is the electron donor for all microsomal P450 enzymes, including the three steroidogenic enzymes P450c17 (17alpha-hydroxylase/17,20-lyase), P450c21 (21-hydroxylase), and P450aro (aromatase). Since the first description of POR mutations in 2004, about 50 patients have been reported. Serum steroid profiles indicate partial deficiencies in 21-hydroxylase, 17alpha-hydroxylase and 17,20-lyase. The 17-OH progesterone levels are elevated, as in 21-hydroxylase deficiency, while androgen levels are low; cortisol may be normal but is poorly responsive to adrenocorticotropic hormone. Most patients also have associated skeletal malfor- mations (craniosynostosis, radio-ulnar synostosis, midface hypoplasia, bowed femora) termed Antley-Bixler syndrome. Antley-Bixler syndrome with normal steroidogenesis is caused by autosomal dominant gain-of-function mutations in fibroblast growth factor receptor 2. Males with POR deficiency are often undervirilized, while females can be virilized. The prognosis for patients with POR deficiency appears to depend on the severity of the bony malformations and their timely treatment. The potential impact of POR mutations on drug metabolism by other hepatic P450 enzymes requires further investigation. Given the varied physical and biochemical phenotype of POR deficiency and the risk of adrenal insufficiency, clinicians should be alert to this potential diagnosis.
Topics: Abnormalities, Multiple; Bone and Bones; Cytochrome P-450 Enzyme System; Endocrine System Diseases; Humans; Hydroxysteroid Dehydrogenases; Models, Biological; NADH, NADPH Oxidoreductases; Steroid 17-alpha-Hydroxylase; Steroid 21-Hydroxylase; Syndrome
PubMed: 18259105
DOI: 10.1159/000114857 -
Experimental Biology and Medicine... Mar 2015Since its discovery in 2000, WW domain-containing oxidoreductase (WWOX, FOR or WOX1) has been considered as a tumor suppressor protein. Global research focus has been...
Since its discovery in 2000, WW domain-containing oxidoreductase (WWOX, FOR or WOX1) has been considered as a tumor suppressor protein. Global research focus has been aimed mainly toward this direction. In this thematic issue, updated information has been collected regarding the structure, function and signaling of WWOX, along with its critical role as a tumor suppressor and participation in metabolism, neurodegeneration, ataxia, epilepsy, neural disorders, neuronal damages, and interactions with oncogenic viruses. WWOX is not a driver of cancer initiation. Chromosomal alterations in the WWOX gene enhance cancer progression. Importantly, a homozygous nonsense mutation of WWOX gene in humans leads to neural pathologies and early death, rather than spontaneous cancer development. These findings suggest new physiological functions of WWOX in metabolism and neural diseases, and these areas require further investigation.
Topics: Humans; Mutation; Neoplasms; Nervous System Diseases; Oxidoreductases; Signal Transduction; Tumor Suppressor Proteins; WW Domain-Containing Oxidoreductase
PubMed: 25802472
DOI: 10.1177/1535370215574226 -
Thrombosis Research Apr 2010Cell exposed tissue factor (TF) is generally in a low procoagulant ("cryptic") state, and requires an activation step (decryption) to exhibit its full procoagulant... (Review)
Review
Cell exposed tissue factor (TF) is generally in a low procoagulant ("cryptic") state, and requires an activation step (decryption) to exhibit its full procoagulant potential. Recent data suggest that TF decryption may be regulated by the redox environment through the oxidoreductase activity of protein disulfide isomerase (PDI). In this article we review PDI contribution to different models of TF decryption, namely the disulfide switch model and the phosphatidylserine dynamics, and hypothesize on PDI contribution to TF self-association and association with lipid domains. Experimental evidence debate the disulfide switch model of TF decryption and its regulation by PDI. More recently we showed that PDI oxidoreductase activity regulates the phosphatidylserine equilibrium at the plasma membrane. Interestingly, PDI reductase activity could maintain TF in the reduced monomeric form, while also maintaining low exposure of PS, both states correlated with low procoagulant function. In contrast, PDI inhibition or oxidants may promote the adverse effects with a net increase in coagulation. The relative contribution of disulfide isomerization and PS exposure needs to be further analyzed to understand the redox control of TF procoagulant function. For the moment however TF regulation remains cryptic.
Topics: Allosteric Site; Blood Coagulation; Factor VIIa; Humans; Lipids; Molecular Chaperones; Oxidants; Oxidation-Reduction; Oxidoreductases; Peptides; Phosphatidylserines; Protein Binding; Protein Disulfide-Isomerases; Thromboplastin
PubMed: 20163832
DOI: 10.1016/j.thromres.2010.01.034