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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 -
Angewandte Chemie (International Ed. in... Oct 2021Drimane-type sesquiterpenes exhibit various biological activities and are widely present in eukaryotes. Here, we completely elucidated the biosynthetic pathway of the...
Drimane-type sesquiterpenes exhibit various biological activities and are widely present in eukaryotes. Here, we completely elucidated the biosynthetic pathway of the drimane-type sesquiterpene esters isolated from Aspergillus calidoustus and we discovered that it involves a drimenol cyclase having the same catalytic function previously only reported in plants. Moreover, since many fungal drimenol derivatives possess a γ-butyrolactone ring, we clarified the functions of the cluster-associated cytochrome P450 and FAD-binding oxidoreductase discovering that these two enzymes are solely responsible for the formation of those structures. Furthermore, swapping of the enoyl reductase domain in the identified polyketide synthase led to the production of metabolites containing various polyketide chains with different levels of saturation. These findings have deepened our understanding of how fungi synthesize drimane-type sesquiterpenes and the corresponding esters.
Topics: Aspergillus; Cytochrome P-450 Enzyme System; Esters; Oxidoreductases; Sesquiterpenes
PubMed: 34468074
DOI: 10.1002/anie.202108970 -
Biochimica Et Biophysica Acta.... Oct 2022The superoxide anion - molecular oxygen reduced by a single electron - is produced in large amounts by enzymatic and adventitious reactions. It can perform a range of...
The superoxide anion - molecular oxygen reduced by a single electron - is produced in large amounts by enzymatic and adventitious reactions. It can perform a range of cellular functions, including bacterial warfare and iron uptake, signalling and host immune response in eukaryotes. However, it also serves as precursor for more deleterious species such as the hydroxyl anion or peroxynitrite and defense mechanisms to neutralize superoxide are important for cellular health. In addition to the soluble proteins superoxide dismutase and superoxide reductase, recently the membrane embedded diheme cytochrome b (CybB) from E. coli has been proposed to act as a superoxide:quinone oxidoreductase. Here, we confirm superoxide and cellular ubiquinones or menaquinones as natural substrates and show that quinone binding to the enzyme accelerates the reaction with superoxide. The reactivity of the substrates is in accordance with the here determined midpoint potentials of the two b hemes (+48 and -23 mV / NHE). Our data suggest that the enzyme can work near the diffusion limit in the forward direction and can also catalyse the reverse reaction efficiently under physiological conditions. The data is discussed in the context of described cytochrome b proteins and potential physiological roles of CybB.
Topics: Bacteria; Cytochromes b; Escherichia coli; Oxidoreductases; Superoxides
PubMed: 35671795
DOI: 10.1016/j.bbabio.2022.148583 -
Angewandte Chemie (International Ed. in... Jul 2018Oxidation chemistry using enzymes is approaching maturity and practical applicability in organic synthesis. Oxidoreductases (enzymes catalysing redox reactions) enable... (Review)
Review
Oxidation chemistry using enzymes is approaching maturity and practical applicability in organic synthesis. Oxidoreductases (enzymes catalysing redox reactions) enable chemists to perform highly selective and efficient transformations ranging from simple alcohol oxidations to stereoselective halogenations of non-activated C-H bonds. For many of these reactions, no "classical" chemical counterpart is known. Hence oxidoreductases open up shorter synthesis routes based on a more direct access to the target products. The generally very mild reaction conditions may also reduce the environmental impact of biocatalytic reactions compared to classical counterparts. In this Review, we critically summarise the most important recent developments in the field of biocatalytic oxidation chemistry and identify the most pressing bottlenecks as well as promising solutions.
Topics: Alcohols; Biocatalysis; Molecular Structure; Oxidation-Reduction; Oxidoreductases
PubMed: 29573076
DOI: 10.1002/anie.201800343 -
Journal of Cellular and Molecular... May 2023Impaired mitochondrial function and dysregulated energy metabolism have been shown to be involved in the pathological progression of kidney diseases such as acute kidney...
Impaired mitochondrial function and dysregulated energy metabolism have been shown to be involved in the pathological progression of kidney diseases such as acute kidney injury (AKI) and diabetic nephropathy. Hence, improving mitochondrial function is a promising strategy for treating renal dysfunction. NADH: ubiquinone oxidoreductase core subunit V1 (NDUFV1) is an important subunit of mitochondrial complex I. In the present study, we found that NDUFV1 was reduced in kidneys of renal ischemia/reperfusion (I/R) mice. Meanwhile, renal I/R induced kidney dysfunction as evidenced by increases in BUN and serum creatinine, severe injury of proximal renal tubules, oxidative stress, and cell apoptosis. All these detrimental outcomes were attenuated by increased expression of NDUFV1 in kidneys. Moreover, knockdown of Ndufv1 aggravated cell insults induced by H O in TCMK-1 cells, which further confirmed the renoprotective roles of NDUFV1. Mechanistically, NDUFV1 improved the integrity and function of mitochondria, leading to reduced oxidative stress and cell apoptosis. Overall, our data indicate that NDUFV1 has an ability to maintain mitochondrial homeostasis in AKI, suggesting therapies by targeting mitochondria are useful approaches for dealing with mitochondrial dysfunction associated renal diseases such as AKI.
Topics: Animals; Mice; Acute Kidney Injury; Apoptosis; Homeostasis; Ischemia; Kidney; Mitochondria; Oxidoreductases; Reperfusion Injury
PubMed: 37029501
DOI: 10.1111/jcmm.17735 -
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 -
The Journal of Biological Chemistry Nov 2018In the vertebrate eye, limiting oxidation of proteins and lipids is key to maintaining lens function and avoiding cataract formation. A study by Serebryany identifies a...
In the vertebrate eye, limiting oxidation of proteins and lipids is key to maintaining lens function and avoiding cataract formation. A study by Serebryany identifies a surprising contributor to the eye's oxidative defense in their demonstration that γD-crystallin (HγD) functions as an oxidoreductase and uses disulfide exchange to initiate aggregation of mutant crystallins that mimic oxidative damage. These insights suggest a mechanism by which a dynamic pool of closely packed proteins might avoid oxidation-driven protein-folding traps, providing new avenues to understand the basis of a human disease with global impact.
Topics: Amino Acid Substitution; Cataract; Cysteine; Disulfides; Humans; Lens, Crystalline; Mutation; Oxidation-Reduction; Oxidoreductases Acting on Sulfur Group Donors; gamma-Crystallins
PubMed: 30446601
DOI: 10.1074/jbc.H118.006240 -
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 -
Endocrine Reviews Apr 2019Aldo-keto reductases (AKRs) are monomeric NAD(P)(H)-dependent oxidoreductases that play pivotal roles in the biosynthesis and metabolism of steroids in humans. AKR1C... (Review)
Review
Aldo-keto reductases (AKRs) are monomeric NAD(P)(H)-dependent oxidoreductases that play pivotal roles in the biosynthesis and metabolism of steroids in humans. AKR1C enzymes acting as 3-ketosteroid, 17-ketosteroid, and 20-ketosteroid reductases are involved in the prereceptor regulation of ligands for the androgen, estrogen, and progesterone receptors and are considered drug targets to treat steroid hormone-dependent malignancies and endocrine disorders. In contrast, AKR1D1 is the only known steroid 5β-reductase and is essential for bile-acid biosynthesis, the generation of ligands for the farnesoid X receptor, and the 5β-dihydrosteroids that have their own biological activity. In this review we discuss the crystal structures of these AKRs, their kinetic and catalytic mechanisms, AKR genomics (gene expression, splice variants, polymorphic variants, and inherited genetic deficiencies), distribution in steroid target tissues, roles in steroid hormone action and disease, and inhibitor design.
Topics: Aldo-Keto Reductases; Humans; Hydroxysteroid Dehydrogenases; Oxidoreductases; Steroids
PubMed: 30137266
DOI: 10.1210/er.2018-00089 -
Circulation Research Mar 2022Oxidative stress in cardiac disease promotes proarrhythmic disturbances in Ca homeostasis, impairing luminal Ca regulation of the sarcoplasmic reticulum (SR) Ca release...
BACKGROUND
Oxidative stress in cardiac disease promotes proarrhythmic disturbances in Ca homeostasis, impairing luminal Ca regulation of the sarcoplasmic reticulum (SR) Ca release channel, the RyR2 (ryanodine receptor), and increasing channel activity. However, exact mechanisms underlying redox-mediated increase of RyR2 function in cardiac disease remain elusive. We tested whether the oxidoreductase family of proteins that dynamically regulate the oxidative environment within the SR are involved in this process.
METHODS
A rat model of hypertrophy induced by thoracic aortic banding (TAB) was used for ex vivo whole heart optical mapping and for Ca and reactive oxygen species imaging in isolated ventricular myocytes (VMs).
RESULTS
The SR-targeted reactive oxygen species biosensor ERroGFP showed increased intra-SR oxidation in TAB VMs that was associated with increased expression of Ero1α (endoplasmic reticulum oxidoreductase 1 alpha). Pharmacological (EN460) or genetic Ero1α inhibition normalized SR redox state, increased Ca transient amplitude and SR Ca content, and reduced proarrhythmic spontaneous Ca waves in TAB VMs under β-adrenergic stimulation (isoproterenol). Ero1α overexpression in Sham VMs had opposite effects. Ero1α inhibition attenuated Ca-dependent ventricular tachyarrhythmias in TAB hearts challenged with isoproterenol. Experiments in TAB VMs and human embryonic kidney 293 cells expressing human RyR2 revealed that an Ero1α-mediated increase in SR Ca-channel activity involves dissociation of intraluminal protein ERp44 (endoplasmic reticulum protein 44) from the RyR2 complex. Site-directed mutagenesis and molecular dynamics simulations demonstrated a novel redox-sensitive association of ERp44 with RyR2 mediated by intraluminal cysteine 4806. ERp44-RyR2 association in TAB VMs was restored by Ero1α inhibition, but not by reducing agent dithiothreitol, as hypo-oxidation precludes formation of covalent bond between RyR2 and ERp44.
CONCLUSIONS
A novel axis of intraluminal interaction between RyR2, ERp44, and Ero1α has been identified. Ero1α inhibition exhibits promising therapeutic potential by stabilizing RyR2-ERp44 complex, thereby reducing spontaneous Ca release and Ca-dependent tachyarrhythmias in hypertrophic hearts, without causing hypo-oxidative stress in the SR.
Topics: Animals; Arrhythmias, Cardiac; Calcium; Calcium Signaling; Heart Diseases; Intracellular Signaling Peptides and Proteins; Isoproterenol; Membrane Glycoproteins; Myocytes, Cardiac; Oxidoreductases; Rats; Reactive Oxygen Species; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum
PubMed: 35086342
DOI: 10.1161/CIRCRESAHA.121.320531