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Redox Biology May 2021In this review, we summarize the multiple functions of NQO1, its established roles in redox processes and potential roles in redox control that are currently emerging.... (Review)
Review
In this review, we summarize the multiple functions of NQO1, its established roles in redox processes and potential roles in redox control that are currently emerging. NQO1 has attracted interest due to its roles in cell defense and marked inducibility during cellular stress. Exogenous substrates for NQO1 include many xenobiotic quinones. Since NQO1 is highly expressed in many solid tumors, including via upregulation of Nrf2, the design of compounds activated by NQO1 and NQO1-targeted drug delivery have been active areas of research. Endogenous substrates have also been proposed and of relevance to redox stress are ubiquinone and vitamin E quinone, components of the plasma membrane redox system. Established roles for NQO1 include a superoxide reductase activity, NAD generation, interaction with proteins and their stabilization against proteasomal degradation, binding and regulation of mRNA translation and binding to microtubules including the mitotic spindles. We also summarize potential roles for NQO1 in regulation of glucose and insulin metabolism with relevance to diabetes and the metabolic syndrome, in Alzheimer's disease and in aging. The conformation and molecular interactions of NQO1 can be modulated by changes in the pyridine nucleotide redox balance suggesting that NQO1 may function as a redox-dependent molecular switch.
Topics: Antioxidants; Humans; NAD(P)H Dehydrogenase (Quinone); Neoplasms; Oxidation-Reduction; Quinones
PubMed: 33774477
DOI: 10.1016/j.redox.2021.101950 -
British Journal of Pharmacology Jul 2017Azoreductases are flavoenzymes that have been characterized in a range of prokaryotes and eukaryotes. Bacterial azoreductases are associated with the activation of two... (Review)
Review
UNLABELLED
Azoreductases are flavoenzymes that have been characterized in a range of prokaryotes and eukaryotes. Bacterial azoreductases are associated with the activation of two classes of drug, azo drugs for the treatment of inflammatory bowel disease and nitrofuran antibiotics. The mechanism of reduction of azo compounds is presented; it requires tautomerisation of the azo compound to a quinoneimine and provides a unifying mechanism for the reduction of azo and quinone substrates by azoreductases. The importance of further work in the characterization of azoreductases from enteric bacteria is highlighted to aid in the development of novel drugs for the treatment of colon related disorders. Human azoreductases are known to play a crucial role in the metabolism of a number of quinone-containing cancer chemotherapeutic drugs. The mechanism of hydride transfer to quinones, which is shared not only between eukaryotic and prokaryotic azoreductases but also the wider family of NAD(P)H quinone oxidoreductases, is outlined. The importance of common single nucleotide polymorphisms (SNPs) in human azoreductases is described not only in cancer prognosis but also with regard to their effects on the efficacy of quinone drug-based cancer chemotherapeutic regimens. This highlights the need to screen patients for azoreductase SNPs ahead of treatment with these regimens.
LINKED ARTICLES
This article is part of a themed section on Drug Metabolism and Antibiotic Resistance in Micro-organisms. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.14/issuetoc.
Topics: Anti-Bacterial Agents; Antineoplastic Agents; Azo Compounds; Bacteria; Humans; NADH, NADPH Oxidoreductases; Neoplasms; Nitrofurans; Nitroreductases; Quinones
PubMed: 27487252
DOI: 10.1111/bph.13571 -
Research in Microbiology 2022Bacterial quinones are lipophilic redox compounds involved in important cellular roles such as electron transport in respiratory and photosynthetic chains. However, a... (Review)
Review
Bacterial quinones are lipophilic redox compounds involved in important cellular roles such as electron transport in respiratory and photosynthetic chains. However, a growing body of research has now revealed that quinones have additional functions in bacterial physiology, with significant consequences for colonization and persistence in different ecological niches. The aim of this review is to provide an updated view of the functions of bacterial quinones, with particular emphasis on their importance for bacterial metabolism, gene regulation, and stress resistance. We provide evidence that quinones have also a deep impact on the composition and function of bacterial ecosystems.
Topics: Bacteria; Ecosystem; Electron Transport; Electrons; Oxidation-Reduction; Quinones
PubMed: 35470045
DOI: 10.1016/j.resmic.2022.103953 -
Biomolecules Jul 2021Neutral cannabinoids are oxidatively unstable and are converted into quinone derivatives by atmospheric- and/or chemical oxidative dearomatization. The study of... (Review)
Review
Neutral cannabinoids are oxidatively unstable and are converted into quinone derivatives by atmospheric- and/or chemical oxidative dearomatization. The study of cannabinoquinones has long been plagued by their lability toward additional oxidative degradation, but full substitution of the quinone ring, as well as the introduction of steric hindrance on the alkyl substituent, have provided sufficient stability for a systematic investigation of their bioactivity and for further clinical development. These studies culminated in the discovery of the aminocannabinoquinone VCE-004.8 (), a compound under phase 2 clinical development with orphan drug status by EMA and FDA for the management of scleroderma. The synthesis and rich chemistry of these compounds will be described, summarizing their biological profile and clinical potential.
Topics: Cannabinoids; Humans; Oxidation-Reduction; Quinones
PubMed: 34356614
DOI: 10.3390/biom11070991 -
Biochemical Society Transactions Apr 2022Cytochrome (cyt) bc1, bcc and b6f complexes, collectively referred to as cyt bc complexes, are homologous isoprenoid quinol oxidising enzymes present in diverse... (Review)
Review
Cytochrome (cyt) bc1, bcc and b6f complexes, collectively referred to as cyt bc complexes, are homologous isoprenoid quinol oxidising enzymes present in diverse phylogenetic lineages. Cyt bc1 and bcc complexes are constituents of the electron transport chain (ETC) of cellular respiration, and cyt b6f complex is a component of the photosynthetic ETC. Cyt bc complexes share in general the same Mitchellian Q cycle mechanism, with which they accomplish proton translocation and thus contribute to the generation of proton motive force which drives ATP synthesis. They therefore require a quinol oxidation (Qo) and a quinone reduction (Qi) site. Yet, cyt bc complexes evolved to adapt to specific electrochemical properties of different quinone species and exhibit structural diversity. This review summarises structural information on native quinones and quinone-like inhibitors bound in cyt bc complexes resolved by X-ray crystallography and cryo-EM structures. Although the Qi site architecture of cyt bc1 complex and cyt bcc complex differs considerably, quinone molecules were resolved at the respective Qi sites in very similar distance to haem bH. In contrast, more diverse positions of native quinone molecules were resolved at Qo sites, suggesting multiple quinone binding positions or captured snapshots of trajectories toward the catalytic site. A wide spectrum of inhibitors resolved at Qo or Qi site covers fungicides, antimalarial and antituberculosis medications and drug candidates. The impact of these structures for characterising the Q cycle mechanism, as well as their relevance for the development of medications and agrochemicals are discussed.
Topics: Benzoquinones; Binding Sites; Cryoelectron Microscopy; Crystallography, X-Ray; Electron Transport; Hydroquinones; Oxidation-Reduction; Phylogeny; Quinones
PubMed: 35356963
DOI: 10.1042/BST20190963 -
The Biochemical Journal Dec 1996This review is concerned with the structure and function of the quinoprotein enzymes, sometimes called quinoenzymes. These have prosthetic groups containing quinones,... (Review)
Review
This review is concerned with the structure and function of the quinoprotein enzymes, sometimes called quinoenzymes. These have prosthetic groups containing quinones, the name thus being analogous to the flavoproteins containing flavin prosthetic groups. Pyrrolo-quinoline quinone (PQQ) is non-covalently attached, whereas tryptophan tryptophylquinone (TTQ), topaquinone (TPQ) and lysine tyrosylquinone (LTQ) are derived from amino acid residues in the backbone of the enzymes. The mechanisms of the quinoproteins are reviewed and related to their recently determined three-dimensional structures. As expected, the quinone structures in the prosthetic groups play important roles in the mechanisms. A second common feature is the presence of a catalytic base (aspartate) at the active site which initiates the reactions by abstracting a proton from the substrate, and it is likely to be involved in multiple reactions in the mechanism. A third common feature of these enzymes is that the first part of the reaction produces a reduced prosthetic group; this part of the mechanism is fairly well understood. This is followed by an oxidative phase involving electron transfer reactions which remain poorly understood. In both types of dehydrogenase (containing PQQ and TTQ), electrons must pass from the reduced prosthetic group to redox centres in a second recipient protein (or protein domain), whereas in amine oxidases (containing TPQ or LTQ), electrons must be transferred to molecular oxygen by way of a redox-active copper ion in the protein.
Topics: Alcohol Oxidoreductases; Amine Oxidase (Copper-Containing); Bacterial Proteins; Binding Sites; Coenzymes; Dihydroxyphenylalanine; Disulfides; Electron Transport; Indolequinones; Lysine; Models, Chemical; Models, Molecular; Molecular Structure; Oxidation-Reduction; Oxidoreductases Acting on CH-NH Group Donors; PQQ Cofactor; Protein-Lysine 6-Oxidase; Quinolones; Quinones; Tryptophan
PubMed: 9003352
DOI: 10.1042/bj3200697 -
Molecules (Basel, Switzerland) Sep 2022Vitamin E, a collection of lipophilic phenolic compounds based on chroman-6-ol, has a rich and fascinating oxidative chemistry involving a range of intermediate forms,... (Review)
Review
Vitamin E, a collection of lipophilic phenolic compounds based on chroman-6-ol, has a rich and fascinating oxidative chemistry involving a range of intermediate forms, some of which are proposed to be important in its biological functions. In this review, the available electrochemical and spectroscopic data on these oxidized intermediates are summarized, along with a discussion on how their lifetimes and chemical stability are either typical of similar phenolic and chroman-6-ol derived compounds, or atypical and unique to the specific oxidized isomeric form of vitamin E. The overall electrochemical oxidation mechanism for vitamin E can be summarized as involving the loss of two-electrons and one-proton, although the electron transfer and chemical steps can be controlled to progress along different pathways to prolong the lifetimes of discreet intermediates by modifying the experimental conditions (applied electrochemical potential, aqueous or non-aqueous solvent, and pH). Depending on the environment, the electrochemical reactions can involve single electron transfer (SET), proton-coupled electron transfer (PCET), as well as homogeneous disproportionation and comproportionation steps. The intermediate species produced via chemical or electrochemical oxidation include phenolates, phenol cation radicals, phenoxyl neutral radicals, dications, diamagnetic cations (phenoxeniums) and -quinone methides. The cation radicals of all the tocopherols are atypically long-lived compared to the cation radicals of other phenols, due to their relatively weak acidity. The diamagnetic cation derived from α-tocopherol is exceptionally long-lived compared to the diamagnetic cations from the other β-, γ- and δ-isomers of vitamin E and compared with other phenoxenium cations derived from phenolic compounds. In contrast, the lifetime of the phenoxyl radical derived from α-tocopherol, which is considered to be critical in biological reactions, is typical for what is expected for a compound with its structural features. Over longer times via hydrolysis reactions, hydroxy -quinone hemiketals and quinones can be formed from the oxidized intermediates, which can themselves undergo reduction processes to form intermediate anion radicals and dianions. Methods for generating the oxidized intermediates by chemical, photochemical and electrochemical methods are discussed, along with a summary of how the final products vary depending on the method used for oxidation. Since the intermediates mainly only survive in solution, they are most often monitored using UV-vis spectroscopy, FTIR or Raman spectroscopies, and EPR spectroscopy, with the spectroscopic techniques sometimes combined with fast photoinitiated excitation and time-resolved spectroscopy for detection of short-lived species.
Topics: Benzoquinones; Chromans; Electron Spin Resonance Spectroscopy; Oxidation-Reduction; Phenol; Phenols; Protons; Solvents; Tocopherols; Vitamin E; alpha-Tocopherol
PubMed: 36234726
DOI: 10.3390/molecules27196194 -
Journal of Natural Products May 2020Spurred by a growing interest in cannabidiolquinone (CBDQ, HU-313, ) as a degradation marker and alledged hepatotoxic metabolite of cannabidiol (CBD, ), we performed a...
Spurred by a growing interest in cannabidiolquinone (CBDQ, HU-313, ) as a degradation marker and alledged hepatotoxic metabolite of cannabidiol (CBD, ), we performed a systematic study on the oxidation of CBD () to CBDQ () under a variety of experimental conditions (base-catalyzed aerobic oxidation, oxidation with metals, oxidation with hypervalent iodine reagents). The best results in terms of reproducibility and scalability were obtained with λ-periodinanes (Dess-Martin periodinane, 1-hydroxy-1λ,2-benziodoxole-1,3-dione (IBX), and SIBX, a stabilized, nonexplosive version of IBX). With these reagents, the oxidative dimerization that plagues the reaction under basic aerobic conditions was completely suppressed. A different reaction course was observed with the copper(II) chloride-hydroxylamine complex (Takehira reagent), which afforded a mixture of the hydroxyiminodienone and the halogenated resorcinol . The λ-periodinane oxidation was general for phytocannabinoids, turning cannabigerol (CBG, ), cannabichromene (CBC, ), and cannabinol (CBN, ) into their corresponding hydroxyquinones (, , and , respectively). All cannabinoquinoids modulated to a various extent peroxisome proliferator-activated receptor gamma (PPAR-γ) activity, outperforming their parent resorcinols in terms of potency, but the iminoquinone , the quinone dimers and , and the haloresorcinol were inactive, suggesting a specific role for the monomeric hydroxyquinone moiety in the interaction with PPAR-γ.
Topics: Cannabidiol; Cannabinoids; Oxidation-Reduction; PPAR gamma; Quinones; Reproducibility of Results; Resorcinols
PubMed: 32315173
DOI: 10.1021/acs.jnatprod.9b01284 -
Genes Jan 2024The flavoenzyme N-ribosyldihydronicotinamide (NRH):quinone oxidoreductase 2 (NQO2) catalyzes two-electron reductions of quinones. NQO2 contributes to the metabolism of... (Review)
Review
The flavoenzyme N-ribosyldihydronicotinamide (NRH):quinone oxidoreductase 2 (NQO2) catalyzes two-electron reductions of quinones. NQO2 contributes to the metabolism of biogenic and xenobiotic quinones, including a wide range of antitumor drugs, with both toxifying and detoxifying functions. Moreover, NQO2 activity can be inhibited by several compounds, including drugs and phytochemicals such as flavonoids. NQO2 may play important roles that go beyond quinone metabolism and include the regulation of oxidative stress, inflammation, and autophagy, with implications in carcinogenesis and neurodegeneration. is a highly polymorphic gene with several allelic variants, including insertions (I), deletions (D) and single-nucleotide (SNP) polymorphisms located mainly in the promoter, but also in other regulatory regions and exons. This is the first systematic review of the literature reporting on NQO2 gene variants as risk factors in degenerative diseases or drug adverse effects. In particular, hypomorphic 29 bp I alleles have been linked to breast and other solid cancer susceptibility as well as to interindividual variability in response to chemotherapy. On the other hand, hypermorphic polymorphisms were associated with Parkinson's and Alzheimer's disease. The I and D promoter variants and other NQO2 polymorphisms may impact cognitive decline, alcoholism and toxicity of several nervous system drugs. Future studies are required to fill several gaps in NQO2 research.
Topics: Benzoquinones; Oxidoreductases; Pharmacogenetics; Quinone Reductases; Humans
PubMed: 38254976
DOI: 10.3390/genes15010087 -
Applied Microbiology and Biotechnology Nov 2022Monotopic membrane-bound flavoproteins, sulfide:quinone oxidoreductases (SQRs), have a variety of physiological functions, including sulfide detoxification. SQR enzymes...
Monotopic membrane-bound flavoproteins, sulfide:quinone oxidoreductases (SQRs), have a variety of physiological functions, including sulfide detoxification. SQR enzymes are classified into six groups. SQRs use the flavin adenine dinucleotide (FAD) cofactor to transfer electrons from sulfide to quinone. A type VI SQR of the photosynthetic purple sulfur bacterium, Thiocapsa roseopersicina (TrSqrF), has been previously characterized, and the mechanism of sulfide oxidation has been proposed. This paper reports the characterization of quinone binding site (QBS) of TrSqrF composed of conserved aromatic and apolar amino acids. Val331, Ile333, and Phe366 were identified near the benzoquinone ring of enzyme-bound decylubiquinone (dUQ) using the TrSqrF homology model. In silico analysis revealed that Val331 and Ile333 alternately connected with the quinone head group via hydrogen bonds, and Phe366 and Trp369 bound the quinones via hydrophobic interactions. TrSqrF variants containing alanine (V331A, I333A, F366A) and aromatic amino acid (V331F, I333F, F366Y), as well as a C-terminal α-helix deletion (CTD) mutant were generated. These amino acids are critical for quinone binding and, thus, catalysis. Spectroscopic analyses proved that all mutants contained FAD. I333F replacement resulted in the lack of the charge transfer complex. In summary, the interactions described above maintain the quinone molecule's head in an optimal position for direct electron transfer from FAD. Surprisingly, the CTD mutant retained a relatively high level of specific activity while remaining membrane-anchored. This is a unique study because it focuses on the QBS and the oxidative stage of a type VI sulfide-dependent quinone reduction. KEY POINTS: • V331, I333, F366, and W369 were shown to interact with decylubiquinone in T. roseopersicina SqrF • These amino acids are involved in proper positioning of quinones next to FAD • I333 is essential in formation of a charge transfer complex from FAD to quinone.
Topics: Flavin-Adenine Dinucleotide; Quinone Reductases; Sulfides; Benzoquinones; Binding Sites; Oxidation-Reduction; Amino Acids
PubMed: 36219222
DOI: 10.1007/s00253-022-12202-8