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Junmin Zhang, Juan Yao, Shoujiao Peng, Xinming Li, Jianguo Fang
Thioredoxin reductase (TrxR) and thioredoxin (Trx) are two major components of the thioredoxin system, which plays essential roles in regulating cellular redox signaling. Mammalian TrxRs are essential seleno-flavoenzymes with a conserved penultimate selenocysteine (Sec) residue at the C-terminus, and have attracted considerable interests as promising targets for anticancer drugs. Securinine (SCR), a major active alkaloid lactone from the Chinese herbal medicine Securinega suffruticosa, has been established clinical success in treatment of neurological disorders...
October 21, 2016: Biochimica et Biophysica Acta
Benjamin W Arentson, Erin L Hayes, Weidong Zhu, Harkewal Singh, John J Tanner, Donald F Becker
Proline utilization A (PutA) is a bifunctional flavoenzyme with proline dehydrogenase (PRODH) and Δ(1)-pyrroline-5-carboxylate dehydrogenase domains that catalyzes the two-step oxidation of proline to glutamate. Trifunctional PutAs also have an N-terminal ribbon-helix-helix (RHH) DNA-binding domain and moonlight as autogenous transcriptional repressors of the put regulon. A unique property of trifunctional PutA is the ability to switch functions from DNA-bound repressor to membrane-associated enzyme in response to cellular nutritional needs and proline availability...
October 14, 2016: Bioscience Reports
Matic Poberznik, Miha Purg, Matej Repič, Janez Mavri, Robert Vianello
Monoamine oxidases (MAOs) A and B are flavoenzymes responsible for the metabolism of biogenic amines such as dopamine, serotonin and noradrenaline, which is why they have been extensively implicated in the etiology and course of various neurodegenerative disorders, and, accordingly, used as primary pharmacological targets to treat these debilitating cognitive diseases. The precise chemical mechanism through which MAOs regulate the amine concentration, which is vital for the development of novel inhibitors, is still not unambiguously determined in the literature...
October 13, 2016: Journal of Physical Chemistry. B
James E Longbotham, Samantha J O Hardman, Stefan Görlich, Nigel S Scrutton, Sam Hay
"Heavy" (isotopically labeled) enzyme isotope effects offer a direct experimental probe of the role of protein vibrations on enzyme-catalyzed reactions. Here we have developed a strategy to generate isotopologues of the flavoenzyme pentaerythritol tetranitrate reductase (PETNR) where the protein and/or intrinsic flavin mononucleotide (FMN) cofactor are isotopically labeled with (2)H, (15)N, and (13)C. Both the protein and cofactor contribute to the enzyme isotope effect on the reductive hydride transfer reaction, but their contributions are not additive and may partially cancel each other out...
October 7, 2016: Journal of the American Chemical Society
Jérémie Piton, Caroline S-Y Foo, Stewart T Cole
The flavoenzyme DprE1 catalyses a crucial step in arabinan production for cell wall biosynthesis in Mycobacterium tuberculosis and is a highly vulnerable drug target. It was first discovered using benzothiazinones (BTZ): exquisitely potent bactericidal agents that are being developed as drugs to treat tuberculosis. Subsequently, many compounds with diverse scaffolds were found to act as either covalent or noncovalent DprE1 inhibitors. Covalent inhibitors, like the BTZ, are all nitroaromatic compounds that serve as suicide substrates after DprE1-mediated nitroreduction...
September 22, 2016: Drug Discovery Today
Jun Kobayashi, Hiromi Yoshida, Toshiharu Yagi, Shigehiro Kamitori, Hideyuki Hayashi, Kimihiko Mizutani, Nobuyuki Takahashi, Bunzo Mikami
The flavoenzyme 2-Methyl-3-hydroxypyridine-5-carboxylic acid oxygenase (MHPCO) catalyzes the cleavage of the pyridine ring of 2-methyl-3-hydroxypyridine-5-carboxylic acid (MHPC) in the presence of NADH, molecular oxygen, and water. MHPCO also catalyzes the NADH oxidation reaction uncoupled with ring opening in the absence of MHPC (the basal activity). The enzyme shows activity toward not only MHPC but also 5-hydroxynicotinic acid (5HN) and 5-pyridoxic acid (5PA). The reaction rate toward 5PA is extremely low (5% of the activity toward MHPC or 5HN)...
August 24, 2016: Journal of Bioscience and Bioengineering
Pranatchareeya Chankhamjon, Yuta Tsunematsu, Mie Ishida-Ito, Yuzuka Sasa, Florian Meyer, Daniela Boettger-Schmidt, Barbara Urbansky, Klaus-Dieter Menzel, Kirstin Scherlach, Kenji Watanabe, Christian Hertweck
The regioselective functionalization of non-activated carbon atoms such as aliphatic halogenation is a major synthetic challenge. A novel multifunctional enzyme catalyzing the geminal dichlorination of a methyl group was discovered in Aspergillus oryzae (Koji mold), an important fungus that is widely used for Asian food fermentation. A biosynthetic pathway encoded on two different chromosomes yields mono- and dichlorinated polyketides (diaporthin derivatives), including the cytotoxic dichlorodiaporthin as the main product...
September 19, 2016: Angewandte Chemie
Bárbara J Henriques, Tânia G Lucas, Cláudio M Gomes
Riboflavin, or vitamin B2, plays an important role in the cell as biological precursor of FAD and FMN, two important flavin cofactors which are essential for the structure and function of flavoproteins. Riboflavin has been used in therapeutic approaches of various inborn errors of metabolism, notably in metabolic disorders resulting either from defects in proteins involved in riboflavin metabolism and transport or from defects in flavoenzymes. The scope of this review is to provide an updated perspective of clinical cases in which riboflavin was used as a potential therapeutic agent in disorders affecting mitochondrial energy metabolism...
2016: Current Drug Targets
Ali Ryan
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...
August 3, 2016: British Journal of Pharmacology
Janis J Füller, René Röpke, Joern Krausze, Kim E Rennhack, Nils P Daniel, Wulf Blankenfeldt, Stefan Schulz, Dieter Jahn, Jürgen Moser
Violacein is a natural purple pigment of Chromobacterium violaceum with potential medical applications as antimicrobial, antiviral, and anticancer drugs. The initial step of violacein biosynthesis is the oxidative conversion of l-tryptophan into the corresponding α-imine catalyzed by the flavoenzyme l-tryptophan oxidase (VioA). A substrate-related (3-(1H-indol-3-yl)-2-methylpropanoic acid) and a product-related (2-(1H-indol-3-ylmethyl)prop-2-enoic acid) competitive VioA inhibitor was synthesized for subsequent kinetic and x-ray crystallographic investigations...
September 16, 2016: Journal of Biological Chemistry
Leila Birolo, Silvia Sacchi, Giovanni Smaldone, Gianluca Molla, Gabriella Leo, Laura Caldinelli, Luciano Pirone, Patrick Eliometri, Sonia Di Gaetano, Ida Orefice, Emilia Pedone, Piero Pucci, Loredano Pollegioni
The human flavoenzyme d-amino acid oxidase (hDAAO) degrades the NMDA-receptor modulator d-serine in the brain. Although hDAAO has been extensively characterized, little is known about its main modulator pLG72, a small protein encoded by the primate-specific gene G72 that has been associated with schizophrenia susceptibility. pLG72 interacts with neosynthesized hDAAO, promoting its inactivation and degradation. In this work, we used low-resolution techniques to characterize the surface topology of the hDAAO-pLG72 complex...
September 2016: FEBS Journal
Nadtanet Nunthaboot, Kiattisak Lugsanangarm, Somsak Pianwanit, Sirirat Kokpol, Fumio Tanaka, Takeshi Nakanishi, Masaya Kitamura
The structural and dynamical properties of five FMN binding protein (FBP) dimers, WT (wild type), E13K (Glu13 replaced by Lys), E13R (Glu13 replaced by Arg), E13T (Glu13 replaced by Thr) and E13Q (Glu13 replaced by Gln), were investigated using a method of molecular dynamics simulation (MDS). In crystal structures, subunit A (Sub A) and subunit B (Sub B) were almost completely equivalent in all of the five FBP dimers. However, the predicted MDS structures of the two subunits were not equivalent in solution, revealed by the distances and inter-planar angles between isoalloxazine (Iso) and aromatic amino acids (Trp32, Tyr35 and Trp106) as well as the hydrogen bonding pairs between Iso and nearby amino acids...
May 27, 2016: Computational Biology and Chemistry
Sona Garajova, Yann Mathieu, Maria Rosa Beccia, Chloé Bennati-Granier, Frédéric Biaso, Mathieu Fanuel, David Ropartz, Bruno Guigliarelli, Eric Record, Hélène Rogniaux, Bernard Henrissat, Jean-Guy Berrin
The enzymatic conversion of plant biomass has been recently revolutionized by the discovery of lytic polysaccharide monooxygenases (LPMOs) that carry out oxidative cleavage of polysaccharides. These very powerful enzymes are abundant in fungal saprotrophs. LPMOs require activation by electrons that can be provided by cellobiose dehydrogenases (CDHs), but as some fungi lack CDH-encoding genes, other recycling enzymes must exist. We investigated the ability of AA3_2 flavoenzymes secreted under lignocellulolytic conditions to trigger oxidative cellulose degradation by AA9 LPMOs...
2016: Scientific Reports
Melodie M Machovina, Robert J Usselman, Jennifer L DuBois
Members of the antibiotic biosynthesis monooxygenase family catalyze O2-dependent oxidations and oxygenations in the absence of any metallo- or organic cofactor. How these enzymes surmount the kinetic barrier to reactions between singlet substrates and triplet O2 is unclear, but the reactions have been proposed to occur via a flavin-like mechanism, where the substrate acts in lieu of a flavin cofactor. To test this model, we monitored the uncatalyzed and enzymatic reactions of dithranol, a substrate for the nogalamycin monooxygenase (NMO) from Streptomyces nogalater As with flavin, dithranol oxidation was faster at a higher pH, although the reaction did not appear to be base-catalyzed...
August 19, 2016: Journal of Biological Chemistry
Thomas Stoisser, Michael Brunsteiner, David K Wilson, Bernd Nidetzky
L-Lactate oxidase (LOX) belongs to a large family of flavoenzymes that catalyze oxidation of α-hydroxy acids. How in these enzymes the protein structure controls reactivity presents an important but elusive problem. LOX contains a prominent tyrosine in the substrate binding pocket (Tyr(215) in Aerococcus viridans LOX) that is partially responsible for securing a flexible loop which sequesters the active site. To characterize the role of Tyr(215), effects of substitutions of the tyrosine (Y215F, Y215H) were analyzed kinetically, crystallographically and by molecular dynamics simulations...
2016: Scientific Reports
Maria Soprano, Daniela Sorriento, Maria Rosaria Rusciano, Angela Serena Maione, Gennaro Limite, Pietro Forestieri, Dario D'Angelo, Matteo D'Alessio, Pietro Campiglia, Pietro Formisano, Guido Iaccarino, Roberto Bianco, Maddalena Illario
The discovery of the anti-proliferative activity of nelfinavir in HIV-free models has encouraged its investigation as anticancer drug. Although the molecular mechanism by which nelfinavir exerts antitumor activity is still unknown, its effects have been related to Akt inhibition. Here we tested the effects of nelfinavir on cell proliferation, viability and death in two human breast cancer cell lines and in human normal primary breast cells. To identify the mechanism of action of nelfinavir in breast cancer, we evaluated the involvement of the Akt pathway as well as the effects of nelfinavir on reactive oxygen species (ROS) production and ROS-related enzymes activities...
2016: PloS One
Maria Barile, Teresa Anna Giancaspero, Piero Leone, Michele Galluccio, Cesare Indiveri
Recent studies elucidated how riboflavin transporters and FAD forming enzymes work in humans and create a coordinated flavin network ensuring the maintenance of cellular flavoproteome. Alteration of this network may be causative of severe metabolic disorders such as multiple acyl-CoA dehydrogenase deficiency (MADD) or Brown-Vialetto-van Laere syndrome. A crucial step in the maintenance of FAD homeostasis is riboflavin uptake by plasma and mitochondrial membranes. Therefore, studies on recently identified human plasma membrane riboflavin transporters are presented, together with those in which still unidentified mitochondrial riboflavin transporter(s) have been described...
July 2016: Journal of Inherited Metabolic Disease
Philip A Ash, Holly A Reeve, Jonathan Quinson, Ricardo Hidalgo, Tianze Zhu, Ian J McPherson, Min-Wen Chung, Adam J Healy, Simantini Nayak, Thomas H Lonsdale, Katia Wehbe, Chris S Kelley, Mark D Frogley, Gianfelice Cinque, Kylie A Vincent
We describe a method for addressing redox enzymes adsorbed on a carbon electrode using synchrotron infrared microspectroscopy combined with protein film electrochemistry. Redox enzymes have high turnover frequencies, typically 10-1000 s(-1), and therefore, fast experimental triggers are needed in order to study subturnover kinetics and identify the involvement of transient species important to their catalytic mechanism. In an electrochemical experiment, this equates to the use of microelectrodes to lower the electrochemical cell constant and enable changes in potential to be applied very rapidly...
July 5, 2016: Analytical Chemistry
Sashka Krumova, Svetla Todinova, Milena Tileva, Latifa Bouzhir-Sima, Marten H Vos, Ursula Liebl, Stefka G Taneva
The bacterial thymidylate synthase ThyX is a multisubstrate flavoenzyme that takes part in the de novo synthesis of thymidylate in a variety of microorganisms. Herein we study the effect of FAD and dUMP binding on the thermal stability of wild type (WT) ThyX from the mesophilic Paramecium bursaria chlorella virus-1 (PBCV-1) and from the thermophilic bacterium Thermotoga maritima (TmThyX), and from two variants of TmThyX, Y91F and S88W, using differential scanning calorimetry. The energetics underlying these processes was characterized by isothermal titration calorimetry...
October 2016: International Journal of Biological Macromolecules
David Leys, Nigel S Scrutton
Flavins are arguably one of the most versatile cofactors by virtue of the reactivity of the isoalloxazine ring system. A varied catalogue of reactions for the diverse family of flavoenzymes has been reported, leading to unifying concepts in (long-range) electron transfer, oxygen activation, photochemistry and substrate redox reactions. Recent examples of unprecedented flavin chemistry have been reported that uncover hidden depths of the flavoenzyme chemical repertoire. These include ring expansion of flavin through prenylation and formation of the superoxidized flavin-N5 oxide species...
June 3, 2016: Current Opinion in Structural Biology
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