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Satoshi Hara, Soichiro Fukumura, Hiroshi Ichinose
6-Pyruvoyl tetrahydropterin synthase (PTS) converts 7, 8-dihydroneopterin triphosphate into 6-pyruvoyltetrahydropterin and is a critical enzyme for the de novo synthesis of tetrahydrobiopterin, an essential cofactor for aromatic amino acid hydroxylases and nitric oxide synthases. Neopterin derived from 7,8-dihydroneopterin triphosphate is secreted by monocytes/macrophages, and is a well-known biomarker for cellular immunity. Because PTS activity in the cell can be a determinant of neopterin production, here we used recombinant human PTS protein to investigate how its activity is regulated, especially depending on redox conditions...
December 4, 2018: Journal of Biological Chemistry
Yuxiang Zheng, Ting-Yu Lin, Gina Lee, Marcia N Paddock, Jessica Momb, Zhe Cheng, Qian Li, Dennis L Fei, Benjamin D Stein, Shivan Ramsamooj, Guoan Zhang, John Blenis, Lewis C Cantley
Mammalian folate metabolism is comprised of cytosolic and mitochondrial pathways with nearly identical core reactions, yet the functional advantages of such an organization are not well understood. Using genome-editing and biochemical approaches, we find that ablating folate metabolism in the mitochondria of mammalian cell lines results in folate degradation in the cytosol. Mechanistically, we show that QDPR, an enzyme in tetrahydrobiopterin metabolism, moonlights to repair oxidative damage to tetrahydrofolate (THF)...
November 29, 2018: Cell
Katja Zschiebsch, Caroline Fischer, Annett Wilken-Schmitz, Gerd Geisslinger, Keith Channon, Katrin Watschinger, Irmgard Tegeder
GTP cyclohydrolase (GCH1) governs de novo synthesis of the enzyme cofactor, tetrahydrobiopterin (BH4), which is essential for biogenic amine production, bioactive lipid metabolism and redox coupling of nitric oxide synthases. Overproduction of BH4 via upregulation of GCH1 in sensory neurons is associated with nociceptive hypersensitivity in rodents, and neuron-specific GCH1 deletion normalizes nociception. The translational relevance is revealed by protective polymorphisms of GCH1 in humans, which are associated with a reduced chronic pain...
November 18, 2018: Journal of Cellular and Molecular Medicine
Gaurav Taneja, Akash Sud, Narayan Pendse, Bishnu Panigrahi, Ashish Kumar, Arun K Sharma
The endothelium is a thin innermost layer of flat cells which release various mediators including endothelin-1 (ET-1), prostanoids, von Willebrand factor (vWF) and endothelium-derived relaxing factor (EDRF; nitric oxide) to regulate vascular tone. Endothelial nitric oxide synthase (eNOS) is a key enzyme that generates nitric oxide (NO). NO maintains vascular homeostasis and cardiac functions by influencing major vascular protective properties such as anti-platelet, anti-proliferative, anti-migratory, antioxidant and anti-inflammatory action in vessels...
November 17, 2018: Cardiovascular Toxicology
Jin Hee Jeong, Nichole Lee, Matthew A Tucker, Paula Rodriguez-Miguelez, Jacob Looney, Jeffrey Thomas, Casandra C Derella, Ahmed A El-Marakby, Jacqueline B Musall, Jennifer C Sullivan, Kathleen T McKie, Caralee Forseen, Gareth W Davison, Ryan A Harris
Cystic fibrosis (CF) is a genetic disorder associated with a wide range of systemic complications, including vascular endothelial dysfunction. Nitric oxide (NO) plays a major role in maintaining vascular function and tetrahydrobiopterin (BH4) is a critical determinant of NO bioavailability. Thus, the purpose of this study was to investigate the effects of oral administration of BH4 on endothelial function in patients with CF. METHODS: 29 patients with CF (18 ± 8 yrs old) and 29 healthy matched controls were recruited...
November 15, 2018: Journal of Applied Physiology
Joshua D McDonald, Eunice Mah, Chureeporn Chitchumroonchokchai, Priyankar Dey, Allison N Labyk, Frederick A Villamena, Jeff S Volek, Richard S Bruno
Postprandial hyperglycemia (PPH) transiently impairs vascular endothelial function (VEF) in an oxidative stress-dependent manner by decreasing nitric oxide (NO• ) bioavailability. Dairy milk and its proteins attenuate PPH, but whether this improves VEF is unknown. We hypothesized that dairy milk, mediated by its whey and/or casein proteins, improves VEF by attenuating PPH-induced oxidative stress that otherwise decreases NO• bioavailability. A randomized, cross-over trial was conducted in adults with prediabetes (n=23) who ingested glucose (75 g, GLU) alone or with 473 mL of non-fat dairy milk (MILK) or isonitrogenous (16...
September 25, 2018: Journal of Nutritional Biochemistry
Shane J F Cronin, Corey Seehus, Adelheid Weidinger, Sebastien Talbot, Sonja Reissig, Markus Seifert, Yann Pierson, Eileen McNeill, Maria Serena Longhi, Bruna Lenfers Turnes, Taras Kreslavsky, Melanie Kogler, David Hoffmann, Melita Ticevic, Débora da Luz Scheffer, Luigi Tortola, Domagoj Cikes, Alexander Jais, Manu Rangachari, Shuan Rao, Magdalena Paolino, Maria Novatchkova, Martin Aichinger, Lee Barrett, Alban Latremoliere, Gerald Wirnsberger, Guenther Lametschwandtner, Meinrad Busslinger, Stephen Zicha, Alexandra Latini, Simon C Robson, Ari Waisman, Nick Andrews, Michael Costigan, Keith M Channon, Guenter Weiss, Andrey V Kozlov, Mark Tebbe, Kai Johnsson, Clifford J Woolf, Josef M Penninger
Genetic regulators and environmental stimuli modulate T cell activation in autoimmunity and cancer. The enzyme co-factor tetrahydrobiopterin (BH4) is involved in the production of monoamine neurotransmitters, the generation of nitric oxide, and pain1,2 . Here we uncover a link between these processes, identifying a fundamental role for BH4 in T cell biology. We find that genetic inactivation of GTP cyclohydrolase 1 (GCH1, the rate-limiting enzyme in the synthesis of BH4) and inhibition of sepiapterin reductase (the terminal enzyme in the synthetic pathway for BH4) severely impair the proliferation of mature mouse and human T cells...
November 7, 2018: Nature
Dennis J Stuehr, Mohammad Mahfuzul Haque
This review briefly summarizes what was known about NO synthase (NOS) enzymology at the time of the Nobel prize award in 1998, and then discusses from the Author's perspective some of the advances in NOS enzymologic research over the subsequent twenty years, focused on five aspects: The maturation process of NOS enzymes and its regulation; the mechanism of NO synthesis; the redox roles played by the 6R-tetrahydrobiopterin cofactor; the role of protein conformational behavior in enabling NOS electron transfer and its regulation by NOS structural elements and calmodulin; and the catalytic cycling pathways of NOS enzymes, their regulation, and their influence on NOS activity...
November 6, 2018: British Journal of Pharmacology
Geoffrey Urbanski, Antoine Caillon, Caroline Poli, Gilles Kauffenstein, Marc-Antoine Begorre, Laurent Loufrani, Daniel Henrion, Cristina Belizna
BACKGROUND: Antiphospholipid syndrome is associated with endothelial dysfunction, which leads to thrombosis and early atheroma. Given that hydroxychloroquine has anti-thrombotic properties in lupus, we hypothesized that it could reduce endothelial dysfunction in an animal model of antiphospholipid syndrome. We evaluated the effect of hydroxychloroquine in preventing endothelial dysfunction in a mouse model of antiphospholipid syndrome. METHODS: Antiphospholipid syndrome was induced by an injection of monoclonal anti-beta-2-GPI antibodies...
2018: PloS One
Kristen D Brantley, Teresa D Douglas, Rani H Singh
BACKGROUND: People with Phenylketonuria (PKU) who respond to tetrahydrobiopterin (BH4) often decrease dependence on medical food (MF) following increased phenylalanine (phe) tolerance. Responders to BH4 may experience a reduction in certain nutrients if not compensated through intact foods or supplements. This study investigated B6, B12, folate, and iron status based on blood levels and dietary intake in patients with PKU responsive to BH4 over 1 year. METHODS: Fifty-eight patients with PKU, ages 4-50 years were recruited and initiated on BH4 therapy...
October 30, 2018: Orphanet Journal of Rare Diseases
Heiko Brennenstuhl, Sabine Jung-Klawitter, Birgit Assmann, Thomas Opladen
Neurotransmitter deficiencies are rare neurological disorders with clinical onset during childhood. The disorders are caused by genetic defects in the enzymes involved in synthesis, degradation, or transport of neurotransmitters or by defects in the cofactor biosynthesis such as tetrahydrobiopterin (BH4 ). With the newly described DNAJC12 deficiency, a chaperon-associated neurotransmitter disorder, the pathophysiological spectrum has been broadened. All deficiencies result in a lack of monoamine neurotransmitters, especially dopamine and its products, with a subset leading to decreased levels of serotonin...
October 29, 2018: Neuropediatrics
Joshua D McDonald, Eunice Mah, Priyankar Dey, Bryan D Olmstead, Geoffrey Y Sasaki, Frederick A Villamena, Richard S Bruno
Postprandial hyperglycemia (PPH) transiently impairs vascular endothelial function (VEF) in an oxidative-stress-dependent manner by decreasing nitric oxide (NO• ) bioavailability. Dairy milk, regardless of fat content, attenuates PPH, but whether this improves VEF by limiting oxidative stress responses that otherwise decrease NO• bioavailability is not known. We hypothesized that nonfat and full-fat dairy milk would similarly improve VEF by attenuating PPH-induced oxidative stress that otherwise decreases NO• biosynthesis and bioavailability...
October 16, 2018: Journal of Nutritional Biochemistry
Penelope D Manta-Vogli, Yannis Dotsikas, Yannis L Loukas, Kleopatra H Schulpis
Phenylalanine hydroxylase (PAH) deficiency, commonly named phenylketonuria (PKU) is a disorder of phenylalanine (Phe) metabolism inherited with an autosomal recessive trait. It is characterized by high blood and cerebral Phe levels, resulting in intellectual disabilities, seizures, etc. Early diagnosis and treatment of the patients prevent major neuro-cognitive deficits. Treatment consists of a lifelong restriction of Phe intake, combined with the supplementation of special medical foods, such as Amino Acid medical food (AA-mf), enriched in tyrosine (Tyr) and other amino acids and nutrients to avoid nutritional deficits...
October 25, 2018: Nutritional Neuroscience
Andreia Z Chignalia, Ayman Isbatan, Milan Patel, Richard Ripper, Jordan Sharlin, Joelle Shosfy, Barry A Borlaug, Randal O Dull
  Acute increases in left ventricular end diastolic pressure (LVEDP) can induce pulmonary edema (PE). The mechanism(s) for this rapid onset edema may involve more than just increased fluid filtration. Lung endothelial cell permeability is regulated by pressure-dependent activation of nitric oxide synthase (NOS). Herein, we demonstrate that pressure-dependent NOS activation contributes to vascular failure and PE in a model of acute heart failure (AHF) caused by hypertension. Methods and Results:  Male Sprague Dawley rats were anesthetized and mechanically ventilated...
October 24, 2018: Bioscience Reports
Osamu Sakamoto, Natsuko Arai-Ichinoi, Kei Murayama, Shigeo Kure
No abstract text is available yet for this article.
October 2018: Pediatrics International: Official Journal of the Japan Pediatric Society
A C Keller, L A Knaub, R L Scalzo, S E Hull, A E Johnston, L A Walker, J E B Reusch
In the vasculature, sedentary behavior leads to endothelial abnormalities, resulting in elevated cardiovascular disease risk. Endothelial nitric oxide synthase (eNOS) aberrations characterize endothelial dysfunction; eNOS also regulates mitochondrial function. We hypothesized that sepiapterin (a precursor to eNOS cofactor tetrahydrobiopterin (BH4 )) supplementation would improve endothelium-dependent vascular relaxation in sedentary animals via modulation of NOS function and mitochondrial activity. Sedentary male Wistar rats were fed ad libitum for a total of 10 weeks...
2018: Oxidative Medicine and Cellular Longevity
Filippo Manti, Francesca Nardecchia, Sabina Barresi, Martina Venditti, Simone Pizzi, Fadi F Hamdan, Nenad Blau, Alberto Burlina, Marco Tartaglia, Vincenzo Leuzzi
INTRODUCTION: Clathrins play a key role in endocytosis, recycling, and trafficking as well as the generation of presynaptic vesicles. We report a new clinical condition associated with a de novo variant in the CLTC gene, which encodes the clathrin heavy polypeptide. CASE REPORT: This 30-year-old woman presented with a developmental disorder during childhood that progressed to mild cognitive decline in late childhood and relapsing-remitting hypokinetic-rigid syndrome with severe achalasia, weight loss, and mood disorder in adulthood...
October 11, 2018: Parkinsonism & related Disorders
Saki Kasuga, Daijiro Kabata, Tomoko Sakaguchi, Satoshi Kudoh, Satsuki Nishigaki, Yusuke Higa, Shiori Fujikawa, Hiroko Fujitani, Ayumi Shintani, Takashi Hamazaki, Haruo Shintaku
BACKGROUND: Pteridines are metabolites of tetrahydrobiopterin, which serves as co-enzyme of nitric oxide synthase. We sought to investigate the usefulness of pteridines as biomarkers for childhood asthma control. METHODS: We conducted a single-center prospective cohort study involving 168 asthmatic children aged 4-17 years who visited the periodical asthma checkup program. Serum neopterin and biopterin levels were measured as pteridines at each visit along with measurement of FeNO, respiratory function tests, nasal eosinophil test, blood eosinophil count, and IgE level...
October 5, 2018: Allergology International: Official Journal of the Japanese Society of Allergology
Ania C Muntau, Marcel du Moulin, Francois Feillet
BACKGROUND: Treatment of phenylketonuria (PKU) with sapropterin dihydrochloride in responsive patients from an early age can have many advantages for the patient over dietary restriction alone. Accordingly, approval of sapropterin in the European Union was extended in 2015 to include patients aged 0-4 years, bringing the treatment age range in line with that in the USA and providing an additional treatment option for those patients with PKU who are responsive or partially responsive to treatment with sapropterin...
September 29, 2018: Orphanet Journal of Rare Diseases
Jade Bailey, Simon Davis, Andrew Shaw, Marina Diotallevi, Roman Fischer, Matthew A Benson, Hanneng Zhu, James Brown, Shoumo Bhattacharya, Benedikt M Kessler, Keith M Channon, Mark J Crabtree
Nitric Oxide (NO) is an intracellular signalling mediator, which affects many biological processes via the posttranslational modification of proteins through S-nitrosation. The availability of NO and NOS-derived reactive oxygen species (ROS) from enzymatic uncoupling are determined by the NO synthase cofactor Tetrahydrobiopterin (BH4). Here, using a global proteomics "biotin-switch" approach, we identified components of the ubiquitin-proteasome system to be altered via BH4-dependent NO signalling by protein S-nitrosation...
September 25, 2018: Scientific Reports
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