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https://www.readbyqxmd.com/read/29595949/orotidine-5-monophosphate-decarboxylase-probing-the-limits-of-the-possible-for-enzyme-catalysis
#1
John P Richard, Tina L Amyes, Archie C Reyes
The mystery associated with catalysis by what were once regarded as protein black boxes, diminished with the X-ray crystallographic determination of the three-dimensional structures of enzyme-substrate complexes. The report that several high-resolution X-ray crystal structures of orotidine 5'-monophosphate decarboxylase (OMPDC) failed to provide a consensus mechanism for enzyme-catalyzed decarboxylation of OMP to form uridine 5'-monophosphate, therefore, provoked a flurry of controversy. This controversy was fueled by the enormous 1023 -fold rate acceleration for this enzyme, which had " jolted many biochemists' assumptions about the catalytic potential of enzymes...
March 29, 2018: Accounts of Chemical Research
https://www.readbyqxmd.com/read/29574270/self-assembling-behavior-of-pyrimidine-analogues-unveiling-the-factors-behind-morphological-diversity
#2
Pavel Banerjee, Arghajit Pyne, Siddhartha Pal, Chandan Kumar Karan, Nilmoni Sarkar
Studying the self-assembly of uracil derivatives has great importance in biochemistry and nanotechnology. Now, in order to architect unique and interesting nucleobase nanostructures, herein, we report a simple, yet robust uracil moiety based platform which is potentially capable to self-assemble into fibrils. The system is validated using eight uracil moiety derivatives and the effect is examined via fluorescence lifetime imaging microscopy (FLIM), field emission scanning electron microscopy (FESEM), steady state DCM fluorescence and fluorescence correlation spectroscopy (FCS)...
March 17, 2018: Journal of Colloid and Interface Science
https://www.readbyqxmd.com/read/29542003/scutellaria-baicalensis-regulates-ffa-metabolism-to-ameliorate-nafld-through-the-ampk-mediated-srebp-signaling-pathway
#3
Qian Chen, Mengyang Liu, Haiyang Yu, Jian Li, Sijian Wang, Yi Zhang, Feng Qiu, Tao Wang
Scutellaria baicalensis has been reported to improve the lipid metabolism of high-fat diet-induced liver dysfunction, but direct evidence is rare. This study aimed to explore the effects and mechanisms of S. baicalensis and its major constituent baicalin on hepatic lipotoxicity. KK-Ay mice and orotic acid (OA)-induced nonalcoholic fatty liver disease (NAFLD) rats were used to evaluate lipid metabolism regulatory effects. Sodium oleate-induced triglyceride-accumulated HepG2 cells were used for the mechanism study, pretreated with or without compound C or STO-609 or transfected with liver kinase B1 (LKB1) siRNA...
March 14, 2018: Journal of Natural Medicines
https://www.readbyqxmd.com/read/29533816/qm-mm-reveals-the-sequence-of-substrate-binding-during-oprt-action
#4
N N Subrahmanyeswara Rao, Parag A Deshpande
Computational investigation of orotate phosphoribosyltransferase (OPRT) action, an enzymatic reaction between phosphoribosyl pyrophosphate (PRPP) and orotic acid (OA) to yield orotidine 5'-monophosphate (OMP), was carried out. Insights into the pathways of the substrate attack step of the reaction were developed under the quantum mechanics/molecular mechanics framework with S. cerevisiae strain as the representative enzyme bearer. Four pathways were proposed for PRPP and OA binding differing in the sequence of PRPP, OA and Mg2+ ion complexation with OPRT...
February 24, 2018: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/29526616/n-acetylcysteine-and-vitamin-e-rescue-animal-longevity-and-cellular-oxidative-stress-in-pre-clinical-models-of-mitochondrial-complex-i-disease
#5
Erzsebet Polyak, Julian Ostrovsky, Min Peng, Stephen D Dingley, Mai Tsukikawa, Young Joon Kwon, Shana E McCormack, Michael Bennett, Rui Xiao, Christoph Seiler, Zhe Zhang, Marni J Falk
Oxidative stress is a known contributing factor in mitochondrial respiratory chain (RC) disease pathogenesis. Yet, no efficient means exists to objectively evaluate the comparative therapeutic efficacy or toxicity of different antioxidant compounds empirically used in human RC disease. We postulated that pre-clinical comparative analysis of diverse antioxidant drugs having suggested utility in primary RC disease using animal and cellular models of RC dysfunction may improve understanding of their integrated effects and physiologic mechanisms, and enable prioritization of lead antioxidant molecules to pursue in human clinical trials...
February 23, 2018: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/29514433/liver-metabolic-perturbations-of-heat-stressed-lactating-dairy-cows
#6
Caiyun Fan, Di Su, He Tian, Xiaojiao Li, Yu Li, Lei Ran, Ruiting Hu, Jianbo Cheng
Objective: The objective of the present study was to elucidate the mechanism underlying liver metabolic perturbations in dairy cows exposed to heat stress (HS). Method: Liquid chromatography mass spectrometry (LC-MS) was used to analyze metabolic differences in livers of 20 dairy cows, with and without exposure to HS. Results: The results revealed 33 potential metabolite candidate biomarkers for the detection of HS in dairy cows. Fifteen of these metabolites (glucose, lactate, pyruvate, acetoacetate, β-hydroxybutyrate (BHBA), fumaric acid, citric acid, choline, glycine, proline, isoleucine, leucine, urea, creatinine, and orotic acid) were previously found to be potential biomarkers of HS in plasma or milk, discriminating dairy cows with and without HS...
March 2, 2018: Asian-Australasian Journal of Animal Sciences
https://www.readbyqxmd.com/read/29493158/-identification-of-biomarkers-in-urine-of-rats-with-spleen-qi-deficiency-and-biological-significance
#7
Wu-Ping Liu, Chan-Yi Li, Jing Huang, Jing-Zhu Liao, Wen-Jie Ma, Hong-Yuan Chen, Wen Rui
To identify biomarkers for spleen Qi deficiency by analyzing small molecule metabolites in urine, in order to expound the relationship between biomarkers and metabolic pathways. The spleen Qi deficiency model was established through dietary restriction and overstrain. All of the rats received D-xylose absorption experiment and blood routine test. Urine samples were collected in the next day. The urine samples were analyzed using UPLC-Q-TOF-MS to obtain the dataset of urine metabolic group. Principal component analysis (PCA), orthogonal partialleast squares-discriminant analysis (OPLS-DA) and other multivariate statistical methods were employed to evaluate the quality of the dataset and screen out potential biomarkers of spleen Qi deficiency...
December 2017: Zhongguo Zhong Yao za Zhi, Zhongguo Zhongyao Zazhi, China Journal of Chinese Materia Medica
https://www.readbyqxmd.com/read/29486129/pyrimidine-nucleotide-synthesis-in-the-emerging-pathogen-i-pseudomonas-monteilii-i
#8
Jayendra Chunduru, Thomas P West
Regulation of pyrimidine biosynthesis by pyrimidines in the emerging, opportunistic human pathogen <i>Pseudomonas monteilii</i> ATCC 700476 was evident. When wild type cells were grown on succinate in the presence of uracil or orotic acid, all five pyrimidine biosynthetic enzyme activities were depressed while three enzyme activities decreased in glucose-grown cells supplemented with uracil or orotic acid compared to unsupplemented cells. Pyrimidine limitation of succinate-grown or glucose-grown pyrimidine auxotrophic cells lacking orotate phosphoribosyltransferase activity resulted in more than a doubling of the pyrimidine biosynthetic enzyme activities relative to their activities in uracil-grown cells...
February 27, 2018: Canadian Journal of Microbiology
https://www.readbyqxmd.com/read/29446045/effects-of-extracellular-orotic-acid-on-acute-contraction-induced-adaptation-patterns-in-c2c12-cells
#9
Thomas Beiter, Jens Hudemann, Christof Burgstahler, Andreas M Nieß, Barbara Munz
Dietary administration of orotic acid (OA), an intermediate in the pyrimidine biosynthetic pathway, is considered to provide a wide range of beneficial effects, including cardioprotection and exercise adaptation. Its mechanisms of action, when applied extracellularly, however, are barely understood. In this study, we evaluated potential effects of OA on skeletal muscle using an in vitro contraction model of electrically pulse-stimulated (EPS) C2C12 myotubes. By analyzing a subset of genes representing inflammatory, metabolic, and structural adaptation pathways, we could show that OA supplementation diminishes the EPS-provoked expression of inflammatory transcripts (interleukin 6, Il6; chemokine (C-X-C Motif) ligand 5, Cxcl5), and attenuated transcript levels of nuclear receptor subfamily 4 group A member 3 (Nr4A3), early growth response 1 (Egr1), activating transcription factor 3 (Atf3), and fast-oxidative MyHC-IIA isoform (Myh2)...
February 14, 2018: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/29433939/targeted-mrna-therapy-for-ornithine-transcarbamylase-deficiency
#10
Mary G Prieve, Pierrot Harvie, Sean D Monahan, Debashish Roy, Allen G Li, Teri L Blevins, Amber E Paschal, Matt Waldheim, Eric C Bell, Anna Galperin, Jean-Rene Ella-Menye, Michael E Houston
We describe a novel, two-nanoparticle mRNA delivery system and show that it is highly effective as a means of intracellular enzyme replacement therapy (i-ERT) using a murine model of ornithine transcarbamylase deficiency (OTCD). Our Hybrid mRNA Technology delivery system (HMT) comprises an inert lipid nanoparticle that protects the mRNA from nucleases in the blood as it distributes to the liver and a polymer micelle that targets hepatocytes and triggers endosomal release of mRNA. This results in high-level synthesis of the desired protein specifically in the liver...
January 4, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29345914/comparative-analysis-of-epa-dha-pl-forage-and-liposomes-in-orotic-acid-induced-nonalcoholic-fatty-liver-rats-and-their-related-mechanisms
#11
COMPARATIVE STUDY
Mengru Chang, Tiantian Zhang, Xiuqing Han, Qingjuan Tang, Teruyoshi Yanagita, Jie Xu, Changhu Xue, Yuming Wang
Nonalcoholic fatty liver disease (NAFLD) has become one predictive factor of death from various illnesses. The present study was to comparatively investigate the effects of eicosapentaenoic acid-enriched and docosahexaenoic acid-enriched phospholipids forage (EPA-PL and DHA-PL) and liposomes (lipo-EPA and lipo-DHA) on NAFLD and demonstrate the possible protective mechanisms involved. The additive doses of EPA-PL and DHA-PL in all treatment groups were 1% of total diets, respectively. The results showed that Lipo-EPA could significantly improve hepatic function by down-regulating orotic acid-induced serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels by 55...
February 14, 2018: Journal of Agricultural and Food Chemistry
https://www.readbyqxmd.com/read/29331465/genome-wide-association-study-for-milk-infrared-wavenumbers
#12
Qiuyu Wang, Henk Bovenhuis
Individual wavenumbers of the infrared (IR) spectra of bovine milk have been shown to be moderately to highly heritable. The objective of this study was to identify genomic regions associated with individual milk IR wavenumbers. This is expected to provide information about the genetic background of milk composition and give insight in the relation between IR wavenumbers and milk components. For this purpose, a genome-wide association study was performed for a selected set of 50 individual IR wavenumbers measured on 1,748 Dutch Holstein cows...
March 2018: Journal of Dairy Science
https://www.readbyqxmd.com/read/29315647/antiviral-activity-of-a771726-the-active-metabolite-of-leflunomide-against-jun%C3%A3-n-virus
#13
Claudia S Sepúlveda, Cybele C García, Elsa B Damonte
The aim of this study was to investigate the effect of A771726, the active metabolite of leflunomide, (CONICET-UBA), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad against the infection with Junín virus (JUNV), agent of Argentine hemorrhagic fever (AHF). The treatment with non-cytotoxic concentrations of A771726 of Vero and A549 cells infected with JUNV inhibited virus replication in a dose-dependent manner, as determined by virus yield reduction assay. The antiviral effectiveness of A771726 was not importantly affected by the multiplicity of infection and the virus strain...
May 2018: Journal of Medical Virology
https://www.readbyqxmd.com/read/29279777/ornithine-transcarbamylase-deficiency-if-at-first-you-do-not-diagnose-try-and-try-again
#14
Christan D Santos, Robert A Ratzlaff, Jennifer C Meder, Paldeep S Atwal, Nicole E Joyce
Ornithine transcarbamylase (OTC) deficiency is well known for its diagnosis in the neonatal period. Presentation often occurs after protein feeding and manifests as poor oral intake, vomiting, lethargy progressing to seizure, respiratory difficulty, and eventually coma. Presentation at adulthood is rare (and likely underdiagnosed); however, OTC deficiency can be life-threatening and requires prompt investigation and treatment. Reports and guidelines are scarce due to its rarity. Here, we present a 59-year-old woman with a past history of irritable bowel syndrome who underwent a reparative operation for rectal prolapse and enterocele...
2017: Case Reports in Critical Care
https://www.readbyqxmd.com/read/29274060/biosynthesis-of-mono-acylated-mannosylerythritol-lipid-in-an-acyltransferase-gene-disrupted-mutant-of-pseudozyma-tsukubaensis
#15
Azusa Saika, Yu Utashima, Hideaki Koike, Shuhei Yamamoto, Takahide Kishimoto, Tokuma Fukuoka, Tomotake Morita
The basidiomycetous yeast genus Pseudozyma produce large amounts of mannosylerythritol lipids (MELs), which are biosurfactants. A few Pseudozyma strains produce mono-acylated MEL as a minor compound using excess glucose as the sole carbon source. Mono-acylated MEL shows higher hydrophilicity than di-acylated MEL and has great potential for aqueous applications. Recently, the gene cluster involved in the MEL biosynthesis pathway was identified in yeast. Here, we generated an acyltransferase (PtMAC2) deletion strain of P...
February 2018: Applied Microbiology and Biotechnology
https://www.readbyqxmd.com/read/29215882/theoretical-models-for-quantitative-description-of-the-acid-base-equilibria-of-the-5-6-substituted-uracils
#16
Margarita G Ilyina, Edward M Khamitov, Sergey P Ivanov, Akhat G Mustafin, Sergey L Khursan
The acidities of 18 5,6-substituted uracils have been numerically estimated as pKa values in terms of three theoretical models. The first scheme includes the calculation of the gas-phase acidity of uracil with the G3MP2B3 method and taking into account the solvent effect using the polarizable continuum approximation PCM(SMD)-TPSS/aug-cc-pVTZ. The second model is one step and implies calculation of the free Gibbs energies of the hydrate complex of uracil (and its anion) with 5 water molecules by the TPSS/aug-cc-pVTZ method...
January 11, 2018: Journal of Physical Chemistry. A
https://www.readbyqxmd.com/read/29197344/lactation-related-metabolic-mechanism-investigated-based-on-mammary-gland-metabolomics-and-4-biofluids-metabolomics-relationships-in-dairy-cows
#17
Hui-Zeng Sun, Kai Shi, Xue-Hui Wu, Ming-Yuan Xue, Zi-Hai Wei, Jian-Xin Liu, Hong-Yun Liu
BACKGROUND: Lactation is extremely important for dairy cows; however, the understanding of the underlying metabolic mechanisms is very limited. This study was conducted to investigate the inherent metabolic patterns during lactation using the overall biofluid metabolomics and the metabolic differences from non-lactation periods, as determined using partial tissue-metabolomics. We analyzed the metabolomic profiles of four biofluids (rumen fluid, serum, milk and urine) and their relationships in six mid-lactation Holstein cows and compared their mammary gland (MG) metabolomic profiles with those of six non-lactating cows by using gas chromatography-time of flight/mass spectrometry...
December 2, 2017: BMC Genomics
https://www.readbyqxmd.com/read/29178779/synthesis-of-bis-phosphate-iminoaltritol-enantiomers-and-structural-characterization-with-adenine-phosphoribosyltransferase
#18
Lawrence D Harris, Rajesh K Harijan, Rodrigo G Ducati, Gary B Evans, Brett M Hirsch, Vern L Schramm
Phosphoribosyl transferases (PRTs) are essential in nucleotide synthesis and salvage, amino acid, and vitamin synthesis. Transition state analysis of several PRTs has demonstrated ribocation-like transition states with a partial positive charge residing on the pentose ring. Core chemistry for synthesis of transition state analogues related to the 5-phospho-α-d-ribosyl 1-pyrophosphate (PRPP) reactant of these enzymes could be developed by stereospecific placement of bis-phosphate groups on an iminoaltritol ring...
January 19, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/29158663/a-comparative-pharmacokinetic-and-tolerability-analysis-of-the-novel-orotic-acid-salt-form-of-tenofovir-disoproxil-and-the-fumaric-acid-salt-form-in-healthy-subjects
#19
Yu Kyong Kim, Mun Ju Choi, Tae Young Oh, Kyung-Sang Yu, SeungHwan Lee
A novel orotic acid salt form of tenofovir disoproxil (DA-2802) was developed and is expected to replace the fumaric acid salt form. The pharmacokinetic (PK) characteristics and tolerability profiles of DA-2802 were compared to those of tenofovir disoproxil fumarate (TDF, Viread® ) in healthy subjects. A randomized, open-label, single-dose study was conducted in 36 healthy subjects using a two-treatment, two-period, and two-sequence crossover design. Subjects received a single oral dose of 319 mg DA-2802 or 300 mg TDF, during each period, with a 7-day washout...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/28939132/peak-hyperammonemia-and-atypical-acute-liver-failure-the-eruption-of-an-urea-cycle-disorder-during-hyperemesis-gravidarum
#20
REVIEW
Nicolas Weiss, Fanny Mochel, Marika Rudler, Sophie Demeret, Pascal Lebray, Filomena Conti, Damien Galanaud, Chris Ottolenghi, Jean-Paul Bonnefont, Marc Dommergues, Jacques Bernuau, Dominique Thabut
Inborn urea cycle disorders are under-recognised metabolic causes of hyperammonemia in adults. A 28-year-old primigravida, seven weeks pregnant, affected by hyperemesis gravidarum developed acute liver injury (ALI) and then acute liver failure (ALF) in less than 48 h. Because the patient developed atypical features, especially mildly elevated aminotransferases contrasting with very high blood ammonia levels (281 μmol/L), concomitant with normal serum creatinine, an inborn error of metabolism was suspected...
September 20, 2017: Journal of Hepatology
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