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metabolizing enzymes defects

Iwai Ohbayashi, Shaobai Huang, Hidehiro Fukaki, Xiaomin Song, Song Sun, Miyo Terao Morita, Masao Tasaka, A Harvey Millar, Masahiko Furutani
Pyruvate dehydrogenase (PDH) is the first enzyme (E1) of the PDH complex (PDC). This multienzyme complex contains E1, E2 and E3 components and controls the entry of carbon into the mitochondrial tricarboxylic acid (TCA) cycle to enable cellular energy production. The E1 component of PDC is composed of an E1α catalytic subunit and an E1β regulatory subunit. In Arabidopsis thaliana, there are two mitochondrial E1α homologs encoded by IAA-Alanine Resistant 4 (IAR4) and IAR4-LIKE (IAR4L), and one mitochondrial E1β homolog...
March 20, 2019: Plant Physiology
Widad Dantoft, Kevin A Robertson, W John Watkins, Birgit Strobl, Peter Ghazal
Molecular determinants underlying interferon (IFN)-macrophage biology can help delineate enzyme systems, pathways and mechanisms for enabling host-directed therapeutic approaches against infection. Notably, while the IFN antiviral response is known to be directly coupled to mevalonate-sterol biosynthesis, mechanistic insight for providing host pathway-therapeutic targets remain incomplete. Here, we show that Nampt and Sirt6 are coordinately regulated upon immune activation of macrophages and contribute to the IFN-sterol antiviral response...
2019: Frontiers in Microbiology
Marguerite Blignaut, Ben Loos, Stanley W Botchway, Anthony W Parker, Barbara Huisamen
The absence of Ataxia-Telangiectasia mutated protein kinase (ATM) is associated with neurological, metabolic and cardiovascular defects. The protein has been associated with mitochondria and its absence results in mitochondrial dysfunction. Furthermore, it can be activated in the cytosol by mitochondrial oxidative stress and mediates a cellular anti-oxidant response through the pentose phosphate pathway (PPP). However, the precise location and function of ATM within mitochondria and its role in oxidative phosphorylation is still unknown...
March 18, 2019: Scientific Reports
James Chon, Martha S Field, Patrick J Stover
Genomic instability is implicated in the etiology of several deleterious health outcomes including megaloblastic anemia, neural tube defects, and neurodegeneration. Uracil misincorporation and its repair are known to cause genomic instability by inducing DNA strand breaks leading to apoptosis, but there is emerging evidence that uracil incorporation may also result in broader modifications of gene expression, including: changes in transcriptional stalling, strand break-mediated transcriptional upregulation, and direct promoter inhibition...
February 27, 2019: DNA Repair
Romain Laurian, Karine Dementhon, Bastien Doumèche, Alexandre Soulard, Thierry Noel, Marc Lemaire, Pascale Cotton
The pathogenic yeast Candida albicans is both a powerful commensal and a pathogen of humans that can infect wide range of organs and body sites. Metabolic flexibility promotes infection and commensal colonization by this opportunistic pathogen. Yeast cell survival depends upon assimilation of fermentable and non-fermentable locally available carbon sources. Physiologically relevant sugars like glucose and fructose are present at low levels in host niches. However, because glucose is the preferred substrate for energy and biosynthesis of structural components, its efficient detection and metabolism are fundamental for the metabolic adaptation of the pathogen...
2019: Frontiers in Microbiology
Sanjit K Dhar, Ines Batinic-Haberle, Daret K St Clair
Mitochondria are major sites of energy metabolism that influence numerous cellular events including immunity and cancer development. Previously, we reported that the mitochondrion specific antioxidant enzyme, manganese containing superoxide dismutase (MnSOD), has dual roles in early- and late- carcinogenesis stages. However, how defective MnSOD impacts the chain of events that leads to cell transformation in pathologically normal epidermal cells that have been exposed to carcinogens is unknown. Here, we show that UVB radiation causes nitration and inactivation of MnSOD leading to mitochondrial injury and mitophagy...
March 11, 2019: Journal of Biological Chemistry
Assaf Ben-Meir, Kyunga Kim, Rosanne McQuaid, Navid Esfandiari, Yaakov Bentov, Robert F Casper, Andrea Jurisicova
Over the past four decades, due to cultural and social changes, women in the developed world have significantly delayed childbirth. This trend is even worse for patients who attend infertility clinics. It is well-known that live birth rates in women older than 35 are significantly lower than in those younger, both naturally and with assisted reproduction. Fertility decline is, in part, due to an increase in oocyte aneuploidy that leads to a reduced embryo quality, as well as an increased incidence of miscarriages and birth defects...
March 8, 2019: Antioxidants (Basel, Switzerland)
Jianjun Zhao, Yuzhu Han, Xingyu Ma, Yang Zhou, Shukai Yuan, Qian Shen, Guogen Ye, Hongrun Liu, Penghui Fu, Gongwei Zhang, Bingke Qiao, Anfang Liu
Epithelial morphogenesis is a common feature in various organs and contributes to functional formation. However, the molecular mechanisms behind epithelial morphogenesis remain largely unknown. Mammary gland is an excellent model system to investigate the molecular mechanisms of epithelial morphogenesis. In this study, we found that cysteine dioxygenase (CDO), a key enzyme in cysteine oxidative metabolism, was involved in mammary epithelial morphogenesis. CDO knockout (KO) females exhibited severe defects in mammary branching morphogenesis and ductal elongation, resulting in poor lactation...
February 18, 2019: IScience
Ma'atem B Fofou-Caillierez, Rosa-Maria Guéant-Rodriguez, Jean-Marc Alberto, Céline Chéry, Thomas Josse, Philippe Gérard, Thierry Forges, Bernard Foliguet, François Feillet, Jean-Louis Guéant
BACKGROUND: The risk of neural tube defects (NTDs) is influenced by nutritional factors and genetic determinants of one-carbon metabolism. A key pathway of this metabolism is the vitamin B-12- and folate-dependent remethylation of homocysteine, which depends on methionine synthase (MS, encoded by MTR), methionine synthase reductase, and methylenetetrahydrofolate reductase. Methionine, the product of this pathway, is the direct precursor of S-adenosylmethionine (SAM), the universal methyl donor needed for epigenetic mechanisms...
March 6, 2019: American Journal of Clinical Nutrition
Su Xu, Yi Lun, Michelle Frascella, Anadina Garcia, Rebecca Soska, Anju Nair, Abdul S Ponery, Adriane Schilling, Jessie Feng, Steven Tuske, Maria Cecilia Della Valle, José A Martina, Evelyn Ralston, Russell Gotschall, Kenneth J Valenzano, Rosa Puertollano, Hung V Do, Nina Raben, Richie Khanna
Pompe disease is a rare inherited disorder of lysosomal glycogen metabolism due to acid α-glucosidase (GAA) deficiency. Enzyme replacement therapy (ERT) using alglucosidase alfa, a recombinant human GAA (rhGAA), is the only approved treatment for Pompe disease. Although alglucosidase alfa has provided clinical benefits, its poor targeting to key disease-relevant skeletal muscles results in suboptimal efficacy. We are developing an rhGAA, ATB200 (Amicus proprietary rhGAA), with high levels of mannose-6-phosphate that are required for efficient cellular uptake and lysosomal trafficking...
March 7, 2019: JCI Insight
Michael P Whyte, William H McAlister, Steven Mumm, Andrew J Bierhals
Hypophosphatasia (HPP) is the inborn-error-of-metabolism characterized enzymatically by insufficient activity of the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP) and caused by either mono- or bi-allelic loss-of-function mutation(s) of the gene ALPL that encodes this cell surface phosphomonoester phosphohydrolase. In HPP, the natural substrates of TNSALP accumulate extracellularly and include inorganic pyrophosphate (PPi), a potent inhibitor of biomineralization. This PPi excess leads to rickets or osteomalacia in all but the most mild "odonto" form of the disease...
February 27, 2019: Bone
A Jochim, T Shi, D Belikova, S Schwarz, A Peschel, S Heilbronner
Multi-drug resistant bacterial pathogens are becoming increasingly prevalent and novel strategies to treat bacterial infections caused by these organisms are desperately needed. Bacterial central metabolism is crucial for catabolic processes and provides precursors for anabolic pathways such as the biosynthesis of essential biomolecules like amino acids or vitamins. However, most essential pathways are not regarded as good targets for antibiotic therapy since their products might be acquired from the environment...
March 1, 2019: Applied and Environmental Microbiology
Peter Vaupel, Heinz Schmidberger, Arnulf Mayer
PURPOSE: In the early 1920s, Warburg published experimental data on the enhanced conversion of glucose to pyruvate (followed by lactate formation) even in the presence of abundant oxygen (aerobic glycolysis, Warburg effect). He attributed this metabolic trait to a respiratory injury and considered this a universal metabolic alteration in carcinogenesis. This interpretation of the data was questioned since the early 1950s. Realistic causative mechanisms and consequences of the Warburg effect were described only during the past 15 years and are summarized in this article...
March 1, 2019: International Journal of Radiation Biology
Qinghua Deng, Dehui Ma, Guoquan Sun, Xue Yuan, Zhe Wang, Guowen Liu
Dairy cows with fatty liver or ketosis display decreased insulin sensitivity and defects in the insulin receptor substrate (IRS)/PI3K/AKT signaling pathway. Phosphatase and tensin homolog (PTEN) is a well-known tumor suppressor and also a negative regulator of insulin signaling and peripheral insulin sensitivity. We investigated the hypothesis that PTEN may affect the insulin pathway-mediated hepatic glucose and lipid metabolism in dairy cows. Adenovirus vectors that over-express and silence PTEN were constructed, and then transfected into hepatocytes isolated from calves to investigate the effect of PTEN on PI3K/AKT signaling pathway...
March 1, 2019: Journal of Dairy Research
María Barreda-Sánchez, Juan Buendía-Martínez, Guillermo Glover-López, Carmen Carazo-Díaz, María Juliana Ballesta-Martínez, Vanesa López-González, María José Sánchez-Soler, Lidya Rodriguez-Peña, Ana Teresa Serrano-Antón, Remedios Gil-Ferrer, Maria Del Carmen Martínez-Romero, Pablo Carbonell-Meseguer, Encarna Guillén-Navarro
BACKGROUND: Acute intermittent porphyria (AIP) is a low-penetrant genetic metabolic disease caused by a deficiency of hydroxymethylbilane synthase (HMBS) in the haem biosynthesis. Manifest AIP (MAIP) is considered when carriers develop typical acute neurovisceral attacks with elevation of porphyrin precursors, while the absence of attacks is referred to as latent AIP (LAIP). Attacks are often triggered by drugs, endocrine factors, fasting or stress. Although AIP penetrance is traditionally considered to be around 10-20%, it has been estimated to be below 1% in general population studies and a higher figure has been found in specific AIP populations...
February 26, 2019: Orphanet Journal of Rare Diseases
Xiulan Lu, Weijian Chen, Liping Li, Xinyuan Zhu, Caizhi Huang, Saijun Liu, Yongjia Yang, Yaowang Zhao
Primary hyperoxaluria type 1 (PH1) is a rare metabolic disorder characterized by a defect in the liver-specific peroxisomal enzyme alanine-glyoxylate and serine-pyruvate aminotransferase (AGT). This disorder results in hyperoxaluria, recurrent urolithiasis, and nephrocalcinosis. Three forms of PH1 have been reported. Data on the infantile form of PH1 are currently limited in literature. Despite the fact that China is the most populated country in the world, only a few AGXT mutations have been reported in several Chinese PH1 patients...
2019: Frontiers in Pharmacology
Chompunut Lumsangkul, Hsin-I Chiang, Neng-Wen Lo, Yang-Kwang Fan, Jyh-Cherng Ju
A teratogenic agent or teratogen can disturb the development of an embryo or a fetus. Fumonisin B₁ (FB₁), produced by Fusarium verticillioides and F. proliferatum , is among the most commonly seen mycotoxins and contaminants from stale maize and other farm products. It may cause physical or functional defects in embryos or fetuses, if the pregnant animal is exposed to mycotoxin FB₁. Due to its high similarity in chemical structure with lipid sphinganine (Sa) and sphingosine (So), the primary component of sphingolipids, FB₁ plays a role in competitively inhibiting Sa and So, which are key enzymes in de novo ceramide synthase in the sphingolipid biosynthetic pathway...
February 13, 2019: Toxins
Minna Pekkinen, Paulien A Terhal, Lorenzo D Botto, Petra Henning, Riikka E Mäkitie, Paul Roschger, Amrita Jain, Matthijs Kol, Matti A Kjellberg, Eleftherios P Paschalis, Koen van Gassen, Mary Murray, Pinar Bayrak-Toydemir, Maria K Magnusson, Judith Jans, Mehran Kausar, John C Carey, Pentti Somerharju, Ulf H Lerner, Olkkonen M Vesa, Klaus Klaushofer, Joost Cm Holthuis, Outi Mäkitie
Mechanisms leading to osteoporosis are incompletely understood. Genetic disorders with skeletal fragility provide insight into metabolic pathways contributing to bone strength. We evaluated six families with rare skeletal phenotypes and osteoporosis by next-generation sequencing. In all families we identified a heterozygous variant in SGMS2, a gene prominently expressed in cortical bone and encoding the plasma membrane-resident sphingomyelin synthase SMS2. Four unrelated families shared the same nonsense variant c...
February 19, 2019: JCI Insight
Cunqi Ye, Benjamin M Sutter, Yun Wang, Zheng Kuang, Xiaozheng Zhao, Yonghao Yu, Benjamin P Tu
Dysregulation of chromatin methylation is associated with defects in cellular differentiation as well as a variety of cancers. How cells regulate the opposing activities of histone methyltransferase and demethylase enzymes to set the methylation status of the epigenome for proper control of gene expression and metabolism remains poorly understood. Here, we show that loss of methylation of the major phosphatase PP2A in response to methionine starvation activates the demethylation of histones through hyperphosphorylation of specific demethylase enzymes...
February 1, 2019: Molecular Cell
David B Beck, Ivona Aksentijevich
Monogenic autoinflammatory disorders are a group of conditions defined by systemic or localized inflammation without identifiable causes, such as infection. In contrast to classical primary immunodeficiencies that manifest with impaired immune responses, these disorders are due to defects in genes that regulate innate immunity leading to constitutive activation of pro-inflammatory signaling. Through studying patients with rare autoinflammatory conditions, novel mechanisms of inflammation have been identified that bare on our understanding not only of basic signaling in inflammatory cells, but also of the pathogenesis of more common inflammatory diseases and have guided treatment modalities...
2019: Frontiers in Immunology
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