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metabolizing enzymes defects

Sophie Croizier, Soyoung Park, Julien Maillard, Sebastien G Bouret
Proopiomelanocortin (POMC) neurons are major negative regulators of energy balance. A distinct developmental property of POMC neurons is that they can adopt an orexigenic neuropeptide Y (NPY) phenotype. However, the mechanisms underlying the differentiation of Pomc progenitors remain unknown. Here, we show that the loss of the microRNA (miRNA)-processing enzyme Dicer in POMC neurons causes metabolic defects, an age-dependent decline in the number of Pomc mRNA-expressing cells, and an increased proportion of Pomc progenitors acquiring a NPY phenotype...
October 12, 2018: ELife
Emilio Siendones, Manuel Ballesteros, Plácido Navas
Cytochrome b5 reductase 3 (CYB5R3) is a membrane-bound NADH-dependent redox enzyme anchored to the mitochondrial outer membrane, endoplasmic reticulum, and plasma membrane. Recessive hereditary methaemoglobinaemia (RHM) type II is caused by CYB5R3 deficiency and is an incurable disease characterized by severe encephalopathy with mental retardation, microcephaly, generalized dystonia, and movement disorders. Currently, the etiology of type II RHM is poorly understood and there is no treatment for encephalopathy associated with this disease...
October 10, 2018: Journal of Clinical Medicine
Sarah Costantino, Shafeeq A Mohammed, Samuele Ambrosini, Francesco Paneni
Albeit a consistent body of evidence supports the notion that genes influence cardiometabolic features and outcomes, the "non-genetic regulation" of this process is gaining increasing attention. Plastic chemical changes of DNA/histone complexes - known as epigenetic changes - critically determine gene activity by rapidly modifying chromatin accessibility to transcription factors. In this review, we describe the emerging role of chromatin modifications as fine tuners of gene transcription in adipogenesis, insulin resistance, macrophage polarization, immuno-metabolism, endothelial dysfunction and metabolic cardiomyopathy...
September 26, 2018: Atherosclerosis
Sasigarn A Bowden, Brian L Foster
Hypophosphatasia (HPP) is a multi-systemic metabolic disorder caused by loss-of-function mutations in the ALPL gene that encodes the mineralization-associated enzyme, tissue-nonspecific alkaline phosphatase (TNSALP). HPP is characterized by defective bone and dental mineralization, leading to skeletal abnormalities with complications resulting in significant morbidity and mortality. Management of HPP has been limited to supportive care until the introduction of a recently approved enzyme replacement therapy employing bone-targeted recombinant human TNSALP, asfotase alfa (AA)...
2018: Drug Design, Development and Therapy
Marisa W Friederich, Sharita Timal, Christopher A Powell, Cristina Dallabona, Alina Kurolap, Sara Palacios-Zambrano, Drago Bratkovic, Terry G J Derks, David Bick, Katelijne Bouman, Kathryn C Chatfield, Nadine Damouny-Naoum, Megan K Dishop, Tzipora C Falik-Zaccai, Fuad Fares, Ayalla Fedida, Ileana Ferrero, Renata C Gallagher, Rafael Garesse, Micol Gilberti, Cristina González, Katherine Gowan, Clair Habib, Rebecca K Halligan, Limor Kalfon, Kaz Knight, Dirk Lefeber, Laura Mamblona, Hanna Mandel, Adi Mory, John Ottoson, Tamar Paperna, Ger J M Pruijn, Pedro F Rebelo-Guiomar, Ann Saada, Bruno Sainz, Hayley Salvemini, Mirthe H Schoots, Jan A Smeitink, Maciej J Szukszto, Hendrik J Ter Horst, Frans van den Brandt, Francjan J van Spronsen, Joris A Veltman, Eric Wartchow, Liesbeth T Wintjes, Yaniv Zohar, Miguel A Fernández-Moreno, Hagit N Baris, Claudia Donnini, Michal Minczuk, Richard J Rodenburg, Johan L K Van Hove
Mitochondrial protein synthesis requires charging mt-tRNAs with their cognate amino acids by mitochondrial aminoacyl-tRNA synthetases, with the exception of glutaminyl mt-tRNA (mt-tRNAGln ). mt-tRNAGln is indirectly charged by a transamidation reaction involving the GatCAB aminoacyl-tRNA amidotransferase complex. Defects involving the mitochondrial protein synthesis machinery cause a broad spectrum of disorders, with often fatal outcome. Here, we describe nine patients from five families with genetic defects in a GatCAB complex subunit, including QRSL1, GATB, and GATC, each showing a lethal metabolic cardiomyopathy syndrome...
October 3, 2018: Nature Communications
Annelise Francisco, Juliana A Ronchi, Claudia D C Navarro, Tiago R Figueira, Roger F Castilho
Among mitochondrial NADP-reducing enzymes, nicotinamide nucleotide transhydrogenase (NNT) establishes an elevated matrix NADPH/NADP+ by catalyzing the reduction of NADP+ at the expense of NADH oxidation coupled to inward proton translocation across the inner mitochondrial membrane. Here, we characterize NNT activity and mitochondrial redox balance in the brain using a congenic mouse model carrying the mutated Nnt gene from the C57BL/6J strain. The absence of NNT activity resulted in lower total NADPH sources activity in the brain mitochondria of young mice, an effect that was partially compensated in aged mice...
October 3, 2018: Journal of Neurochemistry
Annabelle Mouammine, Katharina Eich, Antonio Frandi, Justine Collier
Cellular metabolism recently emerged as a central player modulating the bacterial cell cycle. The Alphaproteobacterium Caulobacter crescentus appears as one of the best models to study these connections, but its metabolism is still poorly characterized. Considering that it lives in oligotrophic environments, its capacity to use amino-acids is often critical for its growth. Here, we characterized the C. crescentus PutA bi-functional enzyme and showed that it is required for the utilization of proline as a carbon source...
October 2, 2018: Scientific Reports
Joshua E Pitzer, Tonya N Zeczycki, John E Baumgartner, Daniel W Martin, R Martin Roop
Pyruvate kinase plays a central role in glucose catabolism in bacteria, and efficient utilization of this hexose has been linked to the virulence of Brucella strains in mice. The brucellae produce a single pyruvate kinase which is an ortholog of the Bradyrhizobium manganese (Mn)-dependent pyruvate kinase PykM. Biochemical analysis of the Brucella pyruvate kinase and phenotypic analysis of a B. abortus mutant defective in high affinity Mn import indicate that this enzyme is an authentic PykM ortholog which functions as a Mn-dependent enzyme in vivo Loss of PykM has a negative impact on the capacity of the parental 2308 strain to utilize the glucose, fructose and galactose, but not on its ability to utilize ribose, xylose, arabinose or erythritol, and a pykM mutant displays significant attenuation in C57/BL6 mice...
October 1, 2018: Journal of Bacteriology
Sarah M Clark, Francesca M Notarangelo, Xin Li, Shuo Chen, Robert Schwarcz, Leonardo H Tonelli
Maternal immune activation (MIA) with the viral mimic poly I:C provides an established rodent model for studying schizophrenia (SZ) and other human neurodevelopmental disorders. Postnatal infections are additional risk factors in SZ and may cumulatively contribute to the emergence of pathophysiology. Underlying mechanisms may involve metabolites of the kynurenine pathway (KP) of tryptophan degradation, which is readily induced by inflammatory stimuli. Here we compared the expression of selected cytokines and KP enzymes, and the levels of selected KP metabolites, in the brain of MIA offspring following a second, acute immune challenge with lipopolysaccharides (LPS) on postnatal day (PND) 35 (adolescence) or PND 60 (early adulthood)...
September 27, 2018: Progress in Neuro-psychopharmacology & Biological Psychiatry
James E Heubi, Kenneth D R Setchell, Kevin E Bove
Inborn errors of bile acid metabolism are rare causes of neonatal cholestasis and liver disease in older children and adults. The diagnosis should be considered in the context of hyperbilirubinemia with normal serum bile acids and made by urinary liquid secondary ionization mass spectrometry or DNA testing. Cholic acid is an effective treatment of most single-enzyme defects and patients with Zellweger spectrum disorder with liver disease.
November 2018: Clinics in Liver Disease
Alicyn Reverdy, Yun Chen, Evan Hunter, Kevin Gozzi, Yunrong Chai
Protein lysine acetylation is a post-translational modification that alters the charge, conformation, and stability of proteins. A number of genome-wide characterizations of lysine-acetylated proteins, or acetylomes, in bacteria have demonstrated that lysine acetylation occurs on proteins with a wide diversity of functions, including central metabolism, transcription, chemotaxis, and cell size regulation. Bacillus subtilis is a model organism for studies of sporulation, motility, cell signaling, and multicellular development (or biofilm formation)...
2018: PloS One
Hamid Nouri, Anne-Françoise Monnier, Solveig Fossum-Raunehaug, Monika Maciag-Dorszynska, Armelle Cabin-Flaman, François Képès, Grzegorz Wegrzyn, Agnieszka Szalewska-Palasz, Vic Norris, Kirsten Skarstad, Laurent Janniere
DNA replication is coupled to growth by an unknown mechanism. Here, we investigated this coupling by analyzing growth and replication in 15 mutants of central carbon metabolism (CCM) cultivated in three rich media. In about one-fourth of the condition tested, defects in replication resulting from changes in initiation or elongation were detected. This uncovered 11 CCM genes important for replication and showed that some of these genes have an effect in one, two or three media. Additional results presented here and elsewhere (Jannière, L...
September 26, 2018: DNA Research: An International Journal for Rapid Publication of Reports on Genes and Genomes
Clare Shute
BACKGROUND: Retinal vascular occlusions are uncommon in young people and require more in-depth investigation into the cause. Studies have revealed that a high level of circulating homocysteine poses a risk for retinal vaso-occlusive events across a wide age range. This case report reflects on how the interplay of genetic mutation and vitamin deficiency can cause a pathological level of homocysteine with resultant branch retinal artery occlusion in a young patient. CASE PRESENTATION: A 16-year-old boy presented to eye casualty with acute inferior visual field loss in the left eye...
September 14, 2018: BMC Ophthalmology
Giulio Kleiner, Emanuele Barca, Marcello Ziosi, Valentina Emmanuele, Yimeng Xu, Agustin Hidalgo-Gutierrez, Changhong Qiao, Saba Tadesse, Estela Area-Gomez, Luis C Lopez, Catarina M Quinzii
Nephrotic syndrome (NS), a frequent chronic kidney disease in children and young adults, is the most common phenotype associated with primary coenzyme Q10 (CoQ10 ) deficiency and is very responsive to CoQ10 supplementation, although the pathomechanism is not clear. Here, using a mouse model of CoQ deficiency-associated NS, we show that long-term oral CoQ10 supplementation prevents kidney failure by rescuing defects of sulfides oxidation and ameliorating oxidative stress, despite only incomplete normalization of kidney CoQ levels and lack of rescue of CoQ-dependent respiratory enzymes activities...
November 2018: Biochimica et biophysica acta. Molecular basis of disease
Xiao-Fang Tong, Fa-Quan Zhao, Ying-Zong Ren, Yi Zhang, Yuan-Lu Cui, Qiang-Song Wang
Injectable hydrogels have been paid more attentions on cell therapy and tissue regeneration resulting from the applications in minimally invasive surgical procedures with ease of handling and complete filling of defect area. Here, a biodegradable and injectable in situ hydrogel formed by glycyrrhizin (GL), alginate (Alg), and calcium (Ca) was developed for three-dimensional (3D) cell culture. Differential scanning calorimetry (DSC), X-ray diffraction (XRD), scanning electron microscope (SEM) and rheology analysis were performed to characterize GL-Alg-Ca hydrogel and evaluate its formation mechanism, properties, and morphology...
September 22, 2018: Journal of Biomedical Materials Research. Part A
Yi-Chun Chen, Austin J Taylor, C Bruce Verchere
Biosynthesis of peptide hormones by pancreatic islet endocrine cells is a tightly orchestrated process that is critical for metabolic homeostasis. Like neuroendocrine peptides, insulin and other islet hormones are first synthesized as larger precursor molecules that are processed to their mature secreted products through a series of proteolytic cleavages, mediated by the prohormone convertases Pc1/3 and Pc2, and carboxypeptidase E. Additional posttranslational modifications including C-terminal amidation of the β-cell peptide islet amyloid polypeptide (IAPP) by peptidyl-glycine α-amidating monooxygenase (Pam) may also occur...
September 2018: Diabetes, Obesity & Metabolism
Lidia Mingorance, Victoria Castro, Ginés Ávila-Pérez, Gema Calvo, María Josefa Rodriguez, José L Carrascosa, Sofía Pérez-Del-Pulgar, Xavier Forns, Pablo Gastaminza
Hepatitis C virus (HCV) infection constitutes a significant health burden worldwide, because it is a major etiologic agent of chronic liver disease, cirrhosis and hepatocellular carcinoma. HCV replication cycle is closely tied to lipid metabolism and infection by this virus causes profound changes in host lipid homeostasis. We focused our attention on a phosphatidate phosphate (PAP) enzyme family (the lipin family), which mediate the conversion of phosphatidate to diacylglycerol in the cytoplasm, playing a key role in triglyceride biosynthesis and in phospholipid homeostasis...
September 2018: PLoS Pathogens
Kensuke Kawade, Yimeng Li, Hiroyuki Koga, Yuji Sawada, Mami Okamoto, Ayuko Kuwahara, Hirokazu Tsukaya, Masami Yokota Hirai
Metabolism often plays an important role in developmental control, in addition to supporting basal physiological requirements. However, our understanding of this interaction remains limited. Here, we performed quantitative phenome analysis of Arabidopsis thaliana cytochrome P450 mutants to identify a novel interaction between development and metabolism. We found that cyp77a4 mutants exhibit specific defects in cotyledon development, including asymmetric positioning and cup-shaped morphology, which could be rescued by introducing the CYP77A4 gene...
September 12, 2018: Development
Chi-Chun Ho, Lilian Li-Yan Tsung, Kam-Tim Liu, Wing-Tat Poon
BACKGROUND: Mucolipidosis alpha/beta is an inborn error of metabolism characterized by deficiency of GlcNAc-1-phosphotransferase, in which essential alpha/beta subunits are encoded by the GNPTAB gene. The autosomal recessive condition is due to disruptions of hydrolase mannose 6-phosphate marker generation, defective lysosomal targeting and subsequent intracellular accumulation of non-degraded material. Clinical severity depends on residual GlcNAc-1-phosphotransferase activity, which distinguishes between the milder type III disease and the severe, neonatal onset type II disease...
September 12, 2018: BMC Medical Genetics
Xintong Tan, Tong Zhao, Zihan Wang, Jia Wang, Yijie Wang, Zhigang Liu, Xuebo Liu
Circadian rhythm helps organisms adapt to their environment and control a variety of physiological and metabolic processes. Acrylamide is a toxic compound that can be produced during food processing. The aim of this research is to investigate whether the circadian clock is involved in the toxicity mechanisms of acrylamide in mice liver. Our results revealed that acrylamide markedly induced circadian gene oscillation disorder and blocked circadian-related protein in mice liver and HepG2 cells. Simultaneously, the balance of the daily oscillation of the antioxidant enzymes was impeded under acrylamide treatment...
October 3, 2018: Journal of Agricultural and Food Chemistry
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