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Tracing metabolic flux through time and space with isotope labeling experiments.
Allen DK, Young JD
(2020) Curr Opin Biotechnol 64: 92-100
MeSH Terms: Animals, Carbon Isotopes, Isotope Labeling, Metabolic Networks and Pathways
Show Abstract · Added March 5, 2020
Metabolism is dynamic and must function in context-specific ways to adjust to changes in the surrounding cellular and ecological environment. When isotopic tracers are used, metabolite flow (i.e. metabolic flux) can be quantified through biochemical networks to assess metabolic pathway operation. The cellular activities considered across multiple tissues and organs result in the observed phenotype and can be analyzed to discover emergent, whole-system properties of biology and elucidate misconceptions about network operation. However, temporal and spatial challenges remain significant hurdles and require novel approaches and creative solutions. We survey current investigations in higher plant and animal systems focused on dynamic isotope labeling experiments, spatially resolved measurement strategies, and observations from re-analysis of our own studies that suggest prospects for future work. Related discoveries will be necessary to push the frontier of our understanding of metabolism to suggest novel solutions to cure disease and feed a growing future world population.
Published by Elsevier Ltd.
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4 MeSH Terms
Engineering cytochrome P450 enzyme systems for biomedical and biotechnological applications.
Li Z, Jiang Y, Guengerich FP, Ma L, Li S, Zhang W
(2020) J Biol Chem 295: 833-849
MeSH Terms: Biocatalysis, Biotechnology, Cytochrome P-450 Enzyme System, Metabolic Engineering, Protein Engineering, Steroids, Substrate Specificity, Xenobiotics
Show Abstract · Added March 3, 2020
Cytochrome P450 enzymes (P450s) are broadly distributed among living organisms and play crucial roles in natural product biosynthesis, degradation of xenobiotics, steroid biosynthesis, and drug metabolism. P450s are considered as the most versatile biocatalysts in nature because of the vast variety of substrate structures and the types of reactions they catalyze. In particular, P450s can catalyze regio- and stereoselective oxidations of nonactivated C-H bonds in complex organic molecules under mild conditions, making P450s useful biocatalysts in the production of commodity pharmaceuticals, fine or bulk chemicals, bioremediation agents, flavors, and fragrances. Major efforts have been made in engineering improved P450 systems that overcome the inherent limitations of the native enzymes. In this review, we focus on recent progress of different strategies, including protein engineering, redox-partner engineering, substrate engineering, electron source engineering, and P450-mediated metabolic engineering, in efforts to more efficiently produce pharmaceuticals and other chemicals. We also discuss future opportunities for engineering and applications of the P450 systems.
© 2020 Li et al.
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8 MeSH Terms
Genome-Scale Model-Based Identification of Metabolite Indicators for Early Detection of Kidney Toxicity.
Pannala VR, Vinnakota KC, Estes SK, Trenary I, OˈBrien TP, Printz RL, Papin JA, Reifman J, Oyama T, Shiota M, Young JD, Wallqvist A
(2020) Toxicol Sci 173: 293-312
MeSH Terms: Animals, Biomarkers, Gene Expression Profiling, Gentamicins, Kidney, Liver, Male, Metabolic Networks and Pathways, Metabolome, Rats, Rats, Sprague-Dawley
Show Abstract · Added March 5, 2020
Identifying early indicators of toxicant-induced organ damage is critical to provide effective treatment. To discover such indicators and the underlying mechanisms of toxicity, we used gentamicin as an exemplar kidney toxicant and performed systematic perturbation studies in Sprague Dawley rats. We obtained high-throughput data 7 and 13 h after administration of a single dose of gentamicin (0.5 g/kg) and identified global changes in genes in the liver and kidneys, metabolites in the plasma and urine, and absolute fluxes in central carbon metabolism. We used these measured changes in genes in the liver and kidney as constraints to a rat multitissue genome-scale metabolic network model to investigate the mechanism of gentamicin-induced kidney toxicity and identify metabolites associated with changes in tissue gene expression. Our experimental analysis revealed that gentamicin-induced metabolic perturbations could be detected as early as 7 h postexposure. Our integrated systems-level analyses suggest that changes in kidney gene expression drive most of the significant metabolite alterations in the urine. The analyses thus allowed us to identify several significantly enriched injury-specific pathways in the kidney underlying gentamicin-induced toxicity, as well as metabolites in these pathways that could serve as potential early indicators of kidney damage.
© The Author(s) 2020. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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11 MeSH Terms
Bacterial Pathogens Hijack the Innate Immune Response by Activation of the Reverse Transsulfuration Pathway.
Gobert AP, Latour YL, Asim M, Finley JL, Verriere TG, Barry DP, Milne GL, Luis PB, Schneider C, Rivera ES, Lindsey-Rose K, Schey KL, Delgado AG, Sierra JC, Piazuelo MB, Wilson KT
(2019) mBio 10:
MeSH Terms: Animals, Bacteria, Gene Silencing, Helicobacter pylori, Histones, Humans, Immune Evasion, Immunity, Innate, Immunoglobulins, Macrophages, Male, Metabolic Networks and Pathways, Mice, Mice, Inbred C57BL, Nitric Oxide Synthase Type II, Phosphatidylinositol 3-Kinases, Polyamines, RAW 264.7 Cells, Spermidine, Spermine, Sulfur, Transcription Factors
Show Abstract · Added November 1, 2019
The reverse transsulfuration pathway is the major route for the metabolism of sulfur-containing amino acids. The role of this metabolic pathway in macrophage response and function is unknown. We show that the enzyme cystathionine γ-lyase (CTH) is induced in macrophages infected with pathogenic bacteria through signaling involving phosphatidylinositol 3-kinase (PI3K)/MTOR and the transcription factor SP1. This results in the synthesis of cystathionine, which facilitates the survival of pathogens within myeloid cells. Our data demonstrate that the expression of CTH leads to defective macrophage activation by (i) dysregulation of polyamine metabolism by depletion of -adenosylmethionine, resulting in immunosuppressive putrescine accumulation and inhibition of spermidine and spermine synthesis, and (ii) increased histone H3K9, H3K27, and H3K36 di/trimethylation, which is associated with gene expression silencing. Thus, CTH is a pivotal enzyme of the innate immune response that disrupts host defense. The induction of the reverse transsulfuration pathway by bacterial pathogens can be considered an unrecognized mechanism for immune escape. Macrophages are professional immune cells that ingest and kill microbes. In this study, we show that different pathogenic bacteria induce the expression of cystathionine γ-lyase (CTH) in macrophages. This enzyme is involved in a metabolic pathway called the reverse transsulfuration pathway, which leads to the production of numerous metabolites, including cystathionine. Phagocytized bacteria use cystathionine to better survive in macrophages. In addition, the induction of CTH results in dysregulation of the metabolism of polyamines, which in turn dampens the proinflammatory response of macrophages. In conclusion, pathogenic bacteria can evade the host immune response by inducing CTH in macrophages.
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22 MeSH Terms
Impact of Acipimox Therapy on Free Fatty Acid Efflux and Endothelial Function in the Metabolic Syndrome: A Randomized Trial.
Aday AW, Goldfine AB, Gregory JM, Beckman JA
(2019) Obesity (Silver Spring) 27: 1812-1819
MeSH Terms: Adult, Aged, Blood Glucose, Cross-Over Studies, Double-Blind Method, Endothelium, Vascular, Fatty Acids, Nonesterified, Female, Humans, Hypolipidemic Agents, Insulin, Insulin Resistance, Lipid Metabolism, Male, Metabolic Syndrome, Middle Aged, Pyrazines, Vasodilation
Show Abstract · Added October 2, 2019
OBJECTIVE - Insulin resistance is associated with increased lipolysis and elevated concentrations of free fatty acids (FFA), which in turn contribute to impaired vascular function. It was hypothesized that lowering FFA with acipimox, a nicotinic acid derivative that impairs FFA efflux, would improve endothelial function, measured by flow-mediated dilation (FMD), in individuals with metabolic syndrome.
METHODS - A total of 18 participants with metabolic syndrome and 17 healthy controls were enrolled and treated with acipimox 250 mg orally every 6 hours or placebo for 7 days in a randomized, double-blind, crossover trial.
RESULTS - Acipimox reduced FFA concentrations among individuals with metabolic syndrome to near normal levels (P = 0.01), but there was no change among healthy controls (P = 0.17). Acipimox did not improve endothelial-dependent FMD in either group (metabolic syndrome: P = 0.42; healthy controls: P = 0.16), although endothelial-independent nitroglycerin-mediated dilation among those with metabolic syndrome tended to increase (20.3%, P = 0.06). There were no changes in blood lipids or markers of inflammation following therapy. There was minimal correlation between change in FMD and baseline measures of BMI ( ρ = -0.09) or waist circumference ( ρ = -0.15).
CONCLUSIONS - In groups with normal or elevated baseline FFA, short-term reductions do not improve endothelial function assessed by FMD.
© 2019 The Obesity Society.
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18 MeSH Terms
Two-week administration of engineered Escherichia coli establishes persistent resistance to diet-induced obesity even without antibiotic pre-treatment.
Dosoky NS, Chen Z, Guo Y, McMillan C, Flynn CR, Davies SS
(2019) Appl Microbiol Biotechnol 103: 6711-6723
MeSH Terms: Acyltransferases, Animals, Anti-Bacterial Agents, Anti-Obesity Agents, Arabidopsis, Diet, High-Fat, Disease Models, Animal, Escherichia coli, Humans, Metabolic Engineering, Mice, Obesity, Phosphatidylethanolamines, Plant Proteins, Probiotics, Recombinant Proteins, Treatment Outcome
Show Abstract · Added July 17, 2019
Adverse alterations in the composition of the gut microbiota have been implicated in the development of obesity and a variety of chronic diseases. Re-engineering the gut microbiota to produce beneficial metabolites is a potential strategy for treating these chronic diseases. N-acyl-phosphatidylethanolamines (NAPEs) are a family of bioactive lipids with known anti-obesity properties. Previous studies showed that administration of Escherichia coli Nissle 1917 (EcN) engineered with Arabidopsis thaliana NAPE synthase to produce NAPEs imparted resistance to obesity induced by a high-fat diet that persisted after ending their administration. In prior studies, mice were pre-treated with ampicillin prior to administering engineered EcN for 8 weeks in drinking water. If use of antibiotics and long-term administration are required for beneficial effects, implementation of this strategy in humans might be problematic. Studies were therefore undertaken to determine if less onerous protocols could still impart persistent resistance and sustained NAPE biosynthesis. Administration of engineered EcN for only 2 weeks without pre-treatment with antibiotics sufficed to establish persistent resistance. Sustained NAPE biosynthesis by EcN was required as antibiotic treatment after administration of the engineered EcN markedly attenuated its effects. Finally, heterologous expression of human phospholipase A/acyltransferase-2 (PLAAT2) in EcN provided similar resistance to obesity as heterologous expression of A. thaliana NAPE synthase, confirming that NAPEs are the bioactive mediator of this resistance.
1 Communities
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17 MeSH Terms
Extrinsic and Intrinsic Immunometabolism Converge: Perspectives on Future Research and Therapeutic Development for Obesity.
Caslin HL, Hasty AH
(2019) Curr Obes Rep 8: 210-219
MeSH Terms: Adaptive Immunity, Adipose Tissue, Animals, Energy Metabolism, Epigenesis, Genetic, Humans, Immunity, Immunologic Memory, Iron, Macrophages, Metabolic Diseases, Metabolic Networks and Pathways, MicroRNAs, Obesity
Show Abstract · Added March 3, 2020
PURPOSE OF REVIEW - Research over the past decade has shown that immunologic and metabolic pathways are intricately linked. This burgeoning field of immunometabolism includes intrinsic and extrinsic pathways and is known to be associated with obesity-accelerated metabolic disease. Intrinsic immunometabolism includes the study of fuel utilization and bioenergetic pathways that influence immune cell function. Extrinsic immunometabolism includes the study of immune cells and products that influence systemic metabolism.
RECENT FINDINGS - Th2 immunity, macrophage iron handling, adaptive immune memory, and epigenetic regulation of immunity, which all require intrinsic metabolic changes, play a role in systemic metabolism and metabolic function, linking the two arms of immunometabolism. Together, this suggests that targeting intrinsic immunometabolism can directly affect immune function and ultimately systemic metabolism. We highlight important questions for future basic research that will help improve translational research and provide therapeutic targets to help establish new treatments for obesity and associated metabolic disorders.
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MeSH Terms
Metabolic plasticity meets gene regulation.
Paudel BB, Quaranta V
(2019) Proc Natl Acad Sci U S A 116: 3370-3372
MeSH Terms: Biochemical Phenomena, Gene Expression Regulation, Humans, Metabolic Networks and Pathways, Neoplasms, Neuronal Plasticity
Added March 23, 2019
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6 MeSH Terms
Heart Disease and Stroke Statistics-2019 Update: A Report From the American Heart Association.
Benjamin EJ, Muntner P, Alonso A, Bittencourt MS, Callaway CW, Carson AP, Chamberlain AM, Chang AR, Cheng S, Das SR, Delling FN, Djousse L, Elkind MSV, Ferguson JF, Fornage M, Jordan LC, Khan SS, Kissela BM, Knutson KL, Kwan TW, Lackland DT, Lewis TT, Lichtman JH, Longenecker CT, Loop MS, Lutsey PL, Martin SS, Matsushita K, Moran AE, Mussolino ME, O'Flaherty M, Pandey A, Perak AM, Rosamond WD, Roth GA, Sampson UKA, Satou GM, Schroeder EB, Shah SH, Spartano NL, Stokes A, Tirschwell DL, Tsao CW, Turakhia MP, VanWagner LB, Wilkins JT, Wong SS, Virani SS, American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee
(2019) Circulation 139: e56-e528
MeSH Terms: American Heart Association, Cholesterol, Heart Diseases, Humans, Hypertension, Metabolic Diseases, Nutritional Status, Obesity, Quality of Health Care, Risk Factors, Smoking, Stroke, United States, Venous Thromboembolism
Added April 2, 2019
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14 MeSH Terms
Microbial-Host Interactions in Inflammatory Bowel Disease, Functional Bowel Disease, Obesity and Obesity-Related Metabolic Disease.
Shah SC, Faith J, Colombel JF
(2018) Gastroenterology 155: 1283-1286
MeSH Terms: Host-Pathogen Interactions, Humans, Inflammatory Bowel Diseases, Irritable Bowel Syndrome, Metabolic Diseases, Microbiota, Obesity
Added March 3, 2020
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MeSH Terms