fatty acid activation
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2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Giovan N. Cholico ◽  
Russell R. Fling ◽  
Nicholas A. Zacharewski ◽  
Kelly A. Fader ◽  
Rance Nault ◽  
...  

Abstract2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a persistent environmental contaminant, induces steatosis by increasing hepatic uptake of dietary and mobilized peripheral fats, inhibiting lipoprotein export, and repressing β-oxidation. In this study, the mechanism of β-oxidation inhibition was investigated by testing the hypothesis that TCDD dose-dependently repressed straight-chain fatty acid oxidation gene expression in mice following oral gavage every 4 days for 28 days. Untargeted metabolomic analysis revealed a dose-dependent decrease in hepatic acyl-CoA levels, while octenoyl-CoA and dicarboxylic acid levels increased. TCDD also dose-dependently repressed the hepatic gene expression associated with triacylglycerol and cholesterol ester hydrolysis, fatty acid binding proteins, fatty acid activation, and 3-ketoacyl-CoA thiolysis while inducing acyl-CoA hydrolysis. Moreover, octenoyl-CoA blocked the hydration of crotonyl-CoA suggesting short chain enoyl-CoA hydratase (ECHS1) activity was inhibited. Collectively, the integration of metabolomics and RNA-seq data suggested TCDD induced a futile cycle of fatty acid activation and acyl-CoA hydrolysis resulting in incomplete β-oxidation, and the accumulation octenoyl-CoA levels that inhibited the activity of short chain enoyl-CoA hydratase (ECHS1).



2021 ◽  
Author(s):  
Giovan N. Cholico ◽  
Russ R. Fling ◽  
Nicholas A. Zacharewski ◽  
Kelly A. Fader ◽  
Rance Nault ◽  
...  

ABSTRACT2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a persistent environmental contaminant, induces steatosis by increasing hepatic uptake of dietary and mobilized peripheral fats, inhibiting lipoprotein export, and repressing β-oxidation. In this study, the mechanism of β-oxidation inhibition was investigated by testing the hypothesis that TCDD dose-dependently repressed straight-chain fatty acid oxidation gene expression in mice following oral gavage every 4 days for 28 days. Untargeted metabolomic analysis revealed a dose-dependent decrease in hepatic acyl-CoA levels, while octenoyl-CoA and dicarboxylic acid levels increased. TCDD also dose-dependently repressed the hepatic gene expression associated with triacylglycerol and cholesterol ester hydrolysis, fatty acid binding proteins, fatty acid activation, and 3-ketoacyl-CoA thiolysis while inducing acyl-CoA hydrolysis. Moreover, octenoyl-CoA blocked the hydration of crotonyl-CoA suggesting short chain enoyl-CoA hydratase (ECHS1) activity was inhibited. Collectively, the integration of metabolomics and RNA-seq data suggested TCDD induced a futile cycle of fatty acid activation and acyl-CoA hydrolysis resulting in incomplete β-oxidation, and the accumulation octenoyl-CoA levels that inhibited the activity of short chain enoyl-CoA hydratase (ECHS1).



2021 ◽  
Author(s):  
Nadia Eusebio ◽  
Adriana Rego ◽  
Nathaniel R. Glasser ◽  
Raquel Castelo-Branco ◽  
Emily P. Balskus ◽  
...  

AbstractHalogenation is a recurring feature in natural products, especially those from marine organisms. The selectivity with which halogenating enzymes act on their substrates renders halogenases interesting targets for biocatalyst development. Recently, CylC – the first predicted dimetal-carboxylate halogenase to be characterized – was shown to regio- and stereoselectively install a chlorine atom onto an unactivated carbon center during cylindrocyclophane biosynthesis. Homologs of CylC are also found in other characterized cyanobacterial secondary metabolite biosynthetic gene clusters. Due to its novelty in biological catalysis, selectivity and ability to perform C-H activation, this halogenase class is of considerable fundamental and applied interest. However, little is known regarding the diversity and distribution of these enzymes in bacteria. In this study, we used both genome mining and PCR-based screening to explore the genetic diversity and distribution of CylC homologs. While we found non-cyanobacterial homologs of these enzymes to be rare, we identified a large number of genes encoding CylC-like enzymes in publicly available cyanobacterial genomes and in our in-house culture collection of cyanobacteria. Genes encoding CylC homologs are widely distributed throughout the cyanobacterial tree of life, within biosynthetic gene clusters of distinct architectures. Their genomic contexts feature a variety of biosynthetic partners, including fatty-acid activation enzymes, type I or type III polyketide synthases, dialkylresorcinol-generating enzymes, monooxygenases or Rieske proteins. Our study also reveals that dimetal-carboxylate halogenases are among the most abundant types of halogenating enzymes in the phylum Cyanobacteria. This work will help to guide the search for new halogenating biocatalysts and natural product scaffolds.Data statementAll supporting data and methods have been provided within the article or through a Supplementary Material file, which includes 14 supplementary figures and 4 supplementary tables.



2020 ◽  
Vol 113 (4) ◽  
pp. 807-825 ◽  
Author(s):  
Christopher D. Radka ◽  
Matthew W. Frank ◽  
Charles O. Rock ◽  
Jiangwei Yao




ACS Catalysis ◽  
2018 ◽  
Vol 9 (1) ◽  
pp. 565-577 ◽  
Author(s):  
Mathias Pickl ◽  
Sara Kurakin ◽  
Fabián G. Cantú Reinhard ◽  
Philipp Schmid ◽  
Alexander Pöcheim ◽  
...  




2017 ◽  
Vol 312 (6) ◽  
pp. C707-C723 ◽  
Author(s):  
John Cuppoletti ◽  
Kirti P. Tewari ◽  
Jayati Chakrabarti ◽  
Danuta H. Malinowska

Fatty acids (including lubiprostone and cobiprostone) are human ClC-2 (hClC-2) Cl− channel activators. Molecular and cellular mechanisms underlying this activation were examined. Role of a four-amino acid PKA activation site, RGET691, of hClC-2 was investigated using wild-type (WT) and mutant (AGET, RGEA, and AGAA) hClC-2 expressed in 293EBNA cells as well as involvement of PKA, intracellular cAMP concentration ([cAMP]i), EP2, or EP4 receptor agonist activity. All fatty acids [lubiprostone, cobiprostone, eicosatetraynoic acid (ETYA), oleic acid, and elaidic acid] caused significant rightward shifts in concentration-dependent Cl− current activation (increasing EC50s) with mutant compared with WT hClC-2 channels, without changing time and voltage dependence, current-voltage rectification, or methadone inhibition of the channel. As with lubiprostone, cobiprostone activation of hClC-2 occurred with PKA inhibitor (myristoylated protein kinase inhibitor) present or when using double PKA activation site (RRAA655/RGEA691) mutant. Cobiprostone did not activate human CFTR. Fatty acids did not increase [cAMP]i in hClC-2/293EBNA or T84 cells. Using T84 CFTR knockdown cells, cobiprostone increased hClC-2 Cl− currents without increasing [cAMP]i, while PGE2 and forskolin-IBMX increased both. Fatty acids were not agonists of EP2 or EP4 receptors. L-161,982, a supposed EP4-selective inhibitor, had no effect on lubiprostone-activated hClC-2 Cl− currents but significantly decreased T84 cell barrier function measured by transepithelial resistance and fluorescent dextran transepithelial movement. The present findings show that RGET691 of hClC-2 (possible binding site) plays an important functional role in fatty acid activation of hClC-2. PKA, [cAMP]i, and EP2 or EP4 receptors are not involved. These studies provide the molecular basis for fatty acid regulation of hClC-2.



2017 ◽  
Author(s):  
Rayner González-Prendes ◽  
Raquel Quintanilla ◽  
Marcel Amills

AbstractDespite their potential involvement in the determination of fatness phenotypes, a comprehensive and systematic view about the genetic regulation of lipid metabolism genes is still lacking in pigs. Herewith, we have used a dataset of 104 pigs, with available genotypes for 62,163 single nucleotide polymorphisms and microarray gene expression measurements in the gluteus medius muscle, to investigate the genetic regulation of 63 genes with crucial roles in the uptake, transport, synthesis and catabolism of lipids. By performing an eQTL scan with the GEMMA software, we have detected 12 cis- and 18 trans-eQTL modulating the expression of 19 loci. Genes regulated by eQTL had a variety of functions such as the β-oxidation of fatty acids, lipid biosynthesis and lipolysis, fatty acid activation and desaturation, lipoprotein uptake, apolipoprotein assembly and cholesterol trafficking. These data provide a first picture about the genetic regulation of loci involved in porcine lipid metabolism.



Author(s):  
Rémi Dulermo ◽  
Heber Gamboa-Meléndez ◽  
Rodrigo Ledesma‐Amaro ◽  
France Thevenieau ◽  
Jean-Marc Nicaud


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