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https://www.readbyqxmd.com/read/28928723/analysis-of-the-sequences-structures-and-functions-of-product-releasing-enzyme-domains-in-fungal-polyketide-synthases
#1
Lu Liu, Zheng Zhang, Chang-Lun Shao, Chang-Yun Wang
Product-releasing enzyme (PRE) domains in fungal non-reducing polyketide synthases (NR-PKSs) play a crucial role in catalysis and editing during polyketide biosynthesis, especially accelerating final biosynthetic reactions accompanied with product offloading. However, up to date, the systematic knowledge about PRE domains is deficient. In the present study, the relationships between sequences, structures, and functions of PRE domains were analyzed with 574 NR-PKSs of eight groups (I-VIII). It was found that the PRE domains in NR-PKSs could be mainly classified into three types, thioesterase (TE), reductase (R), and metallo-β-lactamase-type TE (MβL-TE)...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28927126/overexpression-and-proliferation-dependence-of-acyl-coa-thioesterase-11-and-13-in-lung-adenocarcinoma
#2
Jen-Yu Hung, Shyh-Ren Chiang, Kuan-Ting Liu, Ming-Ju Tsai, Ming-Shyan Huang, Jiunn-Min Shieh, Meng-Chi Yen, Ya-Ling Hsu
The metabolites of fatty acyl-Coenzyme A (CoA) and metabolic enzymes contribute to lipid biosynthesis, signal transduction, and gene transcription. Previous studies have indicated that elevated concentrations of specific free fatty acids in the plasma and overexpression of specific fatty acyl-CoA metabolic enzymes are observed in patients with lung adenocarcinoma. However, there are >30 enzymes in this metabolic network and have been fully investigated. In the present study, the expression levels of enzymes in the acyl-CoA synthetase (ACS) and acyl-CoA thioesterase (ACOT) families were analyzed from six microarray expression datasets that were collected from Gene Expression Omnibus...
September 2017: Oncology Letters
https://www.readbyqxmd.com/read/28899863/a-unified-approach-to-targeting-the-lysosome-s-degradative-and-growth-signaling-roles
#3
Vito W Rebecca, Michael C Nicastri, Noel McLaughlin, Colin Fennelly, Quentin McAfee, Amruta Ronghe, Michel Nofal, Chun-Yan Lim, Eric Witze, Cynthia I Chude, Gao Zhang, Gretchen M Alicea, Shengfu Piao, Sengottuvelan Murugan, Rani Ojha, Samuel M Levi, Zhi Wei, Julie S Barber-Rotenberg, Maureen E Murphy, Gordon B Mills, Yiling Lu, Joshua Rabinowitz, Ronen Marmorstein, Qin Liu, Shujing Liu, Xiaowei Xu, Meenhard Herlyn, Roberto Zoncu, Donita C Brady, David W Speicher, Jeffrey D Winkler, Ravi K Amaravadi
Lysosomes serve dual roles in cancer metabolism, executing catabolic programs (i.e. autophagy and macropinocytosis), while promoting mTORC1-dependent anabolism. Antimalarial compounds such as chloroquine or quinacrine have been used as lysosomal inhibitors, but fail to inhibit mTOR signaling. Further, the molecular target of these agents has not been identified. We report a screen of novel dimeric antimalarials that identifies dimeric quinacrines (DQs) as potent anticancer compounds, which concurrently inhibit mTOR and autophagy...
September 12, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28884166/crystal-structure-of-thioesterase-sgce10-supporting-common-polyene-intermediates-in-9-and-10-membered-enediyne-core-biosynthesis
#4
Thibault Annaval, Jeffrey D Rudolf, Chin-Yuan Chang, Jeremy R Lohman, Youngchang Kim, Lance Bigelow, Robert Jedrzejczak, Gyorgy Babnigg, Andrzej Joachimiak, George N Phillips, Ben Shen
Enediynes are potent natural product anticancer antibiotics, and are classified as 9- or 10-membered according to the size of their enediyne core carbon skeleton. Both 9- and 10-membered enediyne cores are biosynthesized by the enediyne polyketide synthase (PKSE), thioesterase (TE), and PKSE-associated enzymes. Although the divergence between 9- and 10-membered enediyne core biosynthesis remains unclear, it has been observed that nascent polyketide intermediates, tethered to the acyl carrier protein (ACP) domain of PKSE, could be released by TE in the absence of the PKSE-associated enzymes...
August 31, 2017: ACS Omega
https://www.readbyqxmd.com/read/28878621/the-networks-of-genes-encoding-palmitoylated-proteins-in-axonal-and-synaptic-compartments-are-affected-in-ppt1-overexpressing-neuronal-like-cells
#5
Francesco Pezzini, Marzia Bianchi, Salvatore Benfatto, Francesca Griggio, Stefano Doccini, Rosalba Carrozzo, Arvydas Dapkunas, Massimo Delledonne, Filippo M Santorelli, Maciej M Lalowski, Alessandro Simonati
CLN1 disease (OMIM #256730) is an early childhood ceroid-lipofuscinosis associated with mutated CLN1, whose product Palmitoyl-Protein Thioesterase 1 (PPT1) is a lysosomal enzyme involved in the removal of palmitate residues from S-acylated proteins. In neurons, PPT1 expression is also linked to synaptic compartments. The aim of this study was to unravel molecular signatures connected to CLN1. We utilized SH-SY5Y neuroblastoma cells overexpressing wild type CLN1 (SH-p.wtCLN1) and five selected CLN1 patients' mutations...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28846367/structure-and-functional-analysis-of-clbq-an-unusual-intermediate-releasing-thioesterase-from-the-colibactin-biosynthetic-pathway
#6
Naga Sandhya Guntaka, Alan R Healy, Jason M Crawford, Seth B Herzon, Steven D Bruner
Colibactin is a genotoxic hybrid nonribosomal peptide/polyketide secondary metabolite produced by various pathogenic and probiotic bacteria residing in the human gut. The presence of colibactin metabolites has been correlated to colorectal cancer formation in several studies. The specific function of many gene products in the colibactin gene cluster can be predicted. However, the role of ClbQ, a type II editing thioesterase, has not been established. The importance of ClbQ has been demonstrated by genetic deletions that abolish colibactin cytotoxic activity, and recent studies suggest an atypical role in releasing pathway intermediates from the assembly line...
September 8, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28836772/identification-of-a-thioesterase-bottleneck-in-the-pikromycin-pathway-through-full-module-processing-of-unnatural-pentaketides
#7
Douglas A Hansen, Aaron A Koch, David H Sherman
Polyketide biosynthetic pathways have been engineered to generate natural product analogs for over two decades. However, manipulation of modular type I polyketide synthases (PKSs) to make unnatural metabolites commonly results in attenuated yields or entirely inactive pathways, and the mechanistic basis for compromised production is rarely elucidated since rate limiting or inactive domain(s) remain unidentified. Accordingly, we synthesized and assayed a series of modified pikromycin (Pik) pentaketides that mimic early pathway engineering to probe the substrate tolerance of the PikAIII-TE module in vitro...
August 24, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28836768/a-single-active-site-mutation-in-the-pikromycin-thioesterase-generates-a-more-effective-macrocyclization-catalyst
#8
Aaron A Koch, Douglas A Hansen, Vikram V Shende, Lawrence R Furan, Kendall N Houk, Gonzalo Jiménez-Osés, David H Sherman
Macrolactonization of natural product analogs presents a significant challenge to both biosynthetic assembly and synthetic chemistry. In the preceding paper, we identified a thioesterase (TE) domain catalytic bottleneck in the processing of un-natural substrates in the pikromycin (Pik) system, preventing the formation of epimerized macrolactones. Here, we perform molecular dynamics (MD) simulations showing the epimerized hexaketide was accommodated within the Pik TE active site; however, intrinsic conformational preferences of the substrate resulted in predominately unproductive conformations, in agreement with the observed hydrolysis...
August 24, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28826475/identification-and-dynamics-of-the-human-zdhhc16-zdhhc6-palmitoylation-cascade
#9
Laurence Abrami, Tiziano Dallavilla, Patrick A Sandoz, Mustafa Demir, Béatrice Kunz, Georgios Savoglidis, Vassily Hatzimanikatis, F Gisou van der Goot
S-Palmitoylation is the only reversible post-translational lipid modification. Knowledge about the DHHC palmitoyltransferase family is still limited. Here we show that human ZDHHC6, which modifies key proteins of the endoplasmic reticulum, is controlled by an upstream palmitoyltransferase, ZDHHC16, revealing the first palmitoylation cascade. The combination of site specific mutagenesis of the three ZDHHC6 palmitoylation sites, experimental determination of kinetic parameters and data-driven mathematical modelling allowed us to obtain detailed information on the eight differentially palmitoylated ZDHHC6 species...
August 15, 2017: ELife
https://www.readbyqxmd.com/read/28814974/time-resolved-transcriptome-analysis-and-lipid-pathway-reconstruction-of-the-oleaginous-green-microalga-monoraphidium-neglectum-reveal-a-model-for-triacylglycerol-and-lipid-hyperaccumulation
#10
Daniel Jaeger, Anika Winkler, Jan H Mussgnug, Jörn Kalinowski, Alexander Goesmann, Olaf Kruse
BACKGROUND: Oleaginous microalgae are promising production hosts for the sustainable generation of lipid-based bioproducts and as bioenergy carriers such as biodiesel. Transcriptomics of the lipid accumulation phase, triggered efficiently by nitrogen starvation, is a valuable approach for the identification of gene targets for metabolic engineering. RESULTS: An explorative analysis of the detailed transcriptional response to different stages of nitrogen availability was performed in the oleaginous green alga Monoraphidium neglectum...
2017: Biotechnology for Biofuels
https://www.readbyqxmd.com/read/28792770/proteomic-analysis-of-brain-and-cerebrospinal-fluid-from-the-three-major-forms-of-neuronal-ceroid-lipofuscinosis-reveals-potential-biomarkers
#11
David E Sleat, Abla Tannous, Istvan Sohar, Jennifer A Wiseman, Haiyan Zheng, Meiqian Qian, Caifeng Zhou, Winnie Xin, Rosemary Barone, Katherine B Sims, Dirk F Moore, Peter Lobel
Clinical trials have been conducted for the neuronal ceroid lipofuscinoses (NCLs), a group of neurodegenerative lysosomal diseases that primarily affect children. While clinical rating systems will evaluate long-term efficacy, biomarkers to measure short-term response to treatment would be extremely valuable. To identify candidate biomarkers, we analyzed autopsy brain and matching CSF samples from controls and three genetically distinct NCLs due to deficiencies in palmitoyl protein thioesterase 1 (CLN1 disease), tripeptidyl peptidase 1 (CLN2 disease) and CLN3 protein (CLN3 disease)...
August 9, 2017: Journal of Proteome Research
https://www.readbyqxmd.com/read/28769963/tissue-specific-floral-transcriptome-analysis-of-the-sexually-deceptive-orchid-chiloglottis-trapeziformis-provides-insights-into-the-biosynthesis-and-regulation-of-its-unique-uv-b-dependent-floral-volatile-chiloglottone-1
#12
Darren C J Wong, Ranamalie Amarasinghe, Claudia Rodriguez-Delgado, Rodney Eyles, Eran Pichersky, Rod Peakall
The Australian sexually deceptive orchid, Chiloglottis trapeziformis, employs a unique UV-B-dependent floral volatile, chiloglottone 1, for specific male wasp pollinator attraction. Chiloglottone 1 and related variants (2,5-dialkylcyclohexane-1,3-diones), represent a unique class of specialized metabolites presumed to be the product of cyclization between two fatty acid (FA) precursors. However, the genes involved in the biosynthesis of precursors, intermediates, and transcriptional regulation remains to be discovered...
2017: Frontiers in Plant Science
https://www.readbyqxmd.com/read/28741300/the-hotdog-fold-thioesterase-pa1618-catalytic-mechanism-revealed-by-x-ray-structure-determination-of-the-substrate-oxygen-ester-analog-complex
#13
John A Latham, Tianyang Ji, Kaila Matthews, Patrick Mariano, Karen N Allen, Debra Dunaway-Mariano
Thioesterase activity (hydrolysis of thioester bonds) accounts for the majority of the activities in the hotdog-fold superfamily. The structure and mechanism of catalysis for many hotdog enzymes have been elucidated by X-ray crystallography and kinetics to probe the specific substrate usage and cellular functions. However, structures of hotdog thioesterases in complex with substrate analogs reported to date utilize ligands that comprise either truncations of the substrate or include additional atoms to prevent the hydrolysis...
July 24, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28684428/a-lipid-anchored-nac-transcription-factor-is-translocated-into-the-nucleus-and-activates-glyoxalase-i-expression-during-drought-stress
#14
Mei Duan, Rongxue Zhang, Fugui Zhu, Zhenqian Zhang, Lanming Gou, Jiangqi Wen, Jiangli Dong, Tao Wang
The plant-specific NAC (NAM, ATAF1/2, and CUC2) transcription factors (TFs) play a vital role in the response to drought stress. Here, we report a lipid-anchored NACsa TF in Medicago falcata MfNACsa is an essential regulator of plant tolerance to drought stress, resulting in the differential expression of genes involved in oxidation reduction and lipid transport and localization. MfNACsa is associated with membranes under unstressed conditions and, more specifically, is targeted to the plasma membrane through S-palmitoylation...
July 2017: Plant Cell
https://www.readbyqxmd.com/read/28673981/synergistic-effects-of-treating-the-spinal-cord-and-brain-in-cln1-disease
#15
Charles Shyng, Hemanth R Nelvagal, Joshua T Dearborn, Jaana Tyynelä, Robert E Schmidt, Mark S Sands, Jonathan D Cooper
Infantile neuronal ceroid lipofuscinosis (INCL, or CLN1 disease) is an inherited neurodegenerative storage disorder caused by a deficiency of the lysosomal enzyme palmitoyl protein thioesterase 1 (PPT1). It was widely believed that the pathology associated with INCL was limited to the brain, but we have now found unexpectedly profound pathology in the human INCL spinal cord. Similar pathological changes also occur at every level of the spinal cord of PPT1-deficient (Ppt1(-/-) ) mice before the onset of neuropathology in the brain...
July 18, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28669536/development-of-a-novel-lead-that-targets-m-%C3%A2-tuberculosis-polyketide-synthase-13
#16
Anup Aggarwal, Maloy K Parai, Nishant Shetty, Deeann Wallis, Lisa Woolhiser, Courtney Hastings, Noton K Dutta, Stacy Galaviz, Ramesh C Dhakal, Rupesh Shrestha, Shoko Wakabayashi, Chris Walpole, David Matthews, David Floyd, Paul Scullion, Jennifer Riley, Ola Epemolu, Suzanne Norval, Thomas Snavely, Gregory T Robertson, Eric J Rubin, Thomas R Ioerger, Frik A Sirgel, Ruben van der Merwe, Paul D van Helden, Peter Keller, Erik C Böttger, Petros C Karakousis, Anne J Lenaerts, James C Sacchettini
Widespread resistance to first-line TB drugs is a major problem that will likely only be resolved through the development of new drugs with novel mechanisms of action. We have used structure-guided methods to develop a lead molecule that targets the thioesterase activity of polyketide synthase Pks13, an essential enzyme that forms mycolic acids, required for the cell wall of Mycobacterium tuberculosis. Our lead, TAM16, is a benzofuran class inhibitor of Pks13 with highly potent in vitro bactericidal activity against drug-susceptible and drug-resistant clinical isolates of M...
July 13, 2017: Cell
https://www.readbyqxmd.com/read/28644971/simultaneous-silencing-of-ghfad2-1-and-ghfatb-enhances-the-quality-of-cottonseed-oil-with-high-oleic-acid
#17
Feng Liu, Yan-Peng Zhao, Hua-Guo Zhu, Qian-Hao Zhu, Jie Sun
Cottonseed oil has become an important source of edible oil due to its significant cost advantage. However, there is a growing concern over its fatty acid composition and nutritional value. In Gossypium hirsutum, GhFAD2-1 and GhFATB encoding the microsomal oleate desaturase and palmitoyl-acyl carrier protein thioesterase, respectively, play critical roles in regulating the proportions of saturated and polyunsaturated fatty acids in cottonseed lipids. In this study, RNAi technology was used to simultaneously inhibit the expression levels of GhFAD2-1 and GhFATB to improve the quality of cottonseed oil by increasing oleic acid content...
June 15, 2017: Journal of Plant Physiology
https://www.readbyqxmd.com/read/28638070/thioesterase-ybgc-affects-motility-by-modulating-c-di-gmp-levels-in-shewanella-oneidensis
#18
Tong Gao, Qiu Meng, Haichun Gao
Because of ubiquity of thioesters, thioesterases play a critical role in metabolism, membrane biosynthesis, signal transduction, and gene regulation. In many bacteria, YbgC is such an enzyme, whose coding gene mostly resides in the tol-pal cluster. Although all other proteins encoded in the tol-pal cluster are clearly involved in maintaining cell envelope integrity and cell division, little is known about the physiological role of YbgC. In this study, we identify in Shewanella oneidensis, a γ-proteobacterium used as a research model for environmental microbes, YbgC as a motility regulator...
June 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28634299/biosynthesis-of-isonitrile-lipopeptides-by-conserved-nonribosomal-peptide-synthetase-gene-clusters-in-actinobacteria
#19
Nicholas C Harris, Michio Sato, Nicolaus A Herman, Frederick Twigg, Wenlong Cai, Joyce Liu, Xuejun Zhu, Jordan Downey, Ryan Khalaf, Joelle Martin, Hiroyuki Koshino, Wenjun Zhang
A putative lipopeptide biosynthetic gene cluster is conserved in many species of Actinobacteria, including Mycobacterium tuberculosis and M. marinum, but the specific function of the encoding proteins has been elusive. Using both in vivo heterologous reconstitution and in vitro biochemical analyses, we have revealed that the five encoding biosynthetic enzymes are capable of synthesizing a family of isonitrile lipopeptides (INLPs) through a thio-template mechanism. The biosynthesis features the generation of isonitrile from a single precursor Gly promoted by a thioesterase and a nonheme iron(II)-dependent oxidase homolog and the acylation of both amino groups of Lys by the same isonitrile acyl chain facilitated by a single condensation domain of a nonribosomal peptide synthetase...
July 3, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28607105/acyl-coa-thioesterase-1-acot1-regulates-ppar%C3%AE-to-couple-fatty-acid-flux-with-oxidative-capacity-during-fasting
#20
Mallory P Franklin, Aishwarya Sathyanarayan, Douglas G Mashek
Hepatic acyl-CoA thioesterase 1 (ACOT1) catalyzes the conversion of acyl-CoAs to fatty acids (FAs) and CoA. We sought to determine the role of ACOT1 in hepatic lipid metabolism in C57Bl/6J male mice 1 week after adenovirus-mediated Acot1 knockdown. Acot1 knockdown reduced liver triglyceride (TG) as a result of enhanced TG hydrolysis and subsequent FA oxidation. In vitro experiments demonstrated that Acot1 knockdown led to greater TG turnover and FA oxidation, suggesting that ACOT1 is important for controlling the rate of FA oxidation...
August 2017: Diabetes
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