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Acetyl coa

Amit Ghosh, David Ando, Jennifer Gin, Weerawat Runguphan, Charles Denby, George Wang, Edward E K Baidoo, Chris Shymansky, Jay D Keasling, Héctor García Martín
Efficient redirection of microbial metabolism into the abundant production of desired bioproducts remains non-trivial. Here, we used flux-based modeling approaches to improve yields of fatty acids in Saccharomyces cerevisiae. We combined (13)C labeling data with comprehensive genome-scale models to shed light onto microbial metabolism and improve metabolic engineering efforts. We concentrated on studying the balance of acetyl-CoA, a precursor metabolite for the biosynthesis of fatty acids. A genome-wide acetyl-CoA balance study showed ATP citrate lyase from Yarrowia lipolytica as a robust source of cytoplasmic acetyl-CoA and malate synthase as a desirable target for downregulation in terms of acetyl-CoA consumption...
2016: Frontiers in Bioengineering and Biotechnology
Steven Zhao, AnnMarie Torres, Ryan A Henry, Sophie Trefely, Martina Wallace, Joyce V Lee, Alessandro Carrer, Arjun Sengupta, Sydney L Campbell, Yin-Ming Kuo, Alexander J Frey, Noah Meurs, John M Viola, Ian A Blair, Aalim M Weljie, Christian M Metallo, Nathaniel W Snyder, Andrew J Andrews, Kathryn E Wellen
Mechanisms of metabolic flexibility enable cells to survive under stressful conditions and can thwart therapeutic responses. Acetyl-coenzyme A (CoA) plays central roles in energy production, lipid metabolism, and epigenomic modifications. Here, we show that, upon genetic deletion of Acly, the gene coding for ATP-citrate lyase (ACLY), cells remain viable and proliferate, although at an impaired rate. In the absence of ACLY, cells upregulate ACSS2 and utilize exogenous acetate to provide acetyl-CoA for de novo lipogenesis (DNL) and histone acetylation...
October 18, 2016: Cell Reports
Haley Echlin, Matthew W Frank, Amy Iverson, Ti-Cheng Chang, Michael D L Johnson, Charles O Rock, Jason W Rosch
The pneumococcus is one of the most prodigious producers of hydrogen peroxide amongst bacterial pathogens. Hydrogen peroxide production by the pneumococcus has been implicated in antibiotic synergism, competition between other bacterial colonizers of the nasopharynx, and damage to epithelial cells. However, the role during invasive disease has been less clear with mutants defective in hydrogen peroxide production demonstrating both attenuation and heightened invasive disease capacity depending upon strain and serotype background...
October 2016: PLoS Pathogens
Yunpeng Wang, Lei Chen, Weiwen Zhang
BACKGROUND: 3-hydroxypropionic acid (3-HP) is an important platform chemical with a wide range of applications. In our previous study, the biosynthetic pathway of 3-HP was constructed and optimized in cyanobacterium Synechocystis sp. PCC 6803, which led to 3-HP production directly from CO2 at a level of 837.18 mg L(-1) (348.8 mg/g dry cell weight). As the production and accumulation of 3-HP in cells affect cellular metabolism, a better understanding of cellular responses to 3-HP synthesized internally in Synechocystis will be important for further increasing 3-HP productivity in cyanobacterial chassis...
2016: Biotechnology for Biofuels
Hye Yeon Koh, Hyun Park, Jun Hyuck Lee, Se Jong Han, Young Chang Sohn, Sung Gu Lee
Psychrobacter sp. PAMC 21119, isolated from Antarctic permafrost soil, grows and proliferates at subzero temperatures. However, its major mechanism of cold adaptation regulation remains poorly understood. We investigated the transcriptomic and proteomic responses of this species to cold temperatures by comparing profiles at -5°C and 20°C to understand how extreme microorganisms survive under subzero conditions. We found a total of 2,906 transcripts and 584 differentially expressed genes (≥ 2 fold, p <0...
October 17, 2016: Environmental Microbiology
Elissaveta Petrova, Arne Scholz, Juliane Paul, Andrea Sturz, Katja Haike, Franziska Siegel, Dominik Mumberg, Ningshu Liu
Acetyl-CoA carboxylase (ACC) is the rate-limiting enzyme in de novo fatty acid synthesis, and its ACC1 isoform is overexpressed in pancreatic and various other cancers. The activity of many oncogenic signaling molecules, including WNT and Hedgehog (HH), is post-translationally modified by lipidation. Here, we report that inhibition of ACC by a small molecule inhibitor, BAY ACC002, blocked WNT3A lipidation, secretion, and signaling. In pancreatic cancer cells, where WNT and HH are key oncogenic drivers, ACC inhibition simultaneously suppressed WNT and HH signaling, and led to anti-proliferative effects...
October 13, 2016: Oncotarget
Hiroki Otsuka, Hideo Sasai, Mina Nakama, Yuka Aoyama, Elsayed Abdelkreem, Hidenori Ohnishi, Vassiliki Konstantopoulou, Jörn Oliver Sass, Toshiyuki Fukao
Beta-ketothiolase deficiency, also known as mitochondrial acetoacetyl-CoA thiolase (T2) deficiency, is an autosomal recessive disease caused by mutations in the acetyl‑CoA acetyltransferase 1 (ACAT1) gene. A German T2‑deficient patient that developed a severe ketoacidotic episode at the age of 11 months, was revealed to be a compound heterozygote of a previously reported null mutation, c.472A>G (p.N158D) and a novel mutation, c.949G>A (p.D317N), in ACAT1. The c.949G>A mutation was suspected to cause aberrant splicing as it is located within an exonic splicing enhancer sequence (c...
October 10, 2016: Molecular Medicine Reports
Jingxue Wang, Sanjay K Singh, Chunfang Du, Chen Li, Jianchun Fan, Sitakanta Pattanaik, Ling Yuan
Rapeseed (Brassica napus) is an important oil seed crop, providing more than 13% of the world's supply of edible oils. An in-depth knowledge of the gene network involved in biosynthesis and accumulation of seed oil is critical for the improvement of B. napus. Using available genomic and transcriptomic resources, we identified 1,750 acyl-lipid metabolism (ALM) genes that are distributed over 19 chromosomes in the B. napus genome. B. rapa and B. oleracea, two diploid progenitors of B. napus, contributed almost equally to the ALM genes...
2016: Frontiers in Plant Science
Lalit Agrawal, Swati Gupta, Shashank K Mishra, Garima Pandey, Susheel Kumar, Puneet S Chauhan, Debasis Chakrabarty, Chandra S Nautiyal
Along with many adaptive strategies, dynamic changes in protein abundance seem to be the common strategy to cope up with abiotic stresses which can be best explored through proteomics. Understanding of drought response is the key to decipher regulatory mechanism of better adaptation. Rice (Oryza sativa L.) proteome represents a phenomenal source of proteins that govern traits of agronomic importance, such as drought tolerance. In this study, a comparison of root cytoplasmic proteome was done for a drought tolerant rice (Heena) cultivar in PEG induced drought conditions...
2016: Frontiers in Plant Science
Jifeng Yuan, Pranjul Mishra, Chi Bun Ching
Medium branched-chain esters can be used not only as a biofuel but are also useful chemicals with various industrial applications. The development of economically feasible and environment friendly bio-based fuels requires efficient cell factories capable of producing desired products in high yield. Herein, we sought to use a number of strategies to engineer Saccharomyces cerevisiae for high-level production of branched-chain esters. Mitochondrion-based expression of ATF1 gene in a base strain with an overexpressed valine biosynthetic pathway together with expression of mitochondrion-relocalized α-ketoacid decarboxylase (encoded by ARO10) and alcohol dehydrogenase (encoded by ADH7) not only produced isobutyl acetate, but also 3-methyl-1-butyl acetate and 2-methyl-1-butyl acetate...
October 13, 2016: Journal of Biotechnology
Zhenle Yang, Hongying Ji, Dantong Liu
Cyperus esculentus is unique in that it can accumulate rich oil in tuber. However, the underlying mechanism of tuber oil biosynthesis is still unclear. Our transcriptional analyses of the pathways from pyruvate production up to triacylglycerol (TAG) accumulation in tuber revealed many distinct species-specific lipid expression patterns from oil seeds and fruits, indicating that in C. esculentus tuber, (1) carbon flux from sucrose toward plastid pyruvate could be produced mostly through cytosolic glycolytic pathway, (2) acetyl-CoA synthetase might be an important contributor to acetyl-CoA formation for plastid fatty acid biosynthesis, (3) expression pattern for stearoyl-ACP desaturase was associated with high oleic acid composition, (4) it was most likely that endoplasmic reticulum-associated acyl-CoA synthetase played a significant role in the export of fatty acids between the plastid and ER, (5) lipid phosphate phosphatase (LPP)-δ was most probably related to the formation of DAG pool in Kennedy pathway, (6) diacylglyceroltransacylase 2 (DGAT2) and phospholipid:diacylglycerolacyltransferase 1 (PDAT1) might play crucial roles in tuber oil biosynthesis...
October 13, 2016: Plant & Cell Physiology
Parsa Tehranchian, Jason K Norsworthy, Nicholas E Korres, Scott McElroy, Shu Chen, Robert C Scott
Amazon sprangletop is problematic weed of rice in the midsouthern USA. Two biotypes of this species from rice fields approximately 100km apart in Louisiana were unaffected when sprayed with the labeled field rate of cyhalofop-butyl (314g ai ha(-1)) in 2008. Dose response studies were conducted to confirm the level of resistance to cyhalofop-butyl over a range of doses. Cross-resistance to acetyl-CoA carboxylase (ACCase)-inhibiting herbicides from two different chemical families and multiple herbicide resistance to other mechanisms of action were evaluated...
October 2016: Pesticide Biochemistry and Physiology
Huabo Wang, Jie Lu, Lia R Edmunds, Sucheta Kulkarni, James Dolezal, Junyan Tao, Sarangarajan Ranganathan, Laura Jackson, Marc Fromherz, Donna Beer Stolz, Radha Uppala, Sivakama Bharathi, Satdarshan P Monga, Eric S Goetzman, Edward V Prochownik
Hepatoblastoma (HB) is associated with aberrant activation of the β-catenin and Hippo/YAP signaling pathways. Over-expression of mutant β-catenin and YAP in mice induces HBs that express high levels of c-Myc (Myc). In light of recent observations that Myc in unnecessary for long-term hepatocyte proliferation, we have now examined its role in HB pathogenesis using the above model. While Myc was found to be dispensable for in vivo HB initiation it was necessary to sustain rapid tumor growth. Gene expression profiling identified key molecular differences between myc+/+ (WT) and myc-/- (KO) hepatocytes and HBs that explain these behaviors...
October 13, 2016: Journal of Biological Chemistry
Lina Yao, Hui Shen, Nan Wang, Jaspaul Tatlay, Liang Li, Tin Wee Tan, Yuan Kun Lee
Microalgal neutral lipids (mainly in the form of triacylglycerols (TAGs)), feasible substrates for biofuel, are typically accumulated during the stationary growth phase. To make microalgal biofuels economically competitive with fossil fuels, generating strains that trigger TAG accumulation from the exponential growth phase is a promising biological approach. The regulatory mechanisms to trigger TAG accumulation from the exponential growth phase (TAEP) are important to be uncovered for advancing economic feasibility...
October 13, 2016: Plant Biotechnology Journal
Jidong Zhou, Dexin Wang, Chenghong Wang, Jinjie Gu, Chul Ho Kim, Jiping Shi, Biao Jiang, Min Wang, Jian Hao
Pyruvate dehydrogenase-complex (AcoABCD) and pyruvate formate-lyase (PFL) are two pathways responsible for synthesis of acetyl-CoA from pyruvate (pyruvate acetyl-CoA switch). The two pathways were individually deleted in Klebsiella pneumoniae, and the role of the pyruvate acetyl-CoA switch in 1,3-propanediol production was investigated. Fermentation results showed that the two pathways were both active in the wild-type strain. Acetyl-CoA formation between the two pathways was equal in the wild-type strain. The pflB mutant produced high level of lactic acid, and deletion of ldhA eliminated lactic acid synthesis...
October 12, 2016: Applied Biochemistry and Biotechnology
Luciano Galdieri, Himavanth Gatla, Ivana Vancurova, Ales Vancura
AMP-activated protein kinase (AMPK) is an energy sensor and master regulator of metabolism. AMPK functions as a fuel gauge monitoring systemic and cellular energy status. Activation of AMPK occurs when the intracellular AMP/ATP ratio increases and leads to a metabolic switch from anabolism to catabolism. AMPK phosphorylates and inhibits acetyl-CoA carboxylase (ACC), which catalyzes carboxylation of acetyl-CoA to malonyl-CoA, the first and rate-limiting reaction in de-novo synthesis of fatty acids. AMPK thus regulates homeostasis of acetyl-CoA, a key metabolite at the crossroads of metabolism, signaling, chromatin structure, and transcription...
October 12, 2016: Journal of Biological Chemistry
Tomoko Abe, Yoshiteru Hashimoto, Sayaka Sugimoto, Kenta Kobayashi, Takuto Kumano, Michihiko Kobayashi
The adenylation domain of nonribosomal peptide synthetase (NRPS) is responsible for the selective substrate recognition and its activation (as an acyl-O-AMP intermediate) during ATP consumption. DhbE, a stand-alone adenylation domain, acts on an aromatic acid, 2,3-dihydroxybenzoic acid (DHB). This activation is the initial step of the synthesis of bacillibactin that is a high-affinity small-molecule iron chelator also termed siderophore. Subsequently, the activated DHB is transferred and attached covalently to a peptidyl carrier protein domain via a thioester bond...
October 12, 2016: Journal of Antibiotics
Futoshi Taura, Miu Iijima, Eriko Yamanaka, Hironobu Takahashi, Hiromichi Kenmoku, Haruna Saeki, Satoshi Morimoto, Yoshinori Asakawa, Fumiya Kurosaki, Hiroyuki Morita
Rhododendron dauricum L. produces daurichromenic acid, the anti-HIV meroterpenoid consisting of sesquiterpene and orsellinic acid (OSA) moieties. To characterize the enzyme responsible for OSA biosynthesis, a cDNA encoding a novel polyketide synthase (PKS), orcinol synthase (ORS), was cloned from young leaves of R. dauricum. The primary structure of ORS shared relatively low identities to those of PKSs from other plants, and the active site of ORS had a unique amino acid composition. The bacterially expressed, recombinant ORS accepted acetyl-CoA as the preferable starter substrate, and produced orcinol as the major reaction product, along with four minor products including OSA...
2016: Frontiers in Plant Science
Jeremy S Francis, Ireneusz Wojtas, Vladimir Markov, Steven J Gray, Thomas J McCown, R Jude Samulski, Larissa T Bilaniuk, Dah-Jyuu Wang, Darryl C De Vivo, Christopher G Janson, Paola Leone
Breakdown of neuro-glial N-acetyl-aspartate (NAA) metabolism results in the failure of developmental myelination, manifest in the congenital pediatric leukodystrophy Canavan disease caused by mutations to the sole NAA catabolizing enzyme aspartoacylase. Canavan disease is a major point of focus for efforts to define NAA function, with available evidence suggesting NAA serves as an acetyl donor for fatty acid synthesis during myelination. Elevated NAA is a diagnostic hallmark of Canavan disease, which contrasts with a broad spectrum of alternative neurodegenerative contexts in which levels of NAA are inversely proportional to pathological progression...
October 4, 2016: Neurobiology of Disease
Jeong Mo Bae, Jung Ho Kim, Hyeon Jeong Oh, Hye Eun Park, Tae Hun Lee, Nam-Yun Cho, Gyeong Hoon Kang
Acetyl-CoA synthetase-2 is an emerging key enzyme for cancer metabolism, which supplies acetyl-CoA for tumor cells by capturing acetate as a carbon source under stressed conditions. However, implications of acetyl-CoA synthetase-2 in colorectal carcinoma may differ from other malignancies, because normal colonocytes use short-chain fatty acids as an energy source, which are supplied by fermentation of the intestinal flora. Here we analyzed acetyl-CoA synthetase-2 mRNA expression by reverse-transcription quantitative PCR in paired normal mucosa and tumor tissues of 12 colorectal carcinomas, and subsequently evaluated acetyl-CoA synthetase-2 protein expression by immunohistochemistry in 157 premalignant colorectal lesions, including 60 conventional adenomas and 97 serrated polyps, 1,106 surgically resected primary colorectal carcinomas, and 23 metastatic colorectal carcinomas in the liver...
October 7, 2016: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
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