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Citrate lyase

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
Mahmoud El Azzouny, Melissa J Longacre, Israr-Ul H Ansari, Robert T Kennedy, Charles F Burant, Michael J MacDonald
OBJECTIVE: Glucose-stimulated insulin secretion in pancreatic beta cells requires metabolic signals including the generation of glucose-derived short chain acyl-CoAs in the cytosol from mitochondrially-derived metabolites. One concept of insulin secretion is that ATP citrate lyase generates short chain acyl-CoAs in the cytosol from mitochondrially-derived citrate. Of these, malonyl-CoA, is believed to be an important signal in insulin secretion. Malonyl-CoA is also a precursor for lipids...
October 2016: Molecular Metabolism
Anthony J Zera, Rebecca Clark, Spence Behmer
The influence of variable nutritional input on life history adaptation is a central, but incompletely understood aspect of life history physiology. The wing-polymorphic cricket, Gryllus firmus, has been extensively studied with respect to the biochemical basis of life history adaptation, in particular, modification of lipid metabolism that underlies the enhanced accumulation of lipid flight fuel in the dispersing morph [LW(f)=long wings with functional flight muscles] relative to the flightless (SW=short-winged) morph...
September 28, 2016: Journal of Insect Physiology
Cen Zhang, Juan Liu, Grace Huang, Yuhan Zhao, Xuetian Yue, Hao Wu, Jun Li, Junlan Zhu, Zhiyuan Shen, Bruce G Haffty, Wenwei Hu, Zhaohui Feng
Increased lipid synthesis is a key characteristic of many cancers that is critical for cancer progression. ATP-citrate lyase (ACLY), a key enzyme for lipid synthesis, is frequently overexpressed or activated in cancer to promote lipid synthesis and tumor progression. Cullin3 (CUL3), a core protein for the CUL3-RING ubiquitin ligase complex, has been reported to be a tumor suppressor and frequently down-regulated in lung cancer. Here, we found that CUL3 interacts with ACLY through its adaptor protein, KLHL25 (Kelch-like family member 25), to ubiquitinate and degrade ACLY in cells...
September 1, 2016: Genes & Development
Ozlem Bilen, Christie M Ballantyne
Bempedoic acid (ETC-1002), a novel therapeutic approach for low-density lipoprotein cholesterol (LDL-C) lowering, inhibits ATP citrate lyase (ACL), an enzyme involved in fatty acid and cholesterol synthesis. Although rodent studies suggested potential effects of ACL inhibition on both fatty acid and cholesterol synthesis, studies in humans show an effect only on cholesterol synthesis. In phase 2 studies, ETC-1002 reduced LDL-C as monotherapy, combined with ezetimibe, and added to statin therapy, with LDL-C lowering most pronounced when ETC-1002 was combined with ezetimibe in patients who cannot tolerate statins...
October 2016: Current Atherosclerosis Reports
G Li, M Li, J Hu, R Lei, H Xiong, H Ji, H Yin, Q Wei, G Hu
Reprogrammed metabolism is one of the hallmarks of cancer. The dysregulation of glycolysis in cancer has been heavily studied. However, it remains largely unclear how other metabolic processes are regulated in cancer cells. Here we show that microRNA-182 (miR-182) suppresses pyruvate dehydrogenase (PDH) kinase 4 (PDK4) and promotes lung tumorigenesis. miR-182 is dysregulated and inversely correlated with PDK4 in human lung adenocarcinomas. The miR-182-PDK4 axis regulates lung cancer cell growth by modulating the activity of PDH, the gatekeeping enzyme of pyruvate flux into acetyl-CoA, and subsequently de novo lipogenesis of cancer cells...
September 19, 2016: Oncogene
Anja Karlstaedt, Xiaotian Zhang, Heidi Vitrac, Romain Harmancey, Hernan Vasquez, Jing Han Wang, Margaret A Goodell, Heinrich Taegtmeyer
Hematologic malignancies are frequently associated with cardiac pathologies. Mutations of isocitrate dehydrogenase 1 and 2 (IDH1/2) occur in a subset of acute myeloid leukemia patients, causing metabolic and epigenetic derangements. We have now discovered that altered metabolism in leukemic cells has a profound effect on cardiac metabolism. Combining mathematical modeling and in vivo as well as ex vivo studies, we found that increased amounts of the oncometabolite d-2-hydroxyglutarate (D2-HG), produced by IDH2 mutant leukemic cells, cause contractile dysfunction in the heart...
September 13, 2016: Proceedings of the National Academy of Sciences of the United States of America
S Bellou, I-E Triantaphyllidou, P Mizerakis, G Aggelis
Yarrowia lipolytica cultivated under double nitrogen and magnesium limitation, but not under single nitrogen or single magnesium limitation, produced 12.2g/l biomass containing 47.5% lipids, which corresponds to a lipid production 5.8g/l. These yields are the higher described in the literature for wild strains of Y. lipolytica. Transcription of ACL1 and ACL2, encoding for ATP-citrate lyase (ATP:CL) was observed even under non-oleaginous conditions but high activity of ATP:CL was only detected under oleaginous conditions induced by low or zero activity of NAD(+) dependent isocitrate dehydrogenase...
September 20, 2016: Journal of Biotechnology
Min-Chul Lee, Jeonghoon Han, Seung-Hwi Lee, Duck-Hyun Kim, Hye-Min Kang, Eun-Ji Won, Dae-Sik Hwang, Jun Chul Park, Ae-Son Om, Jae-Seong Lee
De novo lipogenesis (DNL) is a fatty acid synthesis process that requires several genes, including sterol regulatory element binding protein (SREBP), ATP-citrate lyase (ACLY), and acetyl-CoA carboxylase (ACC). DNL up-regulation is able to induce fat accumulation through an increase in fatty acids. To investigate the relationship between DNL up-regulation and the accumulation of fatty acids and lipid droplets in response to 2,2',4,4' tetrabrominated diphenyl ether (BDE-47), we examined DNL in the copepod Tigriopus japonicus...
September 2016: Aquatic Toxicology
Chun-Xue Zhou, Xing-Quan Zhu, Hany M Elsheikha, Shuai He, Qian Li, Dong-Hui Zhou, Xun Suo
UNLABELLED: Toxoplasma gondii is a medically and economically important protozoan parasite. However, the molecular mechanisms of its sporulation remain largely unknown. Here, we applied iTRAQ coupled with 2D LC-MS/MS proteomic analysis to investigate the proteomic expression profile of T. gondii oocysts during sporulation. Of the 2095 non-redundant proteins identified, 587 were identified as differentially expressed proteins (DEPs). Based on Gene Ontology enrichment and KEGG pathway analyses the majority of these DEPs were found related to the metabolism of amino acids, carbon and energy...
October 4, 2016: Journal of Proteomics
M N Li, X Guo, P J Bao, X Y Wu, X Z Ding, M Chu, C N Liang, P Yan
ATP citrate lyase (ACLY) is the primary enzyme responsible for the synthesis of cytosolic acetyl-CoA, which is a key precursor of both fatty acid and mevalonate synthesis pathways. Genetic variation of the ACLY gene may influence multiple traits associated with animal production. Here, we identified three non-synonymous mutations in ACLY exons in five beef cattle populations using DNA pool sequencing and high-resolution melting analysis. Results from association analyses revealed that the single nucleotide polymorphism (SNP) g...
2016: Genetics and Molecular Research: GMR
Federico Pietrocola, Jonathan Pol, Erika Vacchelli, Shuan Rao, David P Enot, Elisa E Baracco, Sarah Levesque, Francesca Castoldi, Nicolas Jacquelot, Takahiro Yamazaki, Laura Senovilla, Guillermo Marino, Fernando Aranda, Sylvère Durand, Valentina Sica, Alexis Chery, Sylvie Lachkar, Verena Sigl, Norma Bloy, Aitziber Buque, Simonetta Falzoni, Bernhard Ryffel, Lionel Apetoh, Francesco Di Virgilio, Frank Madeo, Maria Chiara Maiuri, Laurence Zitvogel, Beth Levine, Josef M Penninger, Guido Kroemer
Caloric restriction mimetics (CRMs) mimic the biochemical effects of nutrient deprivation by reducing lysine acetylation of cellular proteins, thus triggering autophagy. Treatment with the CRM hydroxycitrate, an inhibitor of ATP citrate lyase, induced the depletion of regulatory T cells (which dampen anticancer immunity) from autophagy-competent, but not autophagy-deficient, mutant KRAS-induced lung cancers in mice, thereby improving anticancer immunosurveillance and reducing tumor mass. Short-term fasting or treatment with several chemically unrelated autophagy-inducing CRMs, including hydroxycitrate and spermidine, improved the inhibition of tumor growth by chemotherapy in vivo...
July 11, 2016: Cancer Cell
Ling-Xia Guo, Cai-Yun Shi, Xiao Liu, Dong-Yuan Ning, Long-Fei Jing, Huan Yang, Yong-Zhong Liu
'Hong Anliu' (HAL, Citrus sinensis cv. Hong Anliu) is a bud mutant of 'Anliu' (AL), characterized by a comprehensive metabolite alteration, such as lower accumulation of citrate, high accumulation of lycopene and soluble sugars in fruit juice sacs. Due to carboxylic acid metabolism connects other metabolite biosynthesis and/or catabolism networks, we therefore focused analyzing citrate accumulation-related gene expression profiles and/or enzyme activities, along with metabolic fingerprinting between 'HAL' and 'AL'...
2016: Scientific Reports
Imran Ahmad, Ernest Mui, Laura Galbraith, Rachana Patel, Ee Hong Tan, Mark Salji, Alistair G Rust, Peter Repiscak, Ann Hedley, Elke Markert, Carolyn Loveridge, Louise van der Weyden, Joanne Edwards, Owen J Sansom, David J Adams, Hing Y Leung
Prostate cancer (CaP) is the most common adult male cancer in the developed world. The paucity of biomarkers to predict prostate tumor biology makes it important to identify key pathways that confer poor prognosis and guide potential targeted therapy. Using a murine forward mutagenesis screen in a Pten-null background, we identified peroxisome proliferator-activated receptor gamma (Pparg), encoding a ligand-activated transcription factor, as a promoter of metastatic CaP through activation of lipid signaling pathways, including up-regulation of lipid synthesis enzymes [fatty acid synthase (FASN), acetyl-CoA carboxylase (ACC), ATP citrate lyase (ACLY)]...
July 19, 2016: Proceedings of the National Academy of Sciences of the United States of America
Mei Xin, Zhiguang Qiao, Jing Li, Jianjun Liu, Shaoli Song, Xiaoping Zhao, Ping Miao, Tingting Tang, Lei Wang, Weichun Liu, Xiaodi Yang, Kerong Dai, Gang Huang
MicroRNAs (miRNAs) are non-coding small RNAs that function as negative regulators of gene expression involving in the tumor biology. ATP citrate lyase (ACLY), a key enzyme initiating de novo lipid synthesis, has been found to be upregulated in cancer cells, and its inhibition causes suppressive effects in a variety of tumors. At present, although several ACLY inhibitors have been reported, the potential role of miRNAs in interfering ACLY still needs further clarification. Herein, four different types of tumor cells including osteosarcoma, prostate, cervical and lung cancers were adopted in our study, and we have demonstrated that miR-22 directly downregulated ACLY...
June 14, 2016: Oncotarget
Dorota M Krzyżanowska, Adam Ossowicki, Magdalena Rajewska, Tomasz Maciąg, Magdalena Jabłońska, Michał Obuchowski, Stephan Heeb, Sylwia Jafra
Dickeya solani and Pectobacterium carotovorum subsp. brasiliense are recently established species of bacterial plant pathogens causing black leg and soft rot of many vegetables and ornamental plants. Pseudomonas sp. strain P482 inhibits the growth of these pathogens, a desired trait considering the limited measures to combat these diseases. In this study, we determined the genetic background of the antibacterial activity of P482, and established the phylogenetic position of this strain. Pseudomonas sp. P482 was classified as Pseudomonas donghuensis...
2016: Frontiers in Microbiology
Supriya Shah, Whitney J Carriveau, Jinyang Li, Sydney L Campbell, Piotr K Kopinski, Hee-Woong Lim, Natalie Daurio, Sophie Trefely, Kyoung-Jae Won, Douglas C Wallace, Constantinos Koumenis, Anthony Mancuso, Kathryn E Wellen
The androgen receptor (AR) plays a central role in prostate tumor growth. Inappropriate reactivation of the AR after androgen deprivation therapy promotes development of incurable castration-resistant prostate cancer (CRPC). In this study, we provide evidence that metabolic features of prostate cancer cells can be exploited to sensitize CRPC cells to AR antagonism. We identify a feedback loop between ATP-citrate lyase (ACLY)-dependent fatty acid synthesis, AMPK, and the AR in prostate cancer cells that could contribute to therapeutic resistance by maintaining AR levels...
May 27, 2016: Oncotarget
Maria L Balmer, Eric H Ma, Glenn R Bantug, Jasmin Grählert, Simona Pfister, Timo Glatter, Annaïse Jauch, Sarah Dimeloe, Emma Slack, Philippe Dehio, Magdalena A Krzyzaniak, Carolyn G King, Anne-Valérie Burgener, Marco Fischer, Leyla Develioglu, Réka Belle, Mike Recher, Weldy V Bonilla, Andrew J Macpherson, Siegfried Hapfelmeier, Russell G Jones, Christoph Hess
How systemic metabolic alterations during acute infections impact immune cell function remains poorly understood. We found that acetate accumulates in the serum within hours of systemic bacterial infections and that these increased acetate concentrations are required for optimal memory CD8(+) T cell function in vitro and in vivo. Mechanistically, upon uptake by memory CD8(+) T cells, stress levels of acetate expanded the cellular acetyl-coenzyme A pool via ATP citrate lyase and promoted acetylation of the enzyme GAPDH...
June 21, 2016: Immunity
Zhenguo Ma, Frédéric Marsolais, Mark A Bernards, Mark W Sumarah, Natalia V Bykova, Abir U Igamberdiev
During the developmental processes from dry seeds to seedling establishment, the glyoxylate cycle becomes active in the mobilization of stored oils in the scutellum of barley (Hordeum vulgare L.) seeds, as indicated by the activities of isocitrate lyase and malate synthase. The succinate produced is converted to carbohydrates via phosphoenolpyruvate carboxykinase and to amino acids via aminotransferases, while free organic acids may participate in acidifying the endosperm tissue, releasing stored starch into metabolism...
July 2016: Plant Science: An International Journal of Experimental Plant Biology
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