5.9
CiteScore
5.9
Impact Factor
Volume 40 Issue 7
Jul.  2013

Regulatory Roles of Metabolites in Cell Signaling Networks

doi: 10.1016/j.jgg.2013.05.002
More Information
  • Corresponding author: E-mail address: xuwei_0706@fudan.edu.cn (Wei Xu); E-mail address: zhaosm@fudan.edu.cn (Shimin Zhao)
  • Received Date: 2013-05-16
  • Accepted Date: 2013-05-21
  • Rev Recd Date: 2013-05-21
  • Available Online: 2013-05-31
  • Publish Date: 2013-07-20
  • Mounting evidence suggests that cellular metabolites, in addition to being sources of fuel and macromolecular substrates, are actively involved in signaling and epigenetic regulation. Many metabolites, such as cyclic AMP, which regulates phosphorylation/dephosphorylation, have been identified to modulate DNA and histone methylation and protein stability. Metabolite-driven cellular regulation occurs through two distinct mechanisms: proteins allosterically bind or serve as substrates for protein signaling pathways, and metabolites covalently modify proteins to regulate their functions. Such novel protein metabolites include fumarate, succinyl-CoA, propionyl-CoA, butyryl-CoA and crontonyl-CoA. Other metabolites, including α-ketoglutarate, succinate and fumarate, regulate epigenetic processes and cell signaling via protein binding. Here, we summarize recent progress in metabolite-derived post-translational protein modification and metabolite-binding associated signaling regulation. Uncovering metabolites upstream of cell signaling and epigenetic networks permits the linkage of metabolic disorders and human diseases, and suggests that metabolite modulation may be a strategy for innovative therapeutics and disease prevention techniques.
  • [1]
    Adam, J., Hatipoglu, E., O'Flaherty, L. et al. Renal cyst formation in Fh1-deficient mice is independent of the Hif/Phd pathway: roles for fumarate in KEAP1 succination and Nrf2 signaling Cancer Cell, 20 (2011),pp. 524-537
    [2]
    Balaghi, M., Wagner, C. DNA methylation in folate deficiency: use of CpG methylase Biochem. Biophys. Res. Commun., 193 (1993),pp. 1184-1190
    [3]
    Blatnik, M., Frizzell, N., Thorpe, S.R. et al. Inactivation of glyceraldehyde-3-phosphate dehydrogenase by fumarate in diabetes: formation of S-(2-succinyl)cysteine, a novel chemical modification of protein and possible biomarker of mitochondrial stress Diabetes, 57 (2008),pp. 41-49
    [4]
    Bruneau, B.G. The developmental genetics of congenital heart disease Nature, 451 (2008),pp. 943-948
    [5]
    Chen, Y., Sprung, R., Tang, Y. et al. Lysine propionylation and butyrylation are novel post-translational modifications in histones Mol. Cell Proteomics, 6 (2007),pp. 812-819
    [6]
    Choudhary, C., Kumar, C., Gnad, F. et al. Lysine acetylation targets protein complexes and co-regulates major cellular functions Science, 325 (2009),pp. 834-840
    [7]
    Clifton, I.J., McDonough, M.A., Ehrismann, D. et al. Structural studies on 2-oxoglutarate oxygenases and related double-stranded beta-helix fold proteins J. Inorg. Biochem., 100 (2006),pp. 644-669
    [8]
    Colman, R.J., Anderson, R.M., Johnson, S.C. et al. Caloric restriction delays disease onset and mortality in rhesus monkeys Science, 325 (2009),pp. 201-204
    [9]
    Corvi, M.M., Soltys, C.L., Berthiaume, L.G. Regulation of mitochondrial carbamoyl-phosphate synthetase 1 activity by active site fatty acylation J. Biol. Chem., 276 (2001),pp. 45704-45712
    [10]
    Couture, J.F., Collazo, E., Ortiz-Tello, P.A. et al. Specificity and mechanism of JMJD2A, a trimethyllysine-specific histone demethylase Nat. Struct. Mol. Biol., 14 (2007),pp. 689-695
    [11]
    Couzin-Frankel, J. Genetics. Aging genes: the sirtuin story unravels Science, 334 (2011),pp. 1194-1198
    [12]
    Dang, L., White, D.W., Gross, S. et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate Nature, 465 (2010),p. 966
    [13]
    DiFrancesco, D., Tortora, P. Direct activation of cardiac pacemaker channels by intracellular cyclic AMP Nature, 351 (1991),pp. 145-147
    [14]
    Du, J., Zhou, Y., Su, X. et al. Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase Science, 334 (2011),pp. 806-809
    [15]
    Dwivedi, Y., Pandey, G.N. Adrenal glucocorticoids modulate [3H]cyclic AMP binding to protein kinase A (PKA), cyclic AMP-dependent PKA activity, and protein levels of selective regulatory and catalytic subunit isoforms of PKA in rat brain J. Pharmacol. Exp. Ther., 294 (2000),pp. 103-116
    [16]
    Enserink, J.M., Christensen, A.E., de Rooij, J. et al. A novel Epac-specific cAMP analogue demonstrates independent regulation of Rap1 and ERK Nat. Cell Biol., 4 (2002),pp. 901-906
    [17]
    Figueroa, M.E., Abdel-Wahab, O., Lu, C. et al. Cancer Cell, 18 (2010),pp. 553-567
    [18]
    Folkman, J. Role of angiogenesis in tumor growth and metastasis Semin. Oncol., 29 (2002),pp. 15-18
    [19]
    Isaacs, J.S., Jung, Y.J., Mole, D.R. et al. HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability Cancer Cell, 8 (2005),pp. 143-153
    [20]
    Jaeger, T., Mayer, C. J. Bacteriol., 190 (2008),pp. 6598-6608
    [21]
    Jakubowski, H., Zhang, L., Bardeguez, A. et al. Homocysteine thiolactone and protein homocysteinylation in human endothelial cells: implications for atherosclerosis Circ. Res., 87 (2000),pp. 45-51
    [22]
    Kim, S.C., Sprung, R., Chen, Y. et al. Substrate and functional diversity of lysine acetylation revealed by a proteomics survey Mol. Cell, 23 (2006),pp. 607-618
    [23]
    Koivunen, P., Lee, S., Duncan, C.G. et al. Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation Nature, 483 (2012),pp. 484-488
    [24]
    Lawson, C.L., Swigon, D., Murakami, K.S. et al. Catabolite activator protein: DNA binding and transcription activation Curr. Opin. Struct. Biol., 14 (2004),pp. 10-20
    [25]
    Li, X., Gianoulis, T.A., Yip, K.Y. et al. Cell, 143 (2010),pp. 639-650
    [26]
    Lin, S.Y., Li, T.Y., Liu, Q. et al. GSK3-TIP60-ULK1 signaling pathway links growth factor deprivation to autophagy Science, 336 (2012),pp. 477-481
    [27]
    Loenarz, C., Schofield, C.J. Expanding chemical biology of 2-oxoglutarate oxygenases Nat. Chem. Biol., 4 (2008),pp. 152-156
    [28]
    Lorentzen, A., Kinkhabwala, A., Rocks, O. et al. Regulation of Ras localization by acylation enables a mode of intracellular signal propagation Sci. Signal., 3 (2010),p. ra68
    [29]
    Lu, J.Y., Lin, Y.Y., Sheu, J.C. et al. Acetylation of yeast AMPK controls intrinsic aging independently of caloric restriction Cell, 146 (2011),pp. 969-979
    [30]
    Marczak, L., Sikora, M., Stobiecki, M. et al. J. Proteomics, 74 (2011),pp. 967-974
    [31]
    Meyer, C.J., Alenghat, F.J., Rim, P. et al. Mechanical control of cyclic AMP signalling and gene transcription through integrins Nat. Cell Biol., 2 (2000),pp. 666-668
    [32]
    Mor, A., Philips, M.R. Compartmentalized Ras/MAPK signaling Annu. Rev. Immunol., 24 (2006),pp. 771-800
    [33]
    Morozov, A., Muzzio, I.A., Bourtchouladze, R. et al. Rap1 couples cAMP signaling to a distinct pool of p42/44MAPK regulating excitability, synaptic plasticity, learning, and memory Neuron, 39 (2003),pp. 309-325
    [34]
    Nakagawa, T., Lomb, D.J., Haigis, M.C. et al. SIRT5 deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle Cell, 137 (2009),pp. 560-570
    [35]
    Osterrieder, W., Brum, G., Hescheler, J. et al. Nature, 298 (1982),pp. 576-578
    [36]
    Phillips, D.M. The presence of acetyl groups of histones Biochem. J., 87 (1963),pp. 258-263
    [37]
    Resh, M.D. Fatty acylation of proteins: new insights into membrane targeting of myristoylated and palmitoylated proteins Biochim. Biophys. Acta, 1451 (1999),pp. 1-16
    [38]
    Reuter, H. Calcium channel modulation by neurotransmitters, enzymes and drugs Nature, 301 (1983),pp. 569-574
    [39]
    Roy, S., Plowman, S., Rotblat, B. et al. Individual palmitoyl residues serve distinct roles in H-ras trafficking, microlocalization, and signaling Mol. Cell. Biol., 25 (2005),pp. 6722-6733
    [40]
    Schmidt, M.F., Schlesinger, M.J. Fatty acid binding to vesicular stomatitis virus glycoprotein: a new type of post-translational modification of the viral glycoprotein Cell, 17 (1979),pp. 813-819
    [41]
    Simmons, J.M., Muller, T.A., Hausinger, R.P. Fe(II)/alpha-ketoglutarate hydroxylases involved in nucleobase, nucleoside, nucleotide, and chromatin metabolism Dalton Trans., 38 (2008),pp. 5132-5142
    [42]
    Tan, M., Luo, H., Lee, S. et al. Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification Cell, 146 (2011),pp. 1016-1028
    [43]
    Tsukada, Y., Fang, J., Erdjument-Bromage, H. et al. Histone demethylation by a family of JmjC domain-containing proteins Nature, 439 (2006),pp. 811-816
    [44]
    Turcan, S., Rohle, D., Goenka, A. et al. Nature, 483 (2012),pp. 479-483
    [45]
    Veit, M. Biochem. J., 345 (2000),pp. 145-151
    [46]
    Veit, M., Sachs, K., Heckelmann, M. et al. Palmitoylation of rhodopsin with S-protein acyltransferase: enzyme catalyzed reaction versus autocatalytic acylation Biochim. Biophys. Acta, 1394 (1998),pp. 90-98
    [47]
    Wang, Q., Zhang, Y., Yang, C. et al. Acetylation of metabolic enzymes coordinates carbon source utilization and metabolic flux Science, 327 (2010),pp. 1004-1007
    [48]
    Wishart, D.S., Tzur, D., Knox, C. et al. HMDB: the Human Metabolome Database Nucleic Acids Res., 35 (2007),pp. D521-D526
    [49]
    Wright, L.P., Philips, M.R. Thematic review series: lipid posttranslational modifications. CAAX modification and membrane targeting of Ras J. Lipid. Res., 47 (2006),pp. 883-891
    [50]
    Xiao, M., Yang, H., Xu, W. et al. Inhibition of alpha-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors Genes Dev., 26 (2012),pp. 1326-1338
    [51]
    Xu, W., Yang, H., Liu, Y. et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases Cancer Cell, 19 (2011),pp. 17-30
    [52]
    Yi, C., Ma, M., Ran, L. et al. Function and molecular mechanism of acetylation in autophagy regulation Science, 336 (2012),pp. 474-477
    [53]
    Zhang, T., Wang, S., Lin, Y. et al. Acetylation negatively regulates glycogen phosphorylase by recruiting protein phosphatase 1 Cell Metab., 15 (2012),pp. 75-87
    [54]
    Zhang, Z., Tan, M., Xie, Z. et al. Identification of lysine succinylation as a new post-translational modification Nat. Chem. Biol., 7 (2011),pp. 58-63
    [55]
    Zhao, S., Xu, W., Jiang, W. et al. Regulation of cellular metabolism by protein lysine acetylation Science, 327 (2010),pp. 1000-1004
  • Relative Articles

    [1]Zhaoxu Gao, Yue Zhou, Yuehui He. Molecular epigenetic mechanisms for the memory of temperature stresses in plants[J]. Journal of Genetics and Genomics, 2022, 49(11): 991-1001. doi: 10.1016/j.jgg.2022.07.004
    [2]Shiwei Wan, Xiu-Fang Xin. Regulation and integration of plant jasmonate signaling: a comparative view of monocot and dicot[J]. Journal of Genetics and Genomics, 2022, 49(8): 704-714. doi: 10.1016/j.jgg.2022.04.002
    [3]Subhadip Kundu, M.D. Ray, Ashok Sharma. Interplay between genome organization and epigenomic alterations of pericentromeric DNA in cancer[J]. Journal of Genetics and Genomics, 2021, 48(3): 184-197. doi: 10.1016/j.jgg.2021.02.004
    [4]Zhiyao Lv, Rui Dai, Haoran Xu, Yongxin Liu, Bo Bai, Ying Meng, Haiyan Li, Xiaofeng Cao, Yang Bai, Xianwei Song, Jingying Zhang. The rice histone methylation regulates hub species of the root microbiota[J]. Journal of Genetics and Genomics, 2021, 48(9): 836-843. doi: 10.1016/j.jgg.2021.06.005
    [5]Kevin Christian Montecillo Gulay, Keisuke Aoshima, Yuki Shibata, Hironobu Yasui, Qin Yan, Atsushi Kobayashi, Takashi Kimura. KDM2B promotes cell viability by enhancing DNA damage response in canine hemangiosarcoma[J]. Journal of Genetics and Genomics, 2021, 48(7): 618-630. doi: 10.1016/j.jgg.2021.02.005
    [6]Dan Zhu, Jin Ge, Siyuan Guo, Li Hou, Rangjun Shi, Xian Zhou, Xin Nie, Xianhui Wang. Independent variations in genome-wide expression, alternative splicing, and DNA methylation in brain tissues among castes of the buff-tailed bumblebee, Bombus terrestris[J]. Journal of Genetics and Genomics, 2021, 48(8): 681-694. doi: 10.1016/j.jgg.2021.04.008
    [7]Xuezhu Wang, Yucheng Dong, Yongchang Zheng, Yang Chen. Multiomics metabolic and epigenetics regulatory network in cancer: A systems biology perspective[J]. Journal of Genetics and Genomics, 2021, 48(7): 520-530. doi: 10.1016/j.jgg.2021.05.008
    [8]Hyerim Kim, Xudong Wang, Peng Jin. Developing DNA methylation-based diagnostic biomarkers[J]. Journal of Genetics and Genomics, 2018, 45(2): 87-97. doi: 10.1016/j.jgg.2018.02.003
    [9]Ying Cheng, Dahua Chen. Fruit fly research in China[J]. Journal of Genetics and Genomics, 2018, 45(11): 583-592. doi: 10.1016/j.jgg.2018.09.003
    [10]Jacob Brix, Yan Zhou, Yonglun Luo. The Epigenetic Reprogramming Roadmap in Generation of iPSCs from Somatic Cells[J]. Journal of Genetics and Genomics, 2015, 42(12): 661-670. doi: 10.1016/j.jgg.2015.10.001
    [11]Anne Molitor, Wen-Hui Shen. The Polycomb Complex PRC1: Composition and Function in Plants[J]. Journal of Genetics and Genomics, 2013, 40(5): 231-238. doi: 10.1016/j.jgg.2012.12.005
    [12]Moshe Szyf. DNA Methylation, Behavior and Early Life Adversity[J]. Journal of Genetics and Genomics, 2013, 40(7): 331-338. doi: 10.1016/j.jgg.2013.06.004
    [13]Dongfeng Zhang, Shuxia Li, Qihua Tan, Zengchang Pang. Twin-Based DNA Methylation Analysis Takes the Center Stage of Studies of Human Complex Diseases[J]. Journal of Genetics and Genomics, 2012, 39(11): 581-586. doi: 10.1016/j.jgg.2012.07.012
    [14]Shulan Fu, Zhi Gao, James Birchler, Fangpu Han. Dicentric Chromosome Formation and Epigenetics of Centromere Formation in Plants[J]. Journal of Genetics and Genomics, 2012, 39(3): 125-130. doi: 10.1016/j.jgg.2012.01.006
    [15]Zengxiang Pan, Jinbi Zhang, Qifa Li, Yinxia Li, Fangxiong Shi, Zhuang Xie, Honglin Liu. Current Advances in Epigenetic Modification and Alteration during Mammalian Ovarian Folliculogenesis[J]. Journal of Genetics and Genomics, 2012, 39(3): 111-123. doi: 10.1016/j.jgg.2012.02.004
    [16]Yu Zhao, Dao-Xiu Zhou. Epigenomic Modification and Epigenetic Regulation in Rice[J]. Journal of Genetics and Genomics, 2012, 39(7): 307-315. doi: 10.1016/j.jgg.2012.02.009
    [17]Can Zhang, Bo Liu, Guangyao Li, Lei Zhou. Extra sex combs, chromatin, and cancer: Exploring epigenetic regulation and tumorigenesis in Drosophila[J]. Journal of Genetics and Genomics, 2011, 38(10): 453-460. doi: 10.1016/j.jgg.2011.09.007
    [18]Bao Liu, Chunming Xu, Na Zhao, Bao Qi, Josphert N. Kimatu, Jinsong Pang, Fangpu Han. Rapid genomic changes in polyploid wheat and related species: implications for genome evolution and genetic improvement[J]. Journal of Genetics and Genomics, 2009, 36(9): 519-528. doi: 10.1016/S1673-8527(08)60143-5
    [19]Moshe Feldman, Avraham A. Levy. Genome evolution in allopolyploid wheat—a revolutionary reprogramming followed by gradual changes[J]. Journal of Genetics and Genomics, 2009, 36(9): 511-518. doi: 10.1016/S1673-8527(08)60142-3
    [20]Xiaodong Zhao, Yijun Ruan, Chia-Lin Wei. Tackling the epigenome in the pluripotent stem cells[J]. Journal of Genetics and Genomics, 2008, 35(7): 403-412. doi: 10.1016/S1673-8527(08)60058-2
  • Created with Highcharts 5.0.7Amount of accessChart context menuAbstract Views, HTML Views, PDF Downloads StatisticsAbstract ViewsHTML ViewsPDF Downloads2024-062024-072024-082024-092024-102024-112024-122025-012025-022025-032025-042025-0502468
    Created with Highcharts 5.0.7Chart context menuAccess Class DistributionFULLTEXT: 20.2 %FULLTEXT: 20.2 %META: 78.7 %META: 78.7 %PDF: 1.1 %PDF: 1.1 %FULLTEXTMETAPDF
    Created with Highcharts 5.0.7Chart context menuAccess Area DistributionChina: 48.9 %China: 48.9 %Russian Federation: 10.6 %Russian Federation: 10.6 %United States: 40.4 %United States: 40.4 %ChinaRussian FederationUnited States

Catalog

    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索

    Article Metrics

    Article views (73) PDF downloads (1) Cited by ()
    Proportional views
    Related

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return