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Regulatory Role of Free Fatty Acids (FFAs)—Palmitoylation and Myristoylation

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DOI: 10.4236/fns.2013.49A1028    4,738 Downloads   6,547 Views   Citations

ABSTRACT

Multicellular organisms use chemical messengers to transmit signals among organelles and to other cells. Relatively small hydrophobic molecules such as lipids are excellent candidates for this signaling purpose. In most proteins, palmitic acid and other saturated and some unsaturated fatty acids are esterified to the free thiol of cysteines and to the N-amide terminal. This palmitoylation process enhances the surface hydrophobicity and membrane affinity of protein substrates and plays important roles in modulating proteins trafficking, stability, and sorting etc. Protein palmitoylation has been involved in numerous cellular processes, including signaling, apoptosis, and neuronal transmission. The palmitoylation process is involved in multiple diseases such as Huntington’s disease, various cardiovascular and T-cell mediated immune disorders, as well as cancer. Protein palmitoylation through the thioester (S-acylation) is unique in that it is the only reversible lipid modification. Our study on lipopolysaccharide (LPS) and deoxynivalenol (DON) treatment to rats provides some insights to the complex role of protein palmitoylation in chemical and microbial toxicity. In contrast, myrisoylated proteins contain the 14-carbon fatty acid myristate attached via amide linkage to the N-terminal glycine residue of protein, and occur cotranslationally. The bacterial outer membrane enzyme lipid A palmitoyltransferase (PagP) confers resistance to host immune defenses by transferring a palmitate chain from a phospholipid to the lipid A component of LPS. PagP is sensitive to cationic antimicrobial peptides (CAMP) which are included among the products of the Toll-like receptor 4 (TLR4) signal transduction pathway. This modification of lipid A with a palmitate appears to both and protects the pathogenic bacteria from host immune defenses and attenuates the activation of those same defenses through the TLR4 signal transduction pathway.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

C. Kim and I. Ross, "Regulatory Role of Free Fatty Acids (FFAs)—Palmitoylation and Myristoylation," Food and Nutrition Sciences, Vol. 4 No. 9A, 2013, pp. 202-211. doi: 10.4236/fns.2013.49A1028.

References

[1] C. Wilcox, J. S. Hu and E. N. Olson, “Acylation of Proteins with Myristic Acid Occurs Cotranslationally,” Science, Vol. 238, No. 4831, 1987, pp. 1275-1278. doi:10.1126/science.3685978
[2] I. Izawa, M. Nishizawa, Y. Hayashi and M. Inagaki, “Palmitoylation of ERBN Is Required for Its Plasma Membrane Localization,” Genes Cells, Vol. 13, No. 7, 2008, pp. 691-701.
doi:10.1111/j.1365-2443.2008.01198.x
[3] Z. Xie, W. T. Ho and J. H. Exton, “Requirements and Effects of Palmitoylation of Rat PLD1,” The Journal of Biological Chemistry, Vol. 276, No. 12, 2001, pp. 93839391. doi:10.1074/jbc.M009425200
[4] N. D. Holliday and H. M. Cox, “Control of Signaling Efficacy by Palmitoylation of the Rat Y1 Receptor,” British Journal of Pharmacology, Vol. 139, No. 3, 2003, pp. 501-512. doi:10.1038/sj.bjp.0705276
[5] A. Harishchandran and R. Nagaraj, “Interaction of a Pseudosubstrate Peptide of Protein Kinase C and Its Myristoylated from with Lipid Vesicles: Only the Myristoylated Form Translocates into the Lipid Bilayer,” Biochimica et Biophysica Acta, Vol. 1713, No. 2, 2005, pp. 73-82. doi:10.1016/j.bbamem.2005.05.008
[6] F. Uno, J. Sasaki, M. Nishizaki, G. Carboni, K. Xu, E. N. Atkinson, M. Kondo, J. D. Minna , J. A. Roth and L. Ji, “Myristoylation of the Fus1 Protein Is Required for Tumor Suppression in Human Lung Cancer Cells,” Cancer Research, Vol. 64, No. 9, 2004, pp. 2969-2976. doi:10.1158/0008-5472.CAN-03-3702
[7] A. Aitken, P. Cohen, S. Santikarn, D. H. Williams, A. G. Calder, A. Smith and C. B. Klee, “Identification of the NH2-Terminal Blocking Group of Calcineurin B as Myristic Acid,” FEBS Letters, Vol. 150, No. 2, 1982, pp. 314-318. doi:10.1016/0014-5793(82)80759-X
[8] S. A. Carr, K. Biemann, S. Shoji, D. C. Parmalee and K. Titani, “N-Tetradecanoyl Is the NH2-Terminal Blocking Group of the Catalytic Submits of Cyclic AMP-Dependent Protein Kinase from Bovine Cardiac Muscles,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 79, No. 20, 1982, pp. 61286131. doi:10.1073/pnas.79.20.6128
[9] E. N. Olson and G. Spizz, “Fatty Acylation of Cellular Proteins. Temporal and Subcellular Differences between Palmitate and Myristate Acylation,” The Journal of Biological Chemistry, Vol. 261, No. 5, 1986, pp. 2458-2466.
[10] E. N. Olson, “Modification of Proteins with Covalent Lipids,” Progress in Lipid Research, Vol. 27, No. 3, 1988, pp. 177-197. doi:10.1016/0163-7827(88)90012-4
[11] A. M. Dizhoor, L. H. Ericsson, R. S. Johnson, S. Kumar, E. Olshevskaya, S. Zozulya, T. A. Neubert, L. Stryer, J. B. Hurley and K. A. Walsh, “The NH2 Terminus of Retinal Recoverin Is Acylated by a Small Family of Fatty Acids,” The Journal of Biological Chemistry, Vol. 267, No. 23, 1992, pp. 16033-16036.
[12] W. Onkenhout, V. Venizelos, P. F. van der Poel. M. P. van den Heuvel and B. J. Poorthuis, “Identification and Quantification of Intermediates of Unsaturated Fatty Acid Metabolism in Plasma of Patients with Fatty Acid Oxidation Disorders,” Clinical Chemistry, Vol. 41, No. 10, 1995, pp. 1467-1474.
[13] K. Iguchi, N. Okumura, S. Usui, H. Sajiki, K. Hirota and K. Hirano, “Myristoleic Acid, a Cytotoxic Component in the Extract From Serenoa Repens, Induces Apoptosis and Necrosis in Human Prostatic LNCaP Cells,” Prostate, Vol. 47, No. 1, 2001, pp. 59-65. doi:10.1002/pros.1047
[14] A. Wolven, W. van’t Hof and M. D. Resh, “Analysis of Myristoylated and Palmitoylated Src Family Proteins,” Methods in Molecular Biology, Vol. 84, 1998, pp. 261266.
[15] S. Tardivel, A. Gousset-Dupont, V. Robert, M. L. Pourci, A. Grynberg and B. Lacour, “Protective Effects of EPA and Deleterious Effects of DHA on eNOS Activity in Ea hy 926 Culture with Lysophosphatidylcholine,” Lipids, Vol. 44, No. 3, 2009, pp. 225-235. doi:10.1007/s11745-009-3284-8
[16] K. Ramanathan, M. Anusuyadevi, S. Shila and C. Panneerselvam, “Ascorbic Acid and Alpha-Tocopherol as Potent Modulators of Apoptosis on Arsenic Induced Toxicity in Rats,” Toxicology Letters, Vol. 156, No. 2, 2005, pp. 297-306. doi:10.1016/j.toxlet.2004.12.003
[17] I. A. Ross, T. Boyle, W. D. Johnson, R. L. Sprando, M. W. O’Donnell, D. Ruggles and C. S. Kim, “Free Fatty Acids Profile of the Fetal Brain and the Plasma, Liver, Brain, and Kidneys of Pregnant Rats Treated with Sodium Arsenite at Mid-organogenesis,” Toxicology and Industrial Health, Vol. 26, No. 10, 2010, pp. 657-666. doi:10.1177/0748233710375952
[18] J. Dong and S. Y. Su, “The Association between Arsenic and Children’s Intelligence: A Meta-Analysis,” Biological Trace Element Research, Vol. 129, No. 1-3, 2008, pp. 88-93.
[19] J. Kang, Y. Jin, Y. Cheng and K. Wu, “Effects of Arsenic in Drinking Water on Children’s Intelligence,” Wei Sheng Yan Jiu, Vol. 36, No. 3, 2007, pp. 347-349.
[20] G. Samanta, D. Das, B. K. Mandal, T. R. Chowdhury, D. Chakraborti, A. Pal and S. Ahamed, “Arsenic in the Breast Milk of Lactating Women in Arsenic-Affected Areas of West Bengal, India and It Effects on Infants,” Journal of Environmental Science and Health, Part A. Toxic/Hazardous Substances and Environmental Engineerin, Vol. 42, No. 12, 2007, pp. 1815-1825.
[21] K. Hiroyuki, H. Suzuki, M. Naito, T. Tsuruo and Y. Sugiyama, “Characterization of Efflux Transport of Organic Anions in a Mouse Brain Capillary Endothelial Cell Line,” The Journal of Pharmacology and Experimental Therapeutics, Vol. 285, No. 3, 1998, pp. 1260-1265.
[22] A. D. Munday and J. A. Lopez, “Posttranslational Protein Palmitoylation: Promoting Platelet Purpose Arteriosclerosis,” Thrombosis, and Vascular Biology, Vol. 27, No. 7, 2007, pp. 1496-1499.
doi:10.1161/ATVBAHA.106.136226
[23] M. D. Resh, “Fatty Acylation of Proteins: New Insights into Membrane Targeting of Myristoylated and Palmitoylated Proteins,” Biochimica et Biophysica Acta, Vol. 1451, No. 1, 1999, pp. 1-16.
doi:10.1016/S0167-4889(99)00075-0
[24] S. I. Patterson, “Posttranslational Protein S-Palmitoylation and the Compartmentalization of Signaling Molecules in Neurons,” Biological Research, Vol. 35, No. 2, 2002, pp. 139-150.
doi:10.4067/S0716-97602002000200005
[25] A. Mor and M. R. Philips, “Compartmentalized Ras/ MAPK Signaling,” Annual Review of Immunology, Vol. 24, No. 1, 2006, pp. 771-800. doi:10.1146/annurev.immunol.24.021605.090723
[26] S. J. Plowman and J. F. Hancock, “Ras Signaling from Plasma Membrane and Endomembrane Microdomains. Biochim,” Biochimica et Biophysica Acta, Vol. 1746, No. 3, 2005, pp. 274-283.
doi:10.1016/j.bbamcr.2005.06.004
[27] L. P. Wright and M. R. Philips, “Thematic Review Series Lipid Posttranslational Modifications, CAAX Modification and Membrane Targeting of Ras,” The Journal of Lipid Research, Vol. 47, No. 5, 2006, pp. 883-891. doi:10.1194/jlr.R600004-JLR200
[28] M. Bijlmakers and M. Marsh, “The On-Off Story of Protein Palmitoylation,” Trends in Cell Biology, Vol. 13, No. 1, 2003, pp. 32-42. doi:10.1016/S0962-8924(02)00008-9
[29] K. Huang and A. D. El-Husseini, “Modulation of Neuronal Protein Trafficking and Function by Palmitoylation,” Current Opinion in Neurobiology, Vol. 15, No. 5, 2005, pp. 527-535.
doi:10.1016/j.conb.2005.08.001
[30] K. L. Clark, A. Oelke, M. E. Johnson, K. D. Eilert, P. C. Simpson and S. C. Todd, “CD81 Associates with I4-3-3 in a Redox-regulated Palmitoylation-Dependent Manner,” The Journal of Biological Chemistry, Vol. 279, No. 19, 2004, pp. 19401-19406. doi:10.1074/jbc.M312626200
[31] X. Yang, O. V. Kovalenko, W. Tang, C. Claas, C. S. Stipp and M. E. Hemler, “Palmitoylation Supports Assembly and Function of Integrintetraspanin Complexes,” The Journal of Cell Biology, Vol. 167, No. 6, 2004, pp. 1231-1240. doi:10.1083/jcb.200404100
[32] B. Zhou, L. Liu, M. Reddivari and X. A. Zhang, “The Palmitoylation of Metastasis Suppressor KAII/CD82 Is Important for Its Motility-and Invasiveness-Inhibitory Activity,” Cancer Research, Vol. 64, No. 20, 2004, pp. 7455-7463. doi:10.1158/0008-5472.CAN-04-1574
[33] S. W. Wong, M. J. Kwon, A. M. Choi, H. P. Kim, K. Nakahira and D. H. Hwang, “Fatty Acids Modulate TollLike Receptor 4 Activation through Regulation of Receptor Dimerization and Recruitment into Lipid Rafts in a Reactive Oxygen Species-Dependent Manner,” The Journal of Biological Chemistry, Vol. 284, No. 40, 2009, pp. 27384-27392.
[34] E. V. Kalinina and L. D. Fricker, “Palmitoylation of Carboxypeptidase D. Implications for Intracellular Trafficking,” The Journal of Biological Chemistry, Vol. 278, No. 11, 2003, pp. 9244-9249.
doi:10.1074/jbc.M209379200
[35] I. Navarro-Lerida, M. M. Corvi, A. A. Barrientos, F. Gavilanes, L. G. Berthiaume and I. Rodriguez-Crespo, “Palmitoylation of Inducible Nitric Oxide Synthase at Cys-3 is required for Proper Intracellular Traffic and Nitric Oxide Synthesis,” The Journal of Biological Chemistry, Vol. 279, No. 53, 2004, pp. 55682-55689. doi:10.1074/jbc.M406621200
[36] J. M. Draper and C. D. Smith, “Palmitoyl Acyltransferase Assays and Inhibitors (Review),” Molecular Membrane Biology, Vol. 26, No. 1, 2009, pp. 5-13. doi:10.1080/09687680802683839
[37] R. E. Bishop, “Microreview: The Lipid A Pamitoyltransferase PagP: Molecular Mechanisms and Role in Bacterial Pathogenesis,” Molecular Microbiology, Vol. 57, No. 4, 2005, pp. 900-912.
[38] US Food and Drug Administration, “Guidance for Industry and FDA: Advisory levels for Deoxynivalenol (DON) in Finished Wheat Products for Human Consumption and Grains and Grain By-Products used for Animal Feed,” 2010. http://www.fda.gov/Food
[39] J. J. Pestka and A. T. Smolinski, “Deoxynivalenol: Toxicology and Potential Effects on Humans,” Journal of Toxicology and Environmental Health. Part B, Critical Reviews, Vol. 8, No. 1, 2005, pp. 39-69.
doi:10.1080/10937400590889458
[40] V. K. Singh, T. M. Seed and K. Kumar, “N-Palmitoylation of the Radioprotective Domain of Interleukin-I Affords Inhibition of LPS-Induced Nitric Oxide Generation,”Immunopharmacology and
Immunotoxicology, Vol. 26, No. 2, 2004, pp. 193-202. doi:10.1081/IPH-120037714
[41] K. Sugiyama, M. Muroi, K. Tanamoto, M. Nishijima and M. Sugita-Konishi, “Deoxynivalenol and Nivalenol Inhibit Lipopolysaccharide-Induced Nitric Oxide Production by Mouse Macrophage Cells,” Toxicology Letters, Vol. 192, No. 2, 2010, pp. 150-154. doi:10.1016/j.toxlet.2009.10.020
[42] Q. Jia, H. R. Zhou, Y. Shi and J. J. Pestka,” Docosahexaenoic Acid Consumption Inhibits Deoxynivalenol-Induced CREB/ATF1 Activation and IL-6 Gene Transcription in Mouse Macrophages,” The Journal of Nutrition, Vol. 136, No. 2, 2006, pp. 366-372.
[43] I. A. Ross, T. Boyle, W. D. Johnson, L. H. Garthoff, S. M. Ahn, M. W. O’Donnell and C. S. Kim, “The Individual and Interactive Effects of Lipopolysaccharide and Deoxynivalenol on Free Fatty Acids in the Liver and Brain of Rats,” Society of Toxicology Annual Meeting, 2011.
[44] I. A. Ross and C. S. Kim, “The Role of Palmitoylation in Chemical and Microbial Toxicity: Signal Pathways, Protein Binding and Trafficking,” Society of Toxicology Annual Meeting, 2013.
[45] P. L. Wiesenfeld, L. H. Garthoff, T. J. Sobotka, J. K. Suagee and C. N. Barton, “Acute Oral Toxicity of Colchicines in Rats: Effects of Gender, Vehicle Matrix and Pre-Exposure to Lipopolysaccharide,” Journal of Applied Toxicology, Vol. 27, No. 5, 2007, pp. 421-433. doi:10.1002/jat.1198
[46] S. Sahu, L. H. Garthoff, M. G. Robl, S. J. Chirtel, D. I. Ruggles, T. J. Flynn and T. J. Sobotka, “Rat Liver Clone-9 Cells in Culture as a Model for Screening Hepatotoxic Potential of Food-Related Products: Hepatotoxicity of Deoxynivalenol,” Journal of Applied Toxicology, Vol. 28, No. 6, 2008, pp. 765-772. doi:10.1002/jat.1337
[47] H. Huang, L. Tongzheng, J. L. Rose, R. L. Stevens and D. G. Hoyt, “Sensitivity of Mice to Lipopolysaccharide Is Increased by a High Saturated Fat and Cholesterol Diet,” Journal of Inflammation, Vol. 4, No. 22, 2007, pp. 1-11.
[48] S. Doll, J. A. Schrickx, H. Valenta, S. Danicke and J. Fink-Gremmels, “Interactions of Deoxynivalenol and Lipopolysaccharides on Cytotoxicity, Protein Synthesis and Metabolism of DON on Porcine Hepatocytes and Kupffer Cell Enriched Hepatocyte Cultures,” Toxicology Letters, Vol. 189, No. 2, 2009, pp. 121-129. doi:10.1016/j.toxlet.2009.05.011
[49] Y. J. Wache, L. Hbabi-Haddioui, L. Guzylack-Piriou and H. Belkhelfa, “The Mycotoxin Deoxynivalenol Inhibits the Cell Surface Expression of Activation Markers in Human Macrophages,” Toxicology, Vol. 262, No. 3, 2009, pp. 239-244. doi:10.1016/j.tox.2009.06.014
[50] A. S. Baldwin, “The NF-Kappa B and I Kappa B Proteins: New Discoveries and Insights,” Annual Review of Immunology, Vol. 14, 1996, pp. 649-683. doi:10.1146/annurev.immunol.14.1.649
[51] P. Valance and J. Collier, “Biology and Clinical Relevance of Nitric Oxide,” British Medical Journal, Vol. 309, 1994, pp. 453-457. doi:10.1136/bmj.309.6952.453
[52] H. T. Cook and V. Cattell, “Role of Nitric Oxide in Immune-Mediated Diseases,” Clinical Science, Vol. 91, No. 4, 1996. pp. 375-384.
[53] T. Nguyen, D. Brunson, C. L. Crespi, B. W. Penman, J. S. Wishnok and S. R. Tannenbaum, “DNA Damage and Mutation in Human Cells Exposed to Nitric Oxide in Vitro,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 89, No. 7, 1992, pp. 3030-3034. doi:10.1073/pnas.89.7.3030

  
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