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Gene Review

WARS  -  tryptophanyl-tRNA synthetase

Homo sapiens

Synonyms: GAMMA-2, IFI53, IFP53, Interferon-induced protein 53, TrpRS, ...
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Disease relevance of WARS


Psychiatry related information on WARS

  • METHODS: Subjects were US military combat veterans of the Vietnam and Gulf Wars recruited from two metropolitan areas served by allied Department of Veterans Affairs PTSD treatment/research centers [6].
  • Atherosclerosis during periods of food deprivation following World Wars I and II [7].
  • Mapping and molecular characterization of novel monoclonal antibodies to conformational epitopes on NH2 and COOH termini of mammalian tryptophanyl-tRNA synthetase reveal link of the epitopes to aggregation and Alzheimer's disease [8].

High impact information on WARS

  • We deleted the anticodon binding domain from tryptophanyl-tRNA synthetase and fused the discontinuous segments comprising its active site [9].
  • A Minimal TrpRS Catalytic Domain Supports Sense/Antisense Ancestry of Class I and II Aminoacyl-tRNA Synthetases [9].
  • Fragments of TyrRS stimulate angiogenesis, whereas those of TrpRS (T2-TrpRS) inhibit angiogenesis [10].
  • In particular, an N-terminally truncated fragment, T2-TrpRS, that is closely related to a natural splice variant is a potent antagonist of vascular endothelial growth factor-induced angiogenesis in several in vivo models [11].
  • These results demonstrate that T2-TrpRS can regulate extracellular signal-activated protein kinase, Akt, and EC NO synthase activation pathways that are associated with angiogenesis, cytoskeletal reorganization, and shear stress-responsive gene expression [11].

Biological context of WARS


Anatomical context of WARS


Associations of WARS with chemical compounds

  • When B. subtilis, A. fulgidus, and human TrpRS were used to acylate these tRNA(Trp), two distinct preference profiles regarding the discriminator base of different tRNA(Trp) substrates were found: G>A>U>C for B. subtilis TrpRS, and A>C>U>G for A. fulgidus and human TrpRS [1].
  • These similarities suggest that conserved residues in TrpRS may be responsible for both determining tryptophan recognition and discrimination against tyrosine [20].
  • 2.9 A crystal structure of ligand-free tryptophanyl-tRNA synthetase: domain movements fragment the adenine nucleotide binding site [21].
  • The dimeric structure (R = 23.7, Rfree = 26.2) is asymmetric, unlike that of the TrpRS tryptophanyl-5'AMP complex (TAM; Doublié S, Bricogne G, Gilmore CJ, Carter CW Jr, 1995, Structure 3:17-31) [21].
  • A potential polymorphic variant of human tryptophanyl-tRNA synthetase is shown here to sequester tryptophanyl adenylate [22].

Physical interactions of WARS


Regulatory relationships of WARS


Other interactions of WARS


Analytical, diagnostic and therapeutic context of WARS

  • Mini TrpRS is shown here to be angiostatic in a mammalian cell culture system, the chicken embryo, and two independent angiogenesis assays in the mouse [12].
  • Identification of the 53-kDa gamma-IFN-induced protein was confirmed by immunoblotting with an antiserum directed against beef pancreas tryptophanyl-tRNA synthetase [19].
  • Gel-retardation assays showed that the acceptor minihelix and the anticodon microhelix were recognized by the domains of TrpRS spanning residues 108-122 and residues 234-238 respectively [29].
  • Soubbotitch, Senior Surgeon, Belgrade State Hospital, Serbia (now part of Yugoslavia) and a Lieutenant Colonel in the Serbian Army Reserve during the Balkan Wars (Serbo-Turkish and Serbo-Bulgarian) initiated one of the first clinical programs that emphasized repair, rather than ligation, of injured arteries and veins [30].
  • Autoantibodies to highly purified tryptophanyl-tRNA synthetase, consisting of two approximately 60-kDa subunits (, TrpRS), were detected in some sera of donors and patients with various diagnosis using the newly developed 125I-TrpRS-radiodot, 125I-TrpRS-radioblot, ELISA and Western immunoblotting [31].


  1. Recognition by tryptophanyl-tRNA synthetases of discriminator base on tRNATrp from three biological domains. Guo, Q., Gong, Q., Tong, K.L., Vestergaard, B., Costa, A., Desgres, J., Wong, M., Grosjean, H., Zhu, G., Wong, J.T., Xue, H. J. Biol. Chem. (2002) [Pubmed]
  2. Crystal structure of human tryptophanyl-tRNA synthetase catalytic fragment: insights into substrate recognition, tRNA binding, and angiogenesis activity. Yu, Y., Liu, Y., Shen, N., Xu, X., Xu, F., Jia, J., Jin, Y., Arnold, E., Ding, J. J. Biol. Chem. (2004) [Pubmed]
  3. Immunoelectron microscopic location of tryptophanyl-tRNA synthetase in mammalian, prokaryotic and archaebacterial cells. Popenko, V.I., Cherny, N.E., Beresten, S.F., Ivanova, J.L., Filonenko, V.V., Kisselev, L.L. Eur. J. Cell Biol. (1993) [Pubmed]
  4. Bartonella (Rochalimaea) quintana infections. Maurin, M., Raoult, D. Clin. Microbiol. Rev. (1996) [Pubmed]
  5. Regioselective nitration of tryptophan by a complex between bacterial nitric-oxide synthase and tryptophanyl-tRNA synthetase. Buddha, M.R., Tao, T., Parry, R.J., Crane, B.R. J. Biol. Chem. (2004) [Pubmed]
  6. Decreased anterior cingulate volume in combat-related PTSD. Woodward, S.H., Kaloupek, D.G., Streeter, C.C., Martinez, C., Schaer, M., Eliez, S. Biol. Psychiatry (2006) [Pubmed]
  7. Atherosclerosis during periods of food deprivation following World Wars I and II. Schettler, G. Preventive medicine. (1983) [Pubmed]
  8. Mapping and molecular characterization of novel monoclonal antibodies to conformational epitopes on NH2 and COOH termini of mammalian tryptophanyl-tRNA synthetase reveal link of the epitopes to aggregation and Alzheimer's disease. Paley, E.L., Smelyanski, L., Malinovskii, V., Subbarayan, P.R., Berdichevsky, Y., Posternak, N., Gershoni, J.M., Sokolova, O., Denisova, G. Mol. Immunol. (2007) [Pubmed]
  9. A Minimal TrpRS Catalytic Domain Supports Sense/Antisense Ancestry of Class I and II Aminoacyl-tRNA Synthetases. Pham, Y., Li, L., Kim, A., Erdogan, O., Weinreb, V., Butterfoss, G.L., Kuhlman, B., Carter, C.W. Mol. Cell (2007) [Pubmed]
  10. Inhibition of tumor angiogenesis by a natural fragment of a tRNA synthetase. Tzima, E., Schimmel, P. Trends Biochem. Sci. (2006) [Pubmed]
  11. Biologically active fragment of a human tRNA synthetase inhibits fluid shear stress-activated responses of endothelial cells. Tzima, E., Reader, J.S., Irani-Tehrani, M., Ewalt, K.L., Schwartz, M.A., Schimmel, P. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  12. A human aminoacyl-tRNA synthetase as a regulator of angiogenesis. Wakasugi, K., Slike, B.M., Hood, J., Otani, A., Ewalt, K.L., Friedlander, M., Cheresh, D.A., Schimmel, P. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  13. A short peptide insertion crucial for angiostatic activity of human tryptophanyl-tRNA synthetase. Kise, Y., Lee, S.W., Park, S.G., Fukai, S., Sengoku, T., Ishii, R., Yokoyama, S., Kim, S., Nureki, O. Nat. Struct. Mol. Biol. (2004) [Pubmed]
  14. Crystal structures that suggest late development of genetic code components for differentiating aromatic side chains. Yang, X.L., Otero, F.J., Skene, R.J., McRee, D.E., Schimmel, P., Ribas de Pouplana, L. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  15. Interferon induces tryptophanyl-tRNA synthetase expression in human fibroblasts. Rubin, B.Y., Anderson, S.L., Xing, L., Powell, R.J., Tate, W.P. J. Biol. Chem. (1991) [Pubmed]
  16. Assignment of the human tryptophanyl-tRNA synthetase gene (WARS) to chromosome 14q32.2 --> q32.32. Børglum, A.D., Flint, T., Tommerup, N., Fleckner, J., Justesen, J., Kruse, T.A. Cytogenet. Cell Genet. (1996) [Pubmed]
  17. HeLa cell DNA polymerase alpha is tightly associated with tryptophanyl-tRNA synthetase and diadenosine 5',5"'-P1,P4-tetraphosphate binding activities. Rapaport, E., Zamecnik, P.C., Baril, E.F. Proc. Natl. Acad. Sci. U.S.A. (1981) [Pubmed]
  18. Regulation of indoleamine 2,3-dioxygenase and tryptophanyl-tRNA-synthetase by CTLA-4-Fc in human CD4+ T cells. Boasso, A., Herbeuval, J.P., Hardy, A.W., Winkler, C., Shearer, G.M. Blood (2005) [Pubmed]
  19. Gamma interferon potently induces tryptophanyl-tRNA synthetase expression in human keratinocytes. Reano, A., Richard, M.H., Denoroy, L., Viac, J., Benedetto, J.P., Schmitt, D. J. Invest. Dermatol. (1993) [Pubmed]
  20. Ancient adaptation of the active site of tryptophanyl-tRNA synthetase for tryptophan binding. Praetorius-Ibba, M., Stange-Thomann, N., Kitabatake, M., Ali, K., Söll, I., Carter, C.W., Ibba, M., Söll, D. Biochemistry (2000) [Pubmed]
  21. 2.9 A crystal structure of ligand-free tryptophanyl-tRNA synthetase: domain movements fragment the adenine nucleotide binding site. Ilyin, V.A., Temple, B., Hu, M., Li, G., Yin, Y., Vachette, P., Carter, C.W. Protein Sci. (2000) [Pubmed]
  22. Variant of human enzyme sequesters reactive intermediate. Ewalt, K.L., Yang, X.L., Otero, F.J., Liu, J., Slike, B., Schimmel, P. Biochemistry (2005) [Pubmed]
  23. Is Ap4A an activator of eukaryotic DNA replication? Bambara, R.A., Crute, J.J., Wahl, A.F. Cancer Invest. (1985) [Pubmed]
  24. Evidence for annexin II-S100A10 complex and plasmin in mobilization of cytokine activity of human TrpRS. Kapoor, M., Zhou, Q., Otero, F., Myers, C.A., Bates, A., Belani, R., Liu, J., Luo, J.K., Tzima, E., Zhang, D.E., Yang, X.L., Schimmel, P. J. Biol. Chem. (2008) [Pubmed]
  25. Relationship of two human tRNA synthetases used in cell signaling. Yang, X.L., Schimmel, P., Ewalt, K.L. Trends Biochem. Sci. (2004) [Pubmed]
  26. Modulation of cellular tryptophan metabolism in human fibroblasts by transforming growth factor-beta: selective inhibition of indoleamine 2,3-dioxygenase and tryptophanyl-tRNA synthetase gene expression. Yuan, W., Collado-Hidalgo, A., Yufit, T., Taylor, M., Varga, J. J. Cell. Physiol. (1998) [Pubmed]
  27. Differential screening identifies genetic markers of monocyte to macrophage maturation. Krause, S.W., Rehli, M., Kreutz, M., Schwarzfischer, L., Paulauskis, J.D., Andreesen, R. J. Leukoc. Biol. (1996) [Pubmed]
  28. Oxidative stress-responsive intracellular regulation specific for the angiostatic form of human tryptophanyl-tRNA synthetase. Wakasugi, K., Nakano, T., Morishima, I. Biochemistry (2005) [Pubmed]
  29. Two essential regions for tRNA recognition in Bacillus subtilis tryptophanyl-tRNA synthetase. Jia, J., Xu, F., Chen, X., Chen, L., Jin, Y., Wang, D.T. Biochem. J. (2002) [Pubmed]
  30. The Matas/Soubbotitch connection. Rich, N.M., Clagett, G.P., Salander, J.M., Piscević, S. Surgery (1983) [Pubmed]
  31. Tryptophanyl-tRNA synthetase as a human autoantigen. Paley, E.L., Alexandrova, N., Smelansky, L. Immunol. Lett. (1995) [Pubmed]
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