isoleucine trna ligase


Summary: An enzyme that activates isoleucine with its specific transfer RNA. EC

Top Publications

  1. Silvian L, Wang J, Steitz T. Insights into editing from an ile-tRNA synthetase structure with tRNAile and mupirocin. Science. 1999;285:1074-7 pubmed
    ..The amino acid editing activity of the IleRS may result from the incorrect products shuttling between the synthetic and editing active sites, which is reminiscent of the editing mechanism of DNA polymerases. ..
  2. Antonio M, McFerran N, Pallen M. Mutations affecting the Rossman fold of isoleucyl-tRNA synthetase are correlated with low-level mupirocin resistance in Staphylococcus aureus. Antimicrob Agents Chemother. 2002;46:438-42 pubmed
    ..The importance of the V588F mutation was confirmed by an allele-specific PCR survey of 32 additional strains. Additional mutations of uncertain significance were found in residues clustered on the surface of the IleS protein. ..
  3. Hurdle J, O Neill A, Ingham E, Fishwick C, Chopra I. Analysis of mupirocin resistance and fitness in Staphylococcus aureus by molecular genetic and structural modeling techniques. Antimicrob Agents Chemother. 2004;48:4366-76 pubmed
    ..Structural explanations for mupirocin resistance and loss of fitness were obtained by molecular modeling of mutated IRS enzymes, which provided data on mupirocin binding and interaction with the isoleucyl-AMP reactive intermediate. ..
  4. Yanagisawa T, Lee J, Wu H, Kawakami M. Relationship of protein structure of isoleucyl-tRNA synthetase with pseudomonic acid resistance of Escherichia coli. A proposed mode of action of pseudomonic acid as an inhibitor of isoleucyl-tRNA synthetase. J Biol Chem. 1994;269:24304-9 pubmed
  5. Fujimura S, Tokue Y, Watanabe A. Isoleucyl-tRNA synthetase mutations in Staphylococcus aureus clinical isolates and in vitro selection of low-level mupirocin-resistant strains. Antimicrob Agents Chemother. 2003;47:3373-4 pubmed
  6. Yang J, Park D, Sohn J, Yang I, Kim K, Kim M. Molecular analysis of isoleucyl-tRNA synthetase mutations in clinical isolates of methicillin-resistant Staphylococcus aureus with low-level mupirocin resistance. J Korean Med Sci. 2006;21:827-32 pubmed
  7. Shimizu K, Tai H, Kuwano K. [A case of cellular NSIP with anti-OJ (anti-isoleucyl tRNA synthetase) antibodies]. Nihon Kokyuki Gakkai Zasshi. 2010;48:45-8 pubmed
    ..She had a favorable response to the initial treatment of methylprednisolone pulse therapy followed by prednisolone 1 mg/kg/day. Her symptoms, pulmonary function test and chest imaging findings have showed improvement after therapy. ..
  8. Hendrickson T, Nomanbhoy T, De Crecy Lagard V, Fukai S, Nureki O, Yokoyama S, et al. Mutational separation of two pathways for editing by a class I tRNA synthetase. Mol Cell. 2002;9:353-62 pubmed
    ..These results are consistent with a molecular model that shows that the single editing active site contains two valyl binding pockets, one specific for each substrate. ..
  9. Hurdle J, O Neill A, Chopra I. The isoleucyl-tRNA synthetase mutation V588F conferring mupirocin resistance in glycopeptide-intermediate Staphylococcus aureus is not associated with a significant fitness burden. J Antimicrob Chemother. 2004;53:102-4 pubmed
    ..The low fitness cost of the V588F substitution in isoleucyl-tRNA synthetase is consistent with the frequent appearance and maintenance of this mutation in mupirocin-resistant clinical isolates, including GISA-2. ..

More Information


  1. Greenwood R, Gentry D. The effect of antibiotic treatment on the intracellular nucleotide pools of Staphylococcus aureus. FEMS Microbiol Lett. 2002;208:203-6 pubmed
    ..Our results provide the framework for using nucleotide analysis in the assessment of novel antimicrobial compounds with unknown modes of action. ..
  2. Fayerman J, Vann M, Williams L, Umbarger H. ilvU, a locus in Escherichia coli affecting the derepression of isoleucyl-tRNA synthetase and the RPC-5 chromatographic profiles of tRNAIle and tRNAVal. J Biol Chem. 1979;254:9429-40 pubmed
    ..The mutated ilvU loci abolish the derepression and are more efficient in retarding the conversion. ..
  3. Glasfeld E, Landro J, Schimmel P. C-terminal zinc-containing peptide required for RNA recognition by a class I tRNA synthetase. Biochemistry. 1996;35:4139-45 pubmed
    ..The design of this enzyme may be part of a more general scheme for class I tRNA synthetases to acquire acceptor helix binding elements during the development of the genetic code. ..
  4. Cooper S, Laosripaiboon W, Rahman A, Hothersall J, El Sayed A, Winfield C, et al. Shift to Pseudomonic acid B production in P. fluorescens NCIMB10586 by mutation of mupirocin tailoring genes mupO, mupU, mupV, and macpE. Chem Biol. 2005;12:825-33 pubmed
    ..In the mupW mutant, a new metabolite lacking the tetrahydropyran ring is produced, implicating mupW in oxidation of the 16-methyl group. ..
  5. Szczuka E, Kaznowski A, Bosacka K, Strzemieczna E. Antimicrobial resistance and presence of ileS-2 gene encoding mupirocin resistance in clinical isolates of methicillin-resistant Staphylococcus sp. Folia Microbiol (Praha). 2009;54:153-6 pubmed publisher
    ..aureus strains. Thirty-nine % of S. aureus strains were resistant only to beta-lactams. None of the MRSA strains carried ileS-2 gene; this gene was found in two strains of S. epidermidis. ..
  6. Kim S, Kim S, Kim S, Kang T, Lee J. Deoxyribosyl analogues of methionyl and isoleucyl sulfamate adenylates as inhibitors of methionyl-tRNA and isoleucyl-tRNA synthetases. Bioorg Med Chem Lett. 2005;15:3389-93 pubmed
    ..coli MRS revealed that the lack of the two hydroxyl groups on ribose was compensated by the formation of an extra hydrogen bond between the ring oxygen and His24, resulting in a small activity reduction. ..
  7. Airas R. Differences in the magnesium dependences of the class I and class II aminoacyl-tRNA synthetases from Escherichia coli. Eur J Biochem. 1996;240:223-31 pubmed
    ..The binding of ATP to the E. aminoacyl-tRNA complex also speeds up the dissociation of the aminoacyl-tRNA from most of these enzymes. ..
  8. Hirano T, Matsuhashi T, Takeda K, Hara H, Kobayashi N, Kita K, et al. IARS mutation causes prenatal death in Japanese Black cattle. Anim Sci J. 2016;87:1178-81 pubmed publisher
    ..001). The findings suggested that the homozygous IARS mutation not only causes calf death, but also embryonic or fetal death. ..
  9. Mock M, Michon T, van Hest J, Tirrell D. Stereoselective incorporation of an unsaturated isoleucine analogue into a protein expressed in E. coli. Chembiochem. 2006;7:83-7 pubmed
    ..ATP/PPi exchange assays indicated that SS-E-Ile was activated by the isoleucyl-tRNA synthetase at a rate comparable to that characteristic of isoleucine; SR-E-Ile was activated approximately 100-times more slowly than SS-E-Ile. ..
  10. Lin L, Schimmel P. Mutational analysis suggests the same design for editing activities of two tRNA synthetases. Biochemistry. 1996;35:5596-601 pubmed
  11. Cramer F, Englisch U, Freist W, Sternbach H. Aminoacylation of tRNAs as critical step of protein biosynthesis. Biochimie. 1991;73:1027-35 pubmed
    ..The enzyme is unable to catalyze the latter reaction if more than 10 carboxyterminal residues are deleted. ..
  12. Freist W, Sternbach H, Cramer F. Isoleucyl-tRNA synthetase from baker's yeast and from Escherichia coli MRE 600. Discrimination of 20 amino acids in aminoacylation of tRNA(Ile)-C-C-A(3'NH2). Eur J Biochem. 1987;169:33-9 pubmed
    ..A hypothetical model of the binding site can be given in which selection of amino acids is achieved by hydrophobic forces and removal of steric hindrance. ..
  13. Chalker A, Ward J, Fosberry A, Hodgson J. Analysis and toxic overexpression in Escherichia coli of a staphylococcal gene encoding isoleucyl-tRNA synthetase. Gene. 1994;141:103-8 pubmed
    ..The gene was engineered for high-level expression in Escherichia coli. Ile-RS overproduction was toxic to the E. coli host, the magnitude of its observed effects being strain-dependent. ..
  14. Cvetesic N, Dulic M, Bilus M, Sostaric N, Lenhard B, Gruic Sovulj I. Naturally Occurring Isoleucyl-tRNA Synthetase without tRNA-dependent Pre-transfer Editing. J Biol Chem. 2016;291:8618-31 pubmed publisher
    ..griseus IleRS is able to rescue the growth of an E. coli lacking functional IleRS, providing the first evidence that tRNA-dependent pre-transfer editing in IleRS is not essential for cell viability. ..
  15. Glasfeld E, Schimmel P. Zinc-dependent tRNA binding by a peptide element within a tRNA synthetase. Biochemistry. 1997;36:6739-44 pubmed
    ..In addition, the results offer the first direct evidence of a role for zinc in the tRNA-binding activity of one of these peptide elements. ..
  16. Paulander W, Andersson D, Maisnier Patin S. Amplification of the gene for isoleucyl-tRNA synthetase facilitates adaptation to the fitness cost of mupirocin resistance in Salmonella enterica. Genetics. 2010;185:305-12 pubmed publisher
    ..This sequence of events is demonstrated experimentally. A better understanding of adaptation can explain why antibiotic resistance persists in bacterial populations and may help identify drugs that are least subject to this problem...
  17. Martindale D, Gu Z, Csank C. Isolation and complete sequence of the yeast isoleucyl-tRNA synthetase gene (ILS1). Curr Genet. 1989;15:99-106 pubmed
    ..The ILS1 amino acid sequence was compared to isoleucyl-tRNA synthetases from other organisms, as well as to valyl-, leucyl- and methionyl-tRNA synthetases. Regions of conservation between these enzymes were found. ..
  18. Lee J, Kim S, Lee J, Kim S, Kang S, Seo S, et al. N-Alkoxysulfamide, N-hydroxysulfamide, and sulfamate analogues of methionyl and isoleucyl adenylates as inhibitors of methionyl-tRNA and isoleucyl-tRNA synthetases. Bioorg Med Chem Lett. 2003;13:1087-92 pubmed
  19. Sassanfar M, Kranz J, Gallant P, Schimmel P, Shiba K. A eubacterial Mycobacterium tuberculosis tRNA synthetase is eukaryote-like and resistant to a eubacterial-specific antisynthetase drug. Biochemistry. 1996;35:9995-10003 pubmed
    ..The results also demonstrate that mobilization of a pathogen's gene for a drug-resistant protein target can spread resistance to other, normally drug-sensitive pathogens infecting the same host. ..
  20. Shiba K, Suzuki N, Shigesada K, Namba Y, Schimmel P, Noda T. Human cytoplasmic isoleucyl-tRNA synthetase: selective divergence of the anticodon-binding domain and acquisition of a new structural unit. Proc Natl Acad Sci U S A. 1994;91:7435-9 pubmed
    ..This result may have implications for the historical development of an operational RNA code for amino acids. ..
  21. Nomanbhoy T, Morales A, Abraham A, Vörtler C, Giege R, Schimmel P. Simultaneous binding of two proteins to opposite sides of a single transfer RNA. Nat Struct Biol. 2001;8:344-8 pubmed
    ..A thermodynamic and functional analysis is consistent with the tRNA retaining its native structure in the ternary complex. These results may have implications for how the translation apparatus is linked to other cellular machinery. ..
  22. Degoul F, Brulé H, Cepanec C, Helm M, Marsac C, Leroux J, et al. Isoleucylation properties of native human mitochondrial tRNAIle and tRNAIle transcripts. Implications for cardiomyopathy-related point mutations (4269, 4317) in the tRNAIle gene. Hum Mol Genet. 1998;7:347-54 pubmed
    ..The potential implications of these findings on the understanding of the molecular mechanisms involved in the expression of pathology are discussed. ..
  23. Xu B, Trawick B, Krudy G, Phillips R, Zhou L, Rosevear P. Probing the metal binding sites of Escherichia coli isoleucyl-tRNA synthetase. Biochemistry. 1994;33:398-402 pubmed
    ..Metal substitution or removal of one of the two enzyme-bound metals in IleRS was found to have little effect on the Km value for tRNA(Ile) or the kcat value for aminoacylation of tRNA(Ile).(ABSTRACT TRUNCATED AT 250 WORDS) ..
  24. Salowe S, Wiltsie J, Hawkins J, Sonatore L. The catalytic flexibility of tRNAIle-lysidine synthetase can generate alternative tRNA substrates for isoleucyl-tRNA synthetase. J Biol Chem. 2009;284:9656-62 pubmed publisher
    ..coli and Bacillus subtilis. ..
  25. Jovanovic M, Lilic M, Janjusevic R, Jovanovic G, Savic D, Milija J. tRNA synthetase mutants of Escherichia coli K-12 are resistant to the gyrase inhibitor novobiocin. J Bacteriol. 1999;181:2979-83 pubmed
    ..Under conditions of stringent response induction, either by the presence of tRNA synthetase mutations or by constitutive production of RelA protein, inactivation of the cls gene diminishes resistance to novobiocin but not to mecillinam. ..
  26. Shimizu T, Usui T, Fujikura M, Kawatani M, Satoh T, Machida K, et al. Synthesis and biological activities of reveromycin A and spirofungin A derivatives. Bioorg Med Chem Lett. 2008;18:3756-60 pubmed publisher
    ..It was found that 2,3-dihydroreveromycin A is the promising derivative of reveromycin A based on the activity and stability. ..
  27. Nomanbhoy T, Schimmel P. Active site of an aminoacyl-tRNA synthetase dissected by energy-transfer-dependent fluorescence. Bioorg Med Chem Lett. 2001;11:1485-91 pubmed
    ..Amino acid binding and adenylate synthesis by two other aminoacyl-tRNA synthetases was also investigated with mdATP. Thus, a key step in the synthesis of aminoacyl-tRNA can in general be dissected with this probe. ..
  28. Yamasaki Y, Yamada H, Nozaki T, Akaogi J, Nichols C, Lyons R, et al. Unusually high frequency of autoantibodies to PL-7 associated with milder muscle disease in Japanese patients with polymyositis/dermatomyositis. Arthritis Rheum. 2006;54:2004-9 pubmed
    ..Although anti-PL-7, similar to anti-Jo-1, is associated with PM/DM with ILD, muscle involvement in the patients with anti-PL-7 appeared to be milder than that in the anti-Jo-1 subset. ..
  29. Brown J, Gentry D, Becker J, Ingraham K, Holmes D, Stanhope M. Horizontal transfer of drug-resistant aminoacyl-transfer-RNA synthetases of anthrax and Gram-positive pathogens. EMBO Rep. 2003;4:692-8 pubmed
    ..This study shows the importance of understanding complex evolutionary networks of ancient horizontal gene transfer for the development of novel antibiotics. ..
  30. Schmidt E, Schimmel P. Residues in a class I tRNA synthetase which determine selectivity of amino acid recognition in the context of tRNA. Biochemistry. 1995;34:11204-10 pubmed
    ..The mutationally sensitive residues are part of an insertion into the catalytic domain and are themselves completely conserved among all known prokaryotic and eukaryotic sequences of the enzyme. ..
  31. Fukunaga R, Yokoyama S. Crystallization and preliminary X-ray crystallographic study of the editing domain of Thermus thermophilus isoleucyl-tRNA synthetase complexed with pre- and post-transfer editing-substrate analogues. Acta Crystallogr D Biol Crystallogr. 2004;60:1900-2 pubmed publisher
    ..8 A3 Da(-1) and a solvent content of 55.8%. Data sets diffracting to 1.7 A resolution were collected from each single crystal at 100 K...
  32. Norcum M, Boisset N. Three-dimensional architecture of the eukaryotic multisynthetase complex determined from negatively stained and cryoelectron micrographs. FEBS Lett. 2002;512:298-302 pubmed
    ..The structures have openings or indentations on most sides. Maximum dimensions are ca. 19x16x10 nm. The central cavity is 4 nm in diameter and extends two-thirds of the length of the particle. ..
  33. Nichols R, Blinder J, Pai S, Ge Q, Targoff I, Plotz P, et al. Assignment of two human autoantigen genes-isoleucyl-tRNA synthetase locates to 9q21 and lysyl-tRNA synthetase locates to 16q23-q24. Genomics. 1996;36:210-3 pubmed
  34. Muramatsu R, Misawa S, Hayashi H. Finding of an isoleucine derivative of a recombinant protein for pharmaceutical use. J Pharm Biomed Anal. 2003;31:979-87 pubmed
    ..1.1.86) and dihydroxy acid dehydratase (DH) (EC Finally, this is converted to betaMeNle by branched-chain amino acid transaminase (EC, one of the Ile and Val biosynthetic enzymes. ..
  35. Zhou L, Rosevear P. Mutation of the carboxy terminal zinc finger of E. coli isoleucyl-tRNA synthetase alters zinc binding and aminoacylation activity. Biochem Biophys Res Commun. 1995;216:648-54 pubmed
    ..These results suggest that both the C-terminal enzyme-bound zinc and the C-terminal peptide play important roles in aminoacylation of tRNA(Ile). ..
  36. Yamada H, Kitagawa M, Kawakami M, Mizushima S. The gene coding for lipoprotein signal peptidase (lspA) and that for isoleucyl-tRNA synthetase (ileS) constitute a cotranscriptional unit in Escherichia coli. FEBS Lett. 1984;171:245-8 pubmed
    ..The gene order of dnaJ - rpsT - ileS - lspA - dapB around 0.5 min on the E. coli chromosome map was also determined. ..
  37. Ziegelbauer K, Babczinski P, Schonfeld W. Molecular mode of action of the antifungal beta-amino acid BAY 10-8888. Antimicrob Agents Chemother. 1998;42:2197-205 pubmed
    ..BAY 10-8888 was not incorporated into proteins. BAY 10-8888 inhibited isoleucyl-tRNA synthetase with the same concentration dependency as protein biosynthesis in intact cells assuming 200-fold accumulation. ..
  38. Castranova D, Davis A, Lo B, Miller M, Paukstelis P, Swift M, et al. Aminoacyl-Transfer RNA Synthetase Deficiency Promotes Angiogenesis via the Unfolded Protein Response Pathway. Arterioscler Thromb Vasc Biol. 2016;36:655-62 pubmed publisher
    ..Our results suggest that endoplasmic reticulum stress acts as a proangiogenic signal via unfolded protein response pathway-dependent upregulation of vegfaa. ..
  39. Singh M, Matsuo M, Sasaki T, Morimoto Y, Hishinuma T, Hiramatsu K. In Vitro Tolerance of Drug-Naive Staphylococcus aureus Strain FDA209P to Vancomycin. Antimicrob Agents Chemother. 2017;61: pubmed publisher
    ..We have identified mutation of ileS to be one of the bona fide genetic events leading to the acquisition of vancomycin tolerance in S. aureus, potentially acting via inhibition of the function of IleRS. ..
  40. Hughes R, Ellington A. Mistakes in translation don't translate into termination. Proc Natl Acad Sci U S A. 2005;102:1273-4 pubmed
  41. Miyamoto Y, Machida K, Mizunuma M, Emoto Y, Sato N, Miyahara K, et al. Identification of Saccharomyces cerevisiae isoleucyl-tRNA synthetase as a target of the G1-specific inhibitor Reveromycin A. J Biol Chem. 2002;277:28810-4 pubmed
    ..IleRS inhibition by RM-A led to transcriptional activation of the ILS1 gene via the Gcn2-Gcn4 general amino acid control pathway, and this autoregulation seemed to contribute to RM-A resistance. ..
  42. Belghazi M, Bathany K, Hountondji C, Grandier Vazeille X, Manon S, Schmitter J. Analysis of protein sequences and protein complexes by matrix-assisted laser desorption/ionization mass spectrometry. Proteomics. 2001;1:946-54 pubmed
    ..The spectral suppression phenomenon occurring for complex peptide mixtures analysed by MALDI is discussed, as well as the role of post-source decay analysis for confident protein identification. ..
  43. Banwell M, Crasto C, Easton C, Forrest A, Karoli T, March D, et al. Analogues of SB-203207 as inhibitors of tRNA synthetases. Bioorg Med Chem Lett. 2000;10:2263-6 pubmed
    ..The leucine derivative showed low level antibacterial activity, while several of the compounds inhibited IRS from Staphylococcus aureus WCUH29 more strongly than rat liver IRS. ..
  44. Nomanbhoy T, Schimmel P. Misactivated amino acids translocate at similar rates across surface of a tRNA synthetase. Proc Natl Acad Sci U S A. 2000;97:5119-22 pubmed
    ..Thus, the rate of translocation is independent of the nature of the misactivated amino acid. This result suggests that the misactivated amino acid per se has little or no role in directing translocation. ..
  45. Jakubowski H. Aminoacylation of coenzyme A and pantetheine by aminoacyl-tRNA synthetases: possible link between noncoded and coded peptide synthesis. Biochemistry. 1998;37:5147-53 pubmed
  46. Jakubowski H. Synthesis of cysteine-containing dipeptides by aminoacyl-tRNA synthetases. Nucleic Acids Res. 1995;23:4608-15 pubmed
    ..Similar reactions, yielding Ile-Cys and Val-Cys, are catalyzed by isoleucyl- and valyl-tRNA synthetases, respectively. ..
  47. Jenal U, Thurner C, Leisinger T. Transcription of the ileS operon in the archaeon Methanobacterium thermoautotrophicum Marburg. J Bacteriol. 1993;175:5945-52 pubmed
    ..Extensive decay of the orf401-ileS-purL message was observed. Degradation occurred, presumably by endonucleolytic cleavage, within the orf401 region. ..
  48. Tzagoloff A, Shtanko A. Mitochondrial and cytoplasmic isoleucyl-, glutamyl- and arginyl-tRNA synthetases of yeast are encoded by separate genes. Eur J Biochem. 1995;230:582-6 pubmed
  49. Borgford T, Brand N, Gray T, Fersht A. The valyl-tRNA synthetase from Bacillus stearothermophilus has considerable sequence homology with the isoleucyl-tRNA synthetase from Escherichia coli. Biochemistry. 1987;26:2480-6 pubmed
    ..This is the first example of extensive homology found between two different aminoacyl-tRNA synthetases. ..
  50. Fukunaga R, Yokoyama S. Structural basis for substrate recognition by the editing domain of isoleucyl-tRNA synthetase. J Mol Biol. 2006;359:901-12 pubmed publisher
    ..The T233A and H319A mutants have detectable editing activities against the cognate isoleucine...
  51. Rangaswamy V, Hernández Guzmán G, Shufran K, Bender C. Analysis of rILERS, an isoleucyl-tRNA synthetase gene associated with mupirocin production by Pseudomonas fluorescens NCIMB 10586. DNA Seq. 2002;13:343-51 pubmed
    ..Interestingly, the relatedness between rILERS and the ILERS previously described in P. fluorescens 10586 was low (24% similarity), which indicates that P. fluorescens contains two isoforms of isoleucyl-tRNA synthetase. ..
  52. Bishop A, Nomanbhoy T, Schimmel P. Blocking site-to-site translocation of a misactivated amino acid by mutation of a class I tRNA synthetase. Proc Natl Acad Sci U S A. 2002;99:585-90 pubmed
  53. Istvan E, Dharia N, Bopp S, Gluzman I, Winzeler E, Goldberg D. Validation of isoleucine utilization targets in Plasmodium falciparum. Proc Natl Acad Sci U S A. 2011;108:1627-32 pubmed publisher
    ..This approach is generally useful for elucidation of new targets in P. falciparum. Our study shows that isoleucine utilization is an essential pathway that can be targeted for antimalarial drug development. ..