Aminoacyl-Adenylate Analogs

Aminoacyl adenylate analogs (5’-O-[N-(L-aminoacyl)sulfamoyl]adenosines) function as potent inhibitors of the aminoacyl-tRNA synthetase enzymes. tRNA synthetases play vital roles in translation as they are responsible for transferring the correct amino acid to their corresponding tRNA. Analogs of the aminoacyl intermediates have been used in structural and mechanistic studies of the enzymes, uncovering their evolutionary history, and determining the extent of amino acid discrimination exhibited by each synthetase.

More recently, t-RNA synthetases have emerged as a potential platform for the development of new antibiotics that specifically target these enzymes as a way to inhibit bacterial growth. Modified aminoacyl adenosine analogs are also being used to evolve tRNA synthetases that can be used to incorporate modified amino acids into proteins, which are valuable for investigating structure-activity relationships or developing modified peptide based therapeutics. t-RNA synthetases from humans have also been found to possess cytokine activity and play a role in the regulation of angiogenesis.

Place an Order Now

References

1. Castro-Pichel, J. et al. (1987). A facile synthesis of ascamycin and related analogues. Tetrahedron 43, 383-389.
2. Ueda, H. et al. (1991). X-ray crystallographic conformational study of 5´-O-[N-(L-alanyl)-sulfamoyl]adenosine, a substrate analogue for alanyl-tRNA synthetase. Biochim. Biophys. Acta 1080, 126-134.
3. Kamtekar, S. et al. (2003). The structural basis of cysteine aminoacylation of tRNAPro by prolyl-tRNA synthetases. Proc. Natl. Acad. Sci. USA 100, 1673-1678.
4. Forrest, A. K. et al. (2000). Aminoalkyl adenylate and aminoacyl sulfamate intermediate analogues differing greatly in affinity for their cognate Staphylococcus aureus aminoacyl tRNA synthetases. Bioorg. Med. Chem. Letters 10, 1871-1874.
5. Berthet-Colominas, C. et al. (1998). The crystal structure of asparaginyl-tRNA synthetase from Thermus thermophilus and its complexes with ATP and asparaginyl-adenylate: the mechanism of discrimination between asparagine and aspartic acid. EMBO J. 17, 2947-2960.
6. Rath, V. L. et al. (1998). How glutaminyl-tRNA synthetase selects glutamine. Structure 6, 439-449.
7. Sherlin, L. D. et al. (2000). Influence of transfer RNA tertiary structure on aminoacylation efficiency by glutaminyl and cysteinyl-tRNA synthetases. J. Mol. Biol. 299, 431-446.
8. Bovee, M. L. et al. (1999). tRNA discrimination at the binding step by a class II aminoacyl-tRNA synthetase. Biochemistry 38, 13725-13735.
9. Cusack, S. et al. (1996). The crystal structures of T. thermophilus lysyl-tRNA synthetase complexed with E. coli tRNALys and a T. thermophilus tRNALys transcript: anticodon recognition and conformational changes upon binding of a lysyl-adenylate analogue. EMBO J. 15, 6321-6334.
10. Heacock, D. et al. (1996). Synthesis and aminoacyl-tRNA synthetase inhibitory activity of prolyl adenylate analogs. Bioorg. Chem. 24, 273-289.
11. Belrhali, H. et al. (1994). Crystal structures at 2.5 Angstrom resolution of seryl-tRNA synthetase complexed with two analogs of seryl adenylate. Science 263, 1432-1436.
12. Sankaranarayanan, R. et al. (2000). Zinc ion mediated amino acid discrimination by threonyl-tRNA synthetase. Nature Structural Biology 7, 461-465.
13. Bernier, S. et al. (2005). Synthesis and aminoacyl-tRNA synthetase inhibitory activity of aspartyl adenylate analogs. Bioorg. Med. Chem. 13, 69-75.
14. Bernier, S. et al. (2005). Glutamylsulfamoyladenosine and pyroglutamylsulfamoyladenosine are copmpetitive inhibitors of E. coli glutamyl-tRNA synthetase. J. Enzyme Inhib. Med. Chem. 20, 61-67.
15. Dignam, J.D. et al. (2003). Thermodynamic characterization of the binding of nucleotides to glycyl-tRNA synthetase. Biochemistry 42, 5333-5340.
16. Bunjun, S. et al. (2000). A dual-specificity aminoacyl-tRNA synthetase in the deep-rooted eukaryote Giardia lamblia. Proc. Natl. Acad. Sci. USA 97, 12997-13002.
17. Landeka, I. et al. (2000). Characterization of yeast seryl-tRNA synthetase active site mutants with improved discrimination against substrate analogues. Biochim. Biophys. Acta 1480, 160-170.
18. Bovee, M.L. et al. (2003). Induced fit and kinetic mechanism of adenylation catalyzed by Escherichia coli threonyl-tRNA synthetase. Biochemistry 42, 15102-15113.
19. Fukunaga, R. & Yokoyama, S. (2005). Structural basis for non-cognate amino acid discrimination by the valyl-tRNA synthetase editing domain. J. Biol. Chem. 280, 29937-29945.
20. Kotik-Kogan, O. et al. (2005). Structural basis for discrimination of L-phenylalanine from L-tyrosine by phenylalanyl-tRNA synthetase. Structure 13, 1799-1807.
21. Nakama, T. et al. (2001). Structural basis for the recognition of isoleucyl-adenylate and an antibiotic, mupirocin, by isoleucyl-tRNA synthetase. J. Biol. Chem. 276, 47387-47393.
22. Fukunaga, R. & Yokoyama, S. (2004). Crystallization and preliminary X-ray crystallography 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. 60, 1900-1902.
23. Kobayashi, T. et al. (2005). Structural snapshots of the KMSKS loop rearrangement for amino acid activation by bacterial tyrosyl-tRNA synthetase. J. Mol. Biol. 346, 105-117.
24. Iwasaki, W. et al. (2006). Structural basis of the water-assisted asparagine recognition by asparaginyl-tRNA synthetase. J. Mol. Biol. 360, 329-342.
25. Vaughan, M. et al. (2005). Investigation of bioisosteric effects on the interactionof substrates/inhibitors with the methionyl-tRNA synthetase from Escherichia coli. Med. Chem. 1, 227-237.
26. Kanatani, K. et al. (2005). A simple approach to sense codon-templated synthesis of natural/unnatural hybrid peptides. Nucleic Acids Symp. Ser. 49, 265-266.