Aspartyl-tRNA synthetase

Archontis, G. Simonson, T. Karplus, M., Binding free energies and free energy components from molecular dynamics and Poisson-Boltzmann calculations. Application to amino acid recognition by aspartyl-tRNA synthetase, J. Mol. Biol. 2001, 306, 307-327... 

Fig. 13.1. Cartoon of the aspartyl-tRNA synthetase amino acid binding site. The aspartate ligand is shown, along with the most important recognition residues. Groups that have been mutated in free energy simulations are boxed or circled. Flexible loop and Motif 2 refer to conserved motifs in the enzyme structure...

Transitive, iterative searches initiated with the sequences of the anticodon-binding domains of lysyl- and aspartyl-tRNA synthetases provided leads for the identification of biologically interesting, previously unknown OB-fold domains at a statistically significant level (random expectation values <0.01). In particular, OB folds were detected in the eukaryotic replication factor RFA with statistically significant scores this... 

Lorber B, Theobald-Dietrich A, Charron C, Sauter C, Ng JD, et al. 2002. Prom Conventional Crystallization to Better Crystals from Space A Review on Pilot Crystallographic Studies with Aspartyl-tRNA Synthetases. Acta Cryst D58 1674-1680. 

Figure 2 Indirect pathway for Asn-tRNA " and Gln-tRNA° " biosynthesis. ND-AspRS, nondiscriminating aspartyl-tRNA synthetase ND-GluRS, nondiscriminating glutamyl-tRNA systhetase AdT, aminoacyl-tRNA amidotransferase.

AsnRS was first characterized in the early 1960s in L. arabimsus hy its distinct chromatographic properties from aspartyl-tRNA synthetase and Asn synthetase and, at the end of the decade in E. coli as a protein of 90-100 kDa able to aminoacylate tRNA but not tRNA f / ° The enzyme was further characterized in mitochondria from Neurospora crassa" and in rat liver where tRNA asparaginylation activity was found associated with proteins of Air 35 and 90 kDa. The AsnRS purified from B. stearothermophilus of 127 kDa was characterized as a homodimer az (a = 51 kDa).AsnRSs isolated until now from various prokaryotic and eukaryotic organisms show conservation of the homodimeric structure. Investigation of B. stearothermophilus AsnRS allowed the determination of its physicochemical parameters S2o a = 6.6 x 10 s. 

Indirect Pathway Inhibitors of Glutamyl-tRNA Synthetase, Aspartyl-tRNA Synthetase, and Aminoacyl-tRNA Amidotransferase... 

Table 4 Inhibitors of aspartyl-tRNA synthetase (AspRS)...

R. Giege B. Rees, Aspartyl-tRNA Synthetases. In The Aminoacyl-tRNA Synthetases M. Ibba, C. Francklyn, S. Cusack, Eds. Eurekah.com/Landes Bioscience Georgetown TX, 2005 pp 210-226. 

Many proteins have structures related to those of aminoacyl-tRNA synthetases.282 283 For example, asparagine synthetase A functions via an aspartyl-adenylate intermediate (Chapter 24, Section B), and its structure resembls that of aspartyl-tRNA synthetase.284 The his G gene of histidine biosynthesis (Fig. 25-13) encodes an ATP phosphoribosyltransferase with structural homology to the catalytic domain of histidyl-tRNA synthetase.284 The reason is not clear, but some aminoacyl-tRNA synthetases, especially the histidyl-tRNA synthetase, are common autoantigens for the inflammatory disease polymyosititis.285 286... 

Archontis G, Simonson T, Moras D, Karplus M (1998) Specific amino acid recognition by aspartyl-tRNA synthetase studied by free energy simulation, J Mol Biol, 275 823-846... 

Energies and Free Energy Components from Molecular Dynamics and Polsson-Boltzmann Calculations. Application to Amino Acid Recognition by Aspartyl-tRNA Synthetase. 

Several aaRS-like proteins are involved in metabobc pathways (1). For example, E. coli asparagine synthase, an aspartyl-tRNA synthetase (AspRS)-like enzyme, catalyzes the synthesis of asparagine from aspartate and ATP. A paralog of LysRS-II, called PoxA/GenX, is important for pyruvate oxidase activity in E. coli and Salmonella typhimurium and for virulence in S. typhimurium. The E. coli biotin synthetase/repressor protein (BirA), which has a domain that resembles structurally the seryl-tRNA synthetase (SerRS) catalytic domain, activates biotin to modify posttranslationaUy various metabolic proteins involved in carboxylation and decarboxylation. BirA can also bind DNA and regulate its own transcription using biotin as a corepressor. A histidyl-tRNA synthetase (HisRS)-hke protein from Lactococcus lactis, HisZ is involved in the allosteric activation of the phosphoribosyl-transferase reaction. 

T. Imanaka, J. C. Thierry, D. Moras, Crystal structure of aspartyl-tRNA synthetase from Pyrococcus kodakaraensis KOD archaeon specificity and catalytic mechanism of adenylate formation, EMBO J. 1998, 17(17), 5227-5237. 

The hydroxamate derivative is readily complexed with acidified ferric chloride to form a dark brown coloration which may be easily measured in a spectrophotometer. Unfortunately the assay system can also be used to measure two other enzymes—aspartate kinase and aspartyl-tRNA synthetase (although the latter catalyzes the formation of the a-aspartyl hydroxamate). There are two possible ways to distinguish between aspartate kinase and AS. 

The simplest marriage between PB theory and the classical force-field approach is illustrated by the works of Caflisch and Karplus, in which structures from several MD trajectories of barnase were used in PB calculations to determine the electrostatic interaction energy between various groups/ and that of Archontis, Simonson and Karplus, who compared the binding of aspartate and asparagine to aspartyl-tRNA synthetase/ " Other studies are those of Cheatham et ah, on the stability of DNA duplexes/ Srinivasan et ah, on the stability of RNA hairpins/ " Reyes and Kollman, on RNA-protein binding Cubero et al., on triple-stranded DNA formation and Tsui and Case, on trivalent cobalt binding to RNA. 

G. Archontis, T. Simonson, and M. Karplus,/. Molec. Biol., 306, 307 (2001). Binding Free Energies and Free Energy Components from Molecular Dynamics and Poisson-Boltzmann Calculations. Application to Amino Acid Recognition by Aspartyl-tRNA Synthetase. 

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