User:Khadar Abdi/Sandbox1

spinqualitylabelsall models Staphylococcus aureus threonyl-tRNA Synthetase bound to Threonyl-Sulfamoyl Adenosine Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Contents 1 Introduction 2 Mechanism 3 Disease Relevance 4 Structural highlights 5 Evolutionary related proteins 6 List to available structures 7 References

Introduction

Threonyl t-RNA Synthetase or Threonyl-tRNA ligase or TARS is a homodimer (150kDa in bacteria and 170kDa in human) and is classified as a class II Aminoacyl-tRNA synthetase enzymes. These ancient enzymes primary function are to add the respective amino acid to the respective transfer Ribonucleic Acid (tRNA-AA), a necessity prep for the protein synthesis pathway^[1]. As the name implies, TARS function is to add Threonine amino acid (Thr) to threonine specific tRNA (tRNA-thr) in the presence of Adenosine triphosphate (ATP) and diavalent metal cation. Below displays the overview of TARS Aminoacylation rxn^[2].

Mechanism

TARS adds amino acid to tRNA by a two-step mechanism. First the enzyme binds to both and in the catalytic domain to perform an adenylation reaction in which threonyl adenylate (Thr-AMP) is formed and pyrophosphate (PPi) is released as a byproduct. The image to the right displays the binding of adenylate product to the TARS enzyme (PDB entry 1nyq). This is then follow up by a transferring Thr from Adenosine monophosphate (AMP) molecule to 3'OH site of tRNA-thr. ^[4] The image to the above demonstrates the arrow pushing occurring to generate threonine bound tRNA-thr.

Disease Relevance

Lately the aaRS family was found to have more function than just aminoacylation. For instance, many aaRs molecules have been found to link with angiogenesis, blood vessel growth occuring within a cancer environment^[5]. This is seen in human exogenous TARS in its ability to generate blood vessels within ovarian cancer environment^[6]. Studies on the structure of TARS bound to BC194, derivative to the natural antibiotic Borrelidin, were investigated to understand how the angiogenic signaling from TARS occurs^[7].

Structural highlights

Evolutionary related proteins

List to available structures

References

1. ↑ Rajendran V, Kalita P, Shukla H, Kumar A, Tripathi T. Aminoacyl-tRNA synthetases: Structure, function, and drug discovery. Int J Biol Macromol. 2018 May;111:400-414. doi: 10.1016/j.ijbiomac.2017.12.157., Epub 2018 Jan 3. PMID:29305884 doi:http://dx.doi.org/10.1016/j.ijbiomac.2017.12.157
2. ↑ Rajendran V, Kalita P, Shukla H, Kumar A, Tripathi T. Aminoacyl-tRNA synthetases: Structure, function, and drug discovery. Int J Biol Macromol. 2018 May;111:400-414. doi: 10.1016/j.ijbiomac.2017.12.157., Epub 2018 Jan 3. PMID:29305884 doi:http://dx.doi.org/10.1016/j.ijbiomac.2017.12.157
3. ↑ Lehninger, A. L., Nelson, D. L., & Cox, M. M. (2000). Lehninger principles of biochemistry. New York: Worth Publishers.
4. ↑ Lehninger, A. L., Nelson, D. L., & Cox, M. M. (2000). Lehninger principles of biochemistry. New York: Worth Publishers.
5. ↑ Mirando AC, Francklyn CS, Lounsbury KM. Regulation of angiogenesis by aminoacyl-tRNA synthetases. Int J Mol Sci. 2014 Dec 19;15(12):23725-48. doi: 10.3390/ijms151223725. PMID:25535072 doi:http://dx.doi.org/10.3390/ijms151223725
6. ↑ Williams TF, Mirando AC, Wilkinson B, Francklyn CS, Lounsbury KM. Secreted Threonyl-tRNA synthetase stimulates endothelial cell migration and angiogenesis. Sci Rep. 2013;3:1317. doi: 10.1038/srep01317. PMID:23425968 doi:http://dx.doi.org/10.1038/srep01317
7. ↑ Mirando AC, Fang P, Williams TF, Baldor LC, Howe AK, Ebert AM, Wilkinson B, Lounsbury KM, Guo M, Francklyn CS. Aminoacyl-tRNA synthetase dependent angiogenesis revealed by a bioengineered macrolide inhibitor. Sci Rep. 2015 Aug 14;5:13160. doi: 10.1038/srep13160. PMID:26271225 doi:http://dx.doi.org/10.1038/srep13160

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