Physiocrine

Physiocrines are the extracellular signaling regions or alternatively spliced variants of aminoacyl tRNA synthetases (aaRSs) that modulate a range of cellular activities to maintain homeostasis. [1][2][3][4] AARSs were once generally thought to only facilitate in protein synthesis by catalyzing the aminoacylation of tRNAs to their correct amino acid. [5] Since 1999, researchers have demonstrated that AARSs have functional roles outside of protein synthesis due to the extracellular signaling regions and splice variants of aaAARS. [6][7] Those functional roles include regulation of gene expression, angiogenesis, cellular signaling, and immune modulation.[1][2][3][4]

Discovery and Naming

In 1999, Paul Schimmel, Ph.D., and colleagues discovered that aaRSs can possess proteins that act as extracellular ligands to modulate cell activity.[5] Since then, many more functions for AARSs have been described both in eukaryotes and prokaryotes.[6][7][8][9][10][11][12][13]

In 2005, Dr. Schimmel and Xiang-Lei Yang, Ph.D., founded aTyr Pharma, a biotechnology company based on the therapeutic potential of these extracellular regions in AARSs to restore health to dysfunctional tissue. To distinguish between the translational and nontranslational functions of aaRS the extracellular signaling regions and splice variants of aaRSs were coined Physiocrines; physio for life and crine for specific activity.

Evolution of Physiocrines

For over 4 billion years, the core function and structure of aaRSs for protein synthesis have remained primarily unchanged in most organisms. However, as organisms became more complex they acquired additional aaRS domains that are thought to have important function outside of protein synthesis.[14][15]

Functions of Physiocrines

Physiocrines can act intracellularly to regulate gene expression or be released from cells in response to stimuli such as starvation-induced apoptotic stress or the introduction of certain cellular ligands, including tumor necrosis factor alpha (TNF-α) and vascular endothelial growth factor (VEGF).[16]

[17][18][19][20][21][22][23][24][25][26]

Physiocrine Pathways as Potential Therapeutic Targets

The specific regulatory capability of Physiocrines makes this class of proteins potential candidates for several therapeutic applications. A study conducted by researchers at The Scripps Laboratories for tRNA Synthetase, Hong Kong University of Science and Technology and aTyr Pharma on the functions of extracellular regions and alternatively spliced variants of Physiocrines have helped to define potential roles of hundreds of Physiocrines in cellular pathways and provide direction for therapeutic development.[27]

Cellular Pathway Potential Therapeutic Applications Number of Physiocrines
Immunology Rare diseases with an immune component, auto-immune disorders, oncology and fibrosis 99
Stem cells Regenerative medicine, fibrosis and oncology 129
Neurology Neurodegenerative diseases 34
Vascular Cardiovascular diseases, oncology and immunology 35
Skeletal muscle Skeletal muscle diseases 130
Hepatic Liver fibrosis 76
Metabolic Diabetes and obesity 22

References

  1. ↑ Jeeva, Jothi D; Dhanraj, M (January 11, 2016). "Brugia malayi Asparaginyl - tRNA Synthetase Stimulates Endothelial Cell Proliferation, Vasodilation and Angiogenesis". PLoS ONE. doi:10.1371/journal.pone.0171402.
  2. ↑ Havrylenko, Svitlana; Mirande, Marc (March 23, 2015). "Aminoacyl-tRNA Synthetase Complexes in Evolution". Int. J. Mol. Sci. 16 (3): 6571–6594. doi:10.3390/ijms16036571.
  3. ↑ Lo, Wing-Sze; Gardiner, E (July 18, 2014). "Human tRNA Synthetase Catalytic Nulls with Diverse Functions". Nature. 345 (6194): 328–332. doi:10.1126/science.1252943.
  4. ↑ Mirando, Adam C.; Söll, D (Dec 19, 2014). "Regulation of Angiogenesis by Aminoacyl-tRNA Synthetases". Int. J. Mol. Sci. 15 (12): 23725–23748. doi:10.3390/ijms151223725.
  5. ↑ Wakasugi; Schimmel, P (Apr 2, 1999). "Two Distinct Cytokines Released from a Human Aminoacyl-tRNA Synthetase". Science. 284 (5411): 147–151. doi:10.1126/science.284.5411.147.
  6. ↑ Jeeva, Jothi D; Dhanraj, M (January 11, 2016). "Brugia malayi Asparaginyl - tRNA Synthetase Stimulates Endothelial Cell Proliferation, Vasodilation and Angiogenesis". PLoS ONE. doi:10.1371/journal.pone.0171402.
  7. ↑ Havrylenko, Svitlana; Mirande, Marc (March 23, 2015). "Aminoacyl-tRNA Synthetase Complexes in Evolution". Int. J. Mol. Sci. 16 (3): 6571–6594. doi:10.3390/ijms16036571.
  8. ↑ Mirando, Adam C.; Söll, D (Dec 19, 2014). "Regulation of Angiogenesis by Aminoacyl-tRNA Synthetases". Int. J. Mol. Sci. 15 (12): 23725–23748. doi:10.3390/ijms151223725.
  9. ↑ Wakasugi; Schimmel, P (Apr 2, 1999). "Two Distinct Cytokines Released from a Human Aminoacyl-tRNA Synthetase". Science. 284 (5411): 147–151. doi:10.1126/science.284.5411.147.
  10. ↑ Wakasugi, K; Slike, BM (Jan 8, 2002). "A human aminoacyl-tRNA synthetase as a regulator of angiogenesis". 99 (1): 173–177. doi:10.1073/pnas.012602099.
  11. ↑ Yang, X-L; Kapoor, M (Dec 26, 2007). "Gain-of-Function Mutational Activation of Human tRNA Synthetase Procytokine". Chemistry and Biology. 14 (12): 1323–1333. doi:10.1016/j.chembiol.2007.10.016.
  12. ↑ Zhou, Quansheng; Kapoor, M (Dec 13, 2009). "Orthogonal use of a human tRNA synthetase active site to achieve multifunctionality". Nature Structural and Molecular Biology. 17: 57–61. doi:10.1038/nsmb.1706.
  13. ↑ Guo, Min; Yang, X-L; Schimmel, P (Aug 11, 2010). "New functions of tRNA synthetases beyond translation". Nat Rev Mol Cell Biol. 11 (9): 668–674. doi:10.1038/nrm2956.
  14. ↑ Guo, Min; Yang, X-L; Schimmel, P (Aug 11, 2010). "New functions of tRNA synthetases beyond translation". Nat Rev Mol Cell Biol. 11 (9): 668–674. doi:10.1038/nrm2956.
  15. ↑ Katz, A; Elgamal, S; Rajkovic, A (June 28, 2016). "Non-canonical roles of tRNAs and tRNA mimics in bacterial cell biology". Mol. Microbiol.l. 101 (4): 668–674. doi:10.1111/mmi.13419.
  16. ↑ Guo, M; Schimmel , P (March 2013). "Essential nontranslational functions of tRNA synthetases.". Nat Chem Biol. 9 (3): 145–153. doi:10.1038/nchembio.1158.
  17. ↑ Lo, Wing-Sze; Gardiner, E (July 18, 2014). "Human tRNA Synthetase Catalytic Nulls with Diverse Functions". Nature. 345 (6194): 328–332. doi:10.1126/science.1252943.
  18. ↑ Wakasugi; Schimmel, P (Apr 2, 1999). "Two Distinct Cytokines Released from a Human Aminoacyl-tRNA Synthetase". Science. 284 (5411): 147–151. doi:10.1126/science.284.5411.147.
  19. ↑ Wakasugi, K; Slike, BM (Jan 8, 2002). "A human aminoacyl-tRNA synthetase as a regulator of angiogenesis". 99 (1): 173–177. doi:10.1073/pnas.012602099.
  20. ↑ Guo, M; Schimmel , P (March 2013). "Essential nontranslational functions of tRNA synthetases.". Nat Chem Biol. 9 (3): 145–153. doi:10.1038/nchembio.1158.
  21. ↑ Lareau, LF; Green, RE (June 2004). "The evolving roles of alternative splicing". Current Opinion in Structural Biology. 14 (3): 273–282. doi:10.1016/j.sbi.2004.05.002.
  22. ↑ Tzima, E; Reader, JS (Dec 3, 2004). "VE-cadherin Links tRNA Synthetase Cytokine to Anti-angiogenic Function". 280: 2405–2408. doi:10.1074/jbc.C400431200.
  23. ↑ Kawahara, A; Didier, YR (August 2009). "Noncanonical Activity of Seryl-Transfer RNA Synthetase and Vascular Development". Trends in Cardiovascular Medicine. 19 (6): 179–182. doi:10.1016/j.tcm.2009.11.001.
  24. ↑ Zhou, Q; Kapoor, M (Jan 2010). "Orthogonal use of a human tRNA synthetase active site to achieve multifunctionality". Nature Structural & Molecular Biology. 17 (1): 57–61. doi:10.1038/nsmb.1706.
  25. ↑ Park, SG; Hye, JK (May 3, 2005). "Human lysyl-tRNA synthetase is secreted to trigger proinflammatory response". PNAS. 102 (18): 6356–6361. doi:10.1073/pnas.0500226102.
  26. ↑ Arif, A; Jai, J (Jan 25, 2011). "Phosphorylation of glutamyl-prolyl tRNA synthetase by cyclin-dependent kinase 5 dictates transcript-selective translational control". PNAS. 108 (4): 1415–1420. PMC 3029695 Freely accessible. doi:10.1073/pnas.1011275108.
  27. ↑ Lo, Wing-Sze; Gardiner, E (July 18, 2014). "Human tRNA Synthetase Catalytic Nulls with Diverse Functions". Nature. 345 (6194): 328–332. doi:10.1126/science.1252943.

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