Monday, November 22, 2010

Mining aminoacyl tRNA synthases (aaRSs) for anti-angiogenic factors

Aminoacyl tRNA synthases (aaRSs) are ancient catalytic enzymes that catalyze the first step in protein synthesis, transfer of amino acid to its cognate tRNA, something that we learned years ago in Stryer’s Biochemistry.  But, these enzymes are also moonlighting proteins, with alternate splice forms or natural proteolytic fragments, acting as cytokines, angiogenic factors or angiostatic factors. The one that caught my eye was tryptophanyl-tRNA synthase (TrpRS) fragment which is antiangiogenic and is in clinical development for retinal diseases [...][...].

The antiangiogenic activity of T2 proteolytic fragment of TrpRS (TrpRS-T2) is linked to its ability to block VE-cadherin-mediated adhesion, and does not involve binding to VEGF, VEGF receptors or integrins (αvβ3 and αvβ5).  T2 exhibits synergistic effects with an anti-VEGF Macugen and integrin antagonist in retinal  angiogenesis or a highly vascular glioblastoma model [...]   
A tiny startup, Angiosyn was formed to discover and commercialize aaRSs based angiostatic factors in 2003, and by 2005, it was merged into PfizerEyecyte founded by Martin Friedlander and Mohammad A. El-Kalay is another small biotech, targeting age-related macular degeneration (AMD), glaucoma and retinitis pigmentosa.  Neomics of South Korea wants to develop cancer diagnostics and therapeutics based on aaRSs interacting proteins, AIMP2(p38) and AIMP3(p18). 

As a family, aaRSs have a lot to offer: Human tyrosyl-tRNA synthase (TyrRS) is a procytokine/proangiogenic factor.  Its C-terminal domain acts as an IL-8-like cytokine, is a strong chemotatic factor for PMNs and leukocytes and induces secretion of  inflammatory factors, myeloperoxidase, tumor necrosis factor-α, and tissue factor [...], whereas, the NH2-domain (called mini-TyrRS) is proangiogenic.  It is as good as VEGF in various in vitro and mouse assays [...]  The two cytokine domains are released upon proteolytic digestion by elastase.  Seryl-tRNA synthase (SARS) is linked to vascular patterning.  Mutations in Glycyl-tRNA synthase (GlyRS) and TryRS are associated with a common peripheral neuropathy Charcot-Marie-Tooth (CMT) disease.  GlyRS is known to interact with ICAM-1.  aTyr Pharma (and its subsidiary in Hong Kong, Pangu) founded by Paul Schimmel, is developing aaRSs derivatives, called Physiocrines™, with therapeutically useful properties, such as, anti-inflammation, pro or anti-angiogenesis.

Further Readings and Links:

The Paul Schimmel and Xiang-Lei Yang Laboratory at The Scripps Research Institute

Combination angiostatic therapy completely inhibits ocular and tumor angiogenesis. Dorrell MI, Aguilar E, Scheppke L, Barnett FH, Friedlander M. Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):967-972. | PubMed | Scholar

A fragment of human TrpRS as a potent antagonist of ocular angiogenesis. Otani A, Slike BM, Dorrell MI, Hood J, Kinder K, Ewalt KL, Cheresh D, Schimmel P, Friedlander M. Proc Natl Acad Sci U S A. 2002 Jan 8;99(1):178-83. | PubMed |

VE-cadherin links tRNA synthetase cytokine to anti-angiogenic function. Tzima E, Reader JS, Irani-Tehrani M, Ewalt KL, Schwartz MA, Schimmel P. J Biol Chem. 2005 Jan 28;280(4):2405-8. | PubMed |
Two Distinct Cytokines Released from a Human Aminoacyl-tRNA Synthetase. Keisuke Wakasugi and Paul Schimmel. Science 1999;284:147-151 | DOI | PubMed |

Induction of angiogenesis by a fragment of human tyrosyl-tRNA synthetase. Wakasugi K, Slike BM, Hood J, Ewalt KL, Cheresh DA, Schimmel P. J Biol Chem. 2002 Jun 7;277(23):20124-20126. | PubMed |

Scientists Crack Mystery of Protein's Dual Function.  Scripps News. Vol 9. Issue 39, December 21, 2009

Pfizer and EyeCyte collaborations [read at PBS, Forbes, 2008]

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