ATP-directed capture of bioactive herbal-based medicine on human tRNA synthetase

Maeng

Journal of Biological Chemistry

et al. 2015

Background: GST domains have been found in diverse proteins involved in translational systems. Results: Four GST domains from human methionyl-tRNA synthetase, glutaminyl-prolyl-tRNA synthetase, ARS-interacting multifunctional protein (AIMP) 2, and AIMP3 are complexed in an ordered fashion. Conclusion: Four components in the human multisynthetase complex are assembled through a GST domain tetrameric complex. Significance: GST domain assemblies act as scaffolds for the formation of multicomponent protein complexes.

Section: Discussionmentioning

confidence: 99%

“…The KRS dimer is hooked to the flexible N-terminal arm of AIMP2 (35). PRS linked to the C-terminal end of ERS can form a homodimer (36). The WHEP domains between ERS and PRS are replaced by a short dotted line (cyan and dark cyan).…”

Section: Discussionmentioning

confidence: 99%

Assembly of Multi-tRNA Synthetase Complex via Heterotetrameric Glutathione Transferase-homology Domains

Maeng

Journal of Biological Chemistry

et al. 2015

Topics in Current Chemistry

“…Unlike other inhibitors of ARSs, which mimic aminoacyl-adenylates and out-compete the substrate ATP, halofuginone-mediated PRS inhibition requires ATP. By associating with ATP as well as PRS, halofuginone occupies two active sites of PRS: the proline binding pocket and the binding pocket for the tRNA interaction [143]. As a result, halofuginone-mediated PRS inhibition triggers amino acid starvation response, inhibits the differentiation of Th17 cells, and suppresses fibrosis [111].…”

Section: Aminoacyl-trna Synthetasesmentioning

confidence: 99%

“…Halofuginone is a derivative of febrifugine, the active principal of the Chinese herb changshan (Dichroafebrifuga) which is used as an anti-malarial treatment in Chinese traditional medicine [142]. Halofuginone targets prolyl-tRNA synthetase (PRS) in EPRS and is in clinical trials for the treatment of cancer and fibrosis [111,143]. Halofuginone acts as a prolyladenylate-mimetic and inhibits aminoacylation activity of PRS.…”

Section: Aminoacyl-trna Synthetasesmentioning

confidence: 99%

Association of Aminoacyl-tRNA Synthetases with Cancer

Kim

Kwon

Kim

2013

Although aminoacyl-tRNA synthetases (ARSs) and ARS-interacting multi-functional proteins (AIMPs) have long been recognized as housekeeping proteins, evidence indicating that they play a key role in regulating cancer is now accumulating. In this chapter we will review the conventional and non-conventional functions of ARSs and AIMPs with respect to carcinogenesis. First, we will address how ARSs and AIMPs are altered in terms of expression, mutation, splicing, and post-translational modifications. Second, the molecular mechanisms for ARSs' and AIMPs' involvement in the initiation, maintenance, and progress of carcinogenesis will be covered. Finally, we will introduce the development of therapeutic approaches that target ARSs and AIMPs with the goal of treating cancer.

“…One part mimics bound proline and the other mimics the 3 0 end of the bound tRNA. 14 In this way, halofuginone is able to target 2 binding sites to modulate the activity of ProRS. This raises the possibility that similar inhibitors might be applied to other synthetases.…”

mentioning

confidence: 99%

The growing pipeline of natural aminoacyl-tRNA synthetase inhibitors for malaria treatment

Saint-Léger¹,

Sinadinos²,

Pouplana

2016

Bioengineered

Malaria remains a major global health problem. Parasite resistance to existing drugs makes development of new antimalarials an urgency. The protein synthesis machinery is an excellent target for the development of new anti-infectives, and aminoacyl-tRNA synthetases (aaRS) have been validated as antimalarial drug targets. However, avoiding the emergence of drug resistance and improving selectivity to target aaRS in apicomplexan parasites, such as Plasmodium falciparum, remain crucial challenges. Here we discuss such issues using examples of known inhibitors of P. falciparum aaRS, namely halofuginone, cladosporin and borrelidin (inhibitors of ProRS, LysRS and ThrRS, respectively). Encouraging recent results provide useful guidelines to facilitate the development of novel drug candidates which are more potent and selective against these essential enzymes.