Fungal infections have become a worldwide global health problem, affecting millions of patients per year. It is imminent to explore new antifungal drugs or discover novel potential targets for antifungal therapeutics. Rapamycin (TORs) dependent signaling pathway has become an important and valid target for antifungal drug discovery because of its multiple functions.
As a leading service provider in the field of biological research and drug discovery, Creative Biolabs has successfully developed an antifungal drug discovery platform. Aided by this platform, we can offer a series of effective and innovative targets for the TORs dependent signaling pathway, which is a great benefit for the antifungal drug exploration.
TORs Signaling Pathway and Fungi
TOR (target of rapamycin) is a member of phosphatidylinositol kinase-related kinases (or PIKKs) family, which controls cell growth in response to nutrients. Rapamycin is a lipophilic macrolide and has been regarded as an immunosuppressive and anticancer drug that inhibits downstream signaling from the TOR proteins. The action model of rapamycin (TORs) dependent signaling pathway is remarkably conserved from S. cerevisiae to humans. It coordinates the balance between protein synthesis and protein degradation in response to nutrient quality and quantity. In fungi, the highly conserved protein kinases control growth and proliferation of fungal pathogens, representing attractive targets for antifungal drug discovery. The inhibitors of rapamycin (TORs) dependent signaling pathway may be recognized as broad-spectrum antimicrobial therapeutic agents.
Fig.1 Rapamycin (TORs) dependent signaling pathway. (Kim, 2013)
Structure of TOR Proteins
The TOR has several functional domains that are conserved in all TOR proteins, mainly including the N-terminal HEAT domain (up to 20 tandemly repeated HEAT motifs), the central FAT domain (a scaffold or as a protein-protein interaction domain), and the C-terminal FKBP-rapamycin binding domain. Additionally, TOR proteins are characterized by a conserved C-terminal region with strong homology to the related catalytic domains of phosphatidylinositol 3-kinase (PI3K) and phosphatidylinositol 4-kinase.
Fig.2 Structure and conformation of mTOR protein. (Saran, 2015)
Functions of TORs Signaling Pathway
TORs function deficiency in yeast cells results in an early and severe inhibition of translation initiation, which subsequently causes TOR-inhibited cells arrest in the G1 phase of the cell cycle. The most plausible mechanism is that TORs activation triggers translation initiation via activation of eIF4E, mediating translation initiation by facilitating ribosome binding to the 5′ cap structure of the mRNA. Several mTOR inhibitors, e.g. rapamycin, are already used to prevent transplant rejection.
It is documented that the TORs signaling pathway regulates ribosome biogenesis at both the transcriptional and translational levels and plays a key role in coupling nutrient availability to the transcription of genes involved in the formation of ribosomes. Inhibition of the TOR pathway by rapamycin can result in a downregulation of transcription of ribosomal protein mRNAs as well as the transcription of rRNA and tRNA. TORs also regulate the abundance of ribosomal proteins and other components of the translation machinery, such as the poly(A)-binding protein.
TORs signaling can also regulate the activity of phosphatase. In this process, TAP42 (a phosphatase-associated protein of 42 kDa) is an essential, conserved protein that independently associates with SIT4 and with the catalytic subunits of PP2A in response to nutrient availability and TOR activity. By regulating phosphatase activity, TORs signaling participates in the protein synthesis and functional regulation.
TOR pathway plays a prominent role in the regulation of amino acid permease activity, which permits cells to transport nutrients (sugars, amino acids, and peptides) across the plasma membrane supporting fungal growth and viability. It is reported that inhibition of TORs function by rapamycin will induce a decrease in tryptophan import.
In addition to the mentioned functions above, the TORs signaling pathway has many extended roles, such as transcriptional control of nutrient metabolism, the organization of the actin cytoskeleton, control of autophagy, etc.
Advantages of the TORs Signaling Pathway Targets
With decades of experience and advanced technology, Creative Biolabs works all out to offer comprehensive solutions for antifungal targets study. TORs dependent signaling pathway is one of our promising new drug targets. We are proud to offer our customers high quality and reliable services to support their research and projects in antifungal agents discovery. Please contact us to learn about more information.
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