Natural products serve as outstanding small molecule probes to interrogate biology, and many natural products in the NPL at TSRI have been demonstrated as powerful small molecule probes for various cellular targets. Selected natural product probes currently available to the scientific community are:
Lactimidomycin : (i) eukaryotic protein translation inhibitor, blocking the translocation step in translational initiation, and (ii) its utility in global mapping of translation initiation sites, termed Global Translation Initiation Sequencing (GTI-seq).
1. Schneider-Poetsch, T.; Ju, J.; Eyler, D. E.; Dang, Y.; Bhat, S.; Merrick, W. C.; Green, R.; Shen, B.; Liu, J. O. (2010) Inhibition of eukaryotic translation elongation by cycloheximide and lactimidomycin. Nat. Chem. Biol. 6:209-217.
2. Lee, S.; Liu, B.; Lee, S, Huang, S.-X.; Shen, B.; and Qian, S.-B. (2012) Global mapping of translation initiation sites in mammalian cells at single-nucleotide resolution. Proc. Natl. Acad. Sci. USA 109:14728-14729 (E2424-E2432).
3. Stern-Ginossar, N.; Weisburd, B.; Michalski, A.; Le, V. T. K.; Hein, M. Y.; Huang, S.-X.; Ma, m.; Shen, B.; Qian, S.-B.; Hengel, H.; Mann, M.; Ingolia, N. T.; Weissman, J. S. (2012) Decoding human cytomegalovirus. Science 338:1088-1093.
Migrastatin: Cell migration inhibitor.
1. Rajski, S. R.; Shen, B. (2010) Multifaceted modes of action for the glutarimide-containing polyketides revealed. ChemBioChem 11:1951-1954.
2. Gaul, C.; Njardarson, J. T.; Shan, D.; Dorn, D. C.; Wu, K.-D.; Tong, W. P.; Huang, X.-Y.; Moore, M. A. S.; Danishefsky, S. J. (2004) The migrastatin family: discovery of potent cell migration inhibitors by chemical synthesis. J. Am. Chem. Soc. 131:11326-11337.
3. Lim, S.-K.; Ju, J.; Zazopoulos, E.; Jiang, H.; Seo, J.-W.; Chen, Y.; Feng, Z.; Rajski, S. R.; Farnet, C. M.; Shen, B. (2009) iso-Migrastatin, migrastatin, and dorrigocin production in Streptomyces platensis NRRL18993 is governed by a single biosynthetic machinery featuring an acyltransferase-less type I polyketide synthase. J. Biol. Chem. 284:29746-29756.
4. Ju, J.; Rajski, S. R.; Lim, S.-K.; Seo, J.-W.; Peters, N. R.; Hoffmann, F. M.; Shen, B. (2009) Lactimidomycin, iso-migrastatin and related glutarimide-containing 12-membered macrolides are extremely potent inhibitors of cell migration. J. Am. Chem. Soc. 131:1370-1371.
Tautomycin and Tautomycetin: Protein phosphatase 1 (PP1) and 2A (PP2A) inhibitors.
1. MacKintosh, C.; Klumpp, S. (1990) Tautomycin from the bacterium Streptomyces verticillatus: another potent and specific inhibitor of protein phosphatases 1 and 2A. FEBS Lett. 277:137-140.
2. Mitsuhashi, S.; Matsuura, N.; Ubukata, M.; Oikawa, H.; Shima, H.; Kikuchi, K. (2001) Tautomycetin is a novel and specific inhibitor of serine/threonine protein phosphatase type 1, PP1. Biochem. Biopgys. Res. Commun. 287:328-331.
3. Li, W.; Ju, J.; Rajski, S. R.; Osada, H.; Shen, B. (2008) Characterization of the tautomycin biosynthetic gene cluster from Streptomyces Spiroverticillatus unveiling new insights into dialkymaleic anhydride and polyketide Biosynthesis. J. Biol. Chem. 283:28607-28617.
4. Li, W.; Luo, Y.; Ju, J.; Rajski, S. R. ; Osada, H. ; Shen, B. (2009) Characterization of the tautomycetin biosynthetic gene cluster from Streptomyces griseochromogenes provides new insight into dialkylmaleic anhydride biosynthesis. J. Nat. Prod. 72:450-459.
Tautomycetin and Tautomycetin D-1: Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) inhibitors.
1. Li, W.; Luo, Y.; Ju, J.; Rajski, S. R. ; Osada, H. ; Shen, B. (2009) Characterization of the tautomycetin biosynthetic gene cluster from Streptomyces griseochromogenes provides new insight into dialkylmaleic anhydride biosynthesis. J. Nat. Prod. 72:450-459.
2. Luo, Y.; Li, W.; Ju, J.; Yuan Q.; Peters, N. R.; Hoffmann, F. M.; Huang, S.; Bugni, T.; Rajski, S. R.; Osada, H.; Shen, B. (2010) Functional characterization of TtnD and TtnF unveiling new insights into tautomycetin biosynthesis. J. Am. Soc. Chem. 132:6663-6671.
3. Liu, S.; Yu, Z.; Yu, X.; Huang, S.-X., Luo, Y.; Wu, L.; Yang, Z.; Wang, L.; Gunawan, A.; Chan, R.J.; Shen, B.; Zhang, Z.-Y. (2011) SHP2 is a target of the immunosuppressant tautomycetin. Chem. Biol. 18:101-110
4. Yang, D.; Li, W.; Huang, S.-X.; Shen, B. (2012) Functional characterization of ttnI completing the tailoring steps for tautomycetin biosynthesis in Streptomyces griseochromogenes. Org. Lett. 14:1302-1305.
Fredericamycin A: Peptidyl cis-trans isomerase (PPI), such as Pin1, inhibitor.
1. Wendt-Pienkowski, E.; Huang, Y.; Zhang, J.; Li, B.; Jiang, H.; Kwon, H.-J.; Hutchinson, C.R.; Shen, B. (2005) Cloning, Sequencing, Analysis, and Heterologous Expression of the Fredericamycin Biosynthetic Gene Cluster from Streptomyces griseus. J. Am. Chem. Soc. 127:16442-16452.
2. Ryo, A.; Liou, Y.-C.; Lu, K. P.; Wulf, G. (2003) Prolyl isomerase Pin1: a catalyst for oncogenesis and a potential therapeutic target in cancer. J. Cell Sci. 116:773-783.
Platensimycin and Platencin: Bacterial FabB/F inhibitor and FabB/F and FabH dual inhibitor.
1. Wang, J. et al. (2006) Platensimycin is a selective FabF inhibitor with potent antibiotic properties. Nature 441:358–361.
2. Wang, J. et al. (2007) Discovery of platencin, a dual FabF and FabH inhibitor with in vivo antibiotic properties. Proc. Natl. Acad. Sci. U.S.A. 104:7612–7616.
3. Smanski, M. J.; Yu, Z.; Casper, J.; Lin, S.; Peterson, R. M.; Chen, Y.; Wendt-Pienkowski, E.; Rajski, S. R.; Shen, B. (2011) Dedicated ent-kaurene and ent-atiserene synthases for platensimycin and platencin biosynthesis. Proc. Natl. Acad. Sci. U.S.A. 108:13498-13503.
Tirandamycin B and WS9326D: Brugia malayi asparaginyl-tRNA synthetase (AsnRS) inhibitor.
1. Yu, Z.; Vodanovic-Jankovic, S.; Ledeboer, N.; Huang, S.-X.; Rajski, S. R.; Kron, M.; Shen, B. (2011) Tirandamycins from Streptomyces sp. 17944 Inhibiting the Parasite Brugia malayi Asparagine tRNA Synthetase. Org. Lett. 13:2034-2037.
2. Yu, Z.; Vodanovic-Jankovic, S.; Kron, M.; Shen, B. (2012) New WS9326A Congeners from Streptomyces sp. 9078 inhibiting Brugia malayi asparaginyl-tRNA synthetase. Org. Lett. 14:4946-4949.