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Koningic acid, a potent selective GAPDH inhibitor, for metabolic research!

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@5 mg: US$1000

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Contact: Naoko Nishimura, Ph.D.; E-mail: jimu[at]tms-japan.co.jp

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Koningic acid (CAS No. 57710-57-3) (Figure 1) is a sesquiterpene lactone (molecular mass of 280.3) produced by the fungus Trichoderma koningii (1). Koningic acid inhibits glyceraldehyde 3-phosphate dehydrogenase (GAPDH) from various species by binding to the essential Cys residue in the catalytic site through a thioether bond (2-4). The covalent modification of the essential Cys by koningic acid leads to irreversible inactivation of GAPDH (2,3). The affinity of koningic binding to GAPDH for the inactivation is 1.6 M (2). Koningic acid is effective in inhibiting GAPDH of cells in culture at 10-50 M (1,5).
Koningic acid produces glucose-dependent ATP depletion in malignant cells (Figure 2) (5,6). There are many examples of the application of koningic acid in biochemical and biomedical researches (7-20).

1. Endo, A., K. Hasumi, et al. (1985). "Specific inhibition of glyceraldehyde-3-phosphate dehydrogenase by koningic acid (heptelidic acid)." J Antibiot (Tokyo) 38(7): 920-5.
2. Sakai, K., K. Hasumi, et al. (1988). "Inactivation of rabbit muscle glyceraldehyde-3-phosphate dehydrogenase by koningic acid." Biochim Biophys Acta 952(3): 297-303.
3. Sakai, K., K. Hasumi, et al. (1991). "Identification of koningic acid (heptelidic acid)-modified site in rabbit muscle glyceraldehyde-3-phosphate dehydrogenase." Biochim Biophys Acta 1077(2): 192-6.
4. Kato, M., K. Sakai, et al. (1992). "Koningic acid (heptelidic acid) inhibition of glyceraldehyde-3-phosphate dehydrogenases from various sources." Biochim Biophys Acta 1120(1): 113-6.
5. Kumagai, S., R. Narasaki, et al. (2008). "Glucose-dependent active ATP depletion by koningic acid kills high-glycolytic cells." Biochem Biophys Res Commun 365(2): 362-8.
6. Colell, A., D. R. Green, et al. (2009). "Novel roles for GAPDH in cell death and carcinogenesis." Cell Death Differ 16(12): 1573-81.
7. Markos, A., A. Miretsky, et al. (1993). "A glyceraldehyde-3-phosphate dehydrogenase with eubacterial features in the amitochondriate eukaryote, Trichomonas vaginalis." J Mol Evol 37(6): 631-43.
8. McDonald, B., B. Reep, et al. (1993). "Glyceraldehyde-3-phosphate dehydrogenase is required for the transport of nitric oxide in platelets." Proc Natl Acad Sci U S A 90(23): 11122-6.
9. Nakazawa, M., T. Uehara, et al. (1997). "Koningic acid (a potent glyceraldehyde-3-phosphate dehydrogenase inhibitor)-induced fragmentation and condensation of DNA in NG108-15 cells." J Neurochem 68(6): 2493-9.
10. Nomura, Y. (1998). "A transient brain ischemia- and bacterial endotoxin-induced glial iNOS expression and NO-induced neuronal apoptosis." Toxicol Lett 102-103: 65-9.
11. Beisswenger, P. J., S. K. Howell, et al. (2003). "Glyceraldehyde-3-phosphate dehydrogenase activity as an independent modifier of methylglyoxal levels in diabetes." Biochim Biophys Acta 1637(1): 98-106.
12. Kim, J. H., S. Lee, et al. (2003). "Hydrogen peroxide induces association between glyceraldehyde-3-phosphate dehydrogenase and phospholipase D2 to facilitate phospholipase D2 activation in PC12 cells." J Neurochem 85(5): 1228-36.
13. Takahashi, H., P. O. Tran, et al. (2004). "D-Glyceraldehyde causes production of intracellular peroxide in pancreatic islets, oxidative stress, and defective beta cell function via non-mitochondrial pathways." J Biol Chem 279(36): 37316-23.
14. Gregus, Z. and B. Nemeti (2005). "The glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase works as an arsenate reductase in human red blood cells and rat liver cytosol." Toxicol Sci 85(2): 859-69.
15. Yasuda, Y., Y. Miyamoto, et al. (2006). "Mechanism of the stress-induced collapse of the Ran distribution." Exp Cell Res 312(4): 512-20.
16. Nemeti, B. and Z. Gregus (2009). "Mechanism of thiol-supported arsenate reduction mediated by phosphorolytic-arsenolytic enzymes: I. The role of arsenolysis." Toxicol Sci 110(2): 270-81.
17. Gregus, Z., G. Roos, et al. (2009). "Mechanism of thiol-supported arsenate reduction mediated by phosphorolytic-arsenolytic enzymes: II. Enzymatic formation of arsenylated products susceptible for reduction to arsenite by thiols." Toxicol Sci 110(2): 282-92.
18. Kim, J. H. and C. H. Lee (2009). "Heptelidic acid, a sesquiterpene lactone, inhibits Etoposide-induced apoptosis in human leukemia U937 cells." J Microbiol Biotechnol. 19(8):787-91.
19. Rogers, S. C., A. Said, et al. (2009). "Hypoxia limits antioxidant capacity in red blood cells by altering glycolytic pathway dominance." FASEB J 23(9): 3159-70.
20. Zaid, H., I. Talior-Volodarsky, et al. (2009). "GAPDH binds GLUT4 reciprocally to hexokinase-II and regulates glucose transport activity." Biochem J 419(2): 475-84.
21. Maller, C., E. Schroder, et al. (2011). "Glyceraldehyde 3-phosphate dehydrogenase is unlikely to mediate hydrogen peroxide signaling: studies with a novel anti-dimedone sulfenic acid antibody." Antioxid Redox Signal 14(1): 49-60.
22. Sansbury, B. E., D. W. Riggs, et al. (2011) "Responses of hypertrophied myocytes to reactive species: implications for glycolysis and electrophile metabolism." Biochem J 435: 519-528.
23. Dodson, M., Q. Liang, et al. (2013). "Inhibition of glycolysis attenuates 4-hydroxynonenal-dependent autophagy and exacerbates apoptosis in differentiated SH-SY5Y neuroblastoma cells." Autophagy 9(12): 1996-2008.
24. Rogers, S. C., J. G. Ross, et al. (2013). "Sickle hemoglobin disturbs normal coupling among erythrocyte O2 content, glycolysis, and antioxidant capacity." Blood 121(9): 1651-62.

 
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