Geldanamycin
| Geldanamycin | |
|---|---|
| File:Geldanamycin.svg | |
| (4E,6Z,8S,9S,10E,12S,13R,14S,16R)-13-hydroxy -8,14,19-trimethoxy-4,10,12,16-tetramethyl | |
| style="background: #F8EABA; text-align: center;" colspan="2" | Identifiers | |
| CAS number | 30562-34-6 |
| style="background: #F8EABA; text-align: center;" colspan="2" | Properties | |
| Molecular formula | C29H40N2O9 |
| Molar mass | 560.64 g/mol |
| Appearance | Gold-yellow fine crystalline powder |
| Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) | |
| Infobox references | |
Geldanamycin is a benzoquinone ansamycin antibiotic that binds to Hsp90 (Heat Shock Protein 90) and alters its function. HSP90 client proteins play important roles in the regulation of the cell cycle, cell growth, cell survival, apoptosis, angiogenesis and oncogenesis.
Geldanamycin induces the degradation of proteins that are mutated in tumor cells such as v-Src, Bcr-Abl and p53 preferentially over their normal cellular counterparts. This effect is mediated via HSP90. Despite its potent antitumor potential, geldanamycin presents several major drawbacks as a drug candidate (namely, hepatotoxicity) that have led to the development of geldanamycin analogues, in particular analogues containing a derivatisation at the 17 position:
Biosynthesis
Geldanamycin was originally discovered in the organism Streptomyces hygroscopicus.[1] It is a macrocyclic polyketide that is synthesized by a Type I polyketide synthase. The genes gelA, gelB, and gelC encode for the polyketide synthase. The PKS is first loaded with 3-amino-5-hydroxybenzoic acid (AHBA). It then utilizes malonyl-CoA, methylmalonyl-CoA, and methoxymalonyl-CoA to synthesize the precursor molecule Progeldanamycin. [2] This precursor is subjected to several enzymatic and non-enzymatic tailoring steps to produce the active molecule Geldanamycin, which include hydroxylation, o-methylation, carbamoylation, and oxidation.[3]
Figure 1. The PKS domain arrangement and tailoring steps required to synthesize Geldanamycin.
Notes
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References
- Bedin M, Gaben AM, Saucier C, Mester J. Int J Cancer. 2004 May 1;109(5):643-52. Geldanamycin, an inhibitor of the chaperone activity of HSP90, induces MAPK-independent cell cycle arrest.
External links
- A comprehensive review about Geldanamycin, 17AAG and 17DMAG
- Geldanamycin from Fermentekde:Geldanamycin
- ↑ He, W.; Wu, L; Gao, Q.; Du, Y.; Wang, Y. Identification of AHBA Biosynthetic Genes Related to Geldanamycin Biosynthesis in Streptomyces hygroscopicus 17997. Current Microbiology 2006. 52, 197-203.
- ↑ Kim, W.; Lee, D.; Hong, S. S.; Na, Z.; Shin, J. C.; Roh, S. H.; Wu, C.; Choi, O.; Lee, K.; Shen, Y.; Paik, S.; Lee, J. J.; Hong, Y. Rational Biosynthetic Engineering for Optimization of Geldanamycin Analogues. ChemBioChem 2009. 10, 1243-1251.
- ↑ Lee, D.; Lee, K; Cai, X. F.; Dat, N. T.; Boovanahalli, S. K.; Lee, M.; Shin, J. C.; Kim, W.; Jeong, J. K.; Lee, J. S.; Lee, C.; Lee, J.; Hong, Y.; Lee, J. J. Biosynthesis of the Heat-Shock Protein 90 Inhibitor Geldanamycin: New Insight into the Formation of the Benzoquinone Moiety. ChemBioChem 2006. 7, 246-248.
