Geldanamycin Explained

Geldanamycin is a 1,4-benzoquinone ansamycin antitumor antibiotic that inhibits the function of Hsp90 (Heat Shock Protein 90) by binding to the unusual ADP/ATP-binding pocket of the protein.^[1] HSP90 client proteins play important roles in the regulation of the cell cycle, cell growth, cell survival, apoptosis, angiogenesis and oncogenesis.^[2]

Geldanamycin induces the degradation of proteins that are mutated or overexpressed in tumor cells such as v-Src, Bcr-Abl, p53, and ERBB2. This effect is mediated via HSP90. Despite its potent antitumor potential, geldanamycin presents several major drawbacks as a drug candidate such as hepatotoxicity, further, Jilani et al.. reported that geldanamycin induces the apoptosis of erythrocytes under physiological concentrations.^[3] These side effects have led to the development of geldanamycin analogues, in particular analogues containing a derivatisation at the 17 position:

• 17-AAG
• 17-DMAG

Biosynthesis

Geldanamycin was originally discovered in the organism Streptomyces hygroscopicus.^[4] 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.^[5] 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.^[6]

References

• Bedin . M. . Gaben . A. M. . Saucier . C. C. . Mester . J. . Geldanamycin, an inhibitor of the chaperone activity of HSP90, induces MAPK-independent cell cycle arrest . 10.1002/ijc.20010 . International Journal of Cancer . 109 . 5 . 643–652 . 2004 . 14999769 . 39451213 . free .

External links

• A comprehensive review about Geldanamycin, 17AAG and 17DMAG
• Geldanamycin from Fermentek
• Geldanamycin from Center for Pharmaceutical Research and Innovation
• Geldanamycin bound to proteins in the PDB

Notes and References

1. Schulte . T. W. . Akinaga . S. . Soga . S. . Sullivan . W. . Stensgard . B. . Toft . D. . Neckers . L. M. . Antibiotic radicicol binds to the N-terminal domain of Hsp90 and shares important biologic activities with geldanamycin . Cell Stress & Chaperones . 3 . 2 . 100–108 . 1998 . 10.1379/1466-1268(1998)003<0100:ARBTTN>2.3.CO;2 . 2024-04-26 . 9672245 . 312953.
2. Book: Wayne . N. . Mishra . P. . Bolon . D.N. . Molecular Chaperones . Hsp90 and Client Protein Maturation . Methods Mol Biol. . 2011 . 787 . 33–44 . 10.1007/978-1-61779-295-3_3 . 21898225 . 5078872 . 978-1-61779-294-6 .
3. Jilani. Kashif. Qadri. Syed M.. Lang. Florian. 2013 . Geldanamycin-Induced Phosphatidylserine Translocation in the Erythrocyte Membrane . Cell Physiol Biochem . 32 . 6. 1600–1609 . 10.1159/000356596 . 24335345. free.
4. He . W. . Wu . L. . Gao . Q. . Du . Y. . Wang . Y. . Identification of AHBA Biosynthetic Genes Related to Geldanamycin Biosynthesis in Streptomyces hygroscopicus 17997 . 10.1007/s00284-005-0203-y . Current Microbiology . 52 . 3 . 197–203 . 2006 . 16502293 . 22291736 .
5. Kim . W. . Lee . D. . Hong . S. S. . Na . Z. . Shin . J. C. . Roh . S. H. . Wu . C. Z. . Choi . O. . Lee . K. . Shen . Y. M. . Paik . S. G. . Lee . J. J. . Hong . Y. S. . Rational Biosynthetic Engineering for Optimization of Geldanamycin Analogues . 10.1002/cbic.200800763 . ChemBioChem . 10 . 7 . 1243–1251 . 2009 . 19308924 . 3273370 .
6. 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. H. . Lee . J. H. . Hong . Y. S. . Lee . J. J. . Biosynthesis of the Heat-Shock Protein 90 Inhibitor Geldanamycin: New Insight into the Formation of the Benzoquinone Moiety . 10.1002/cbic.200500441 . ChemBioChem . 7 . 2 . 246–248 . 2006 . 16381049 . 42998903 .