Geldanamycin

 ( 1,4-benzoquinones ) 

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

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. 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

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Biosynthesis Geldanamycin was originally discovered in the organism Streptomyces hygroscopicus. 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. 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.

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Notes

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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

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