Geldanamycin induces the degradation of proteins in tumor cells such as v-Src, Bcr-Abl and p53 are mutated in preference to their normal cellular counterparts. This effect is mediated via HSP90. Despite its potent anti-tumor potential of geldanamycin shows some important drawbacks as active ingredient (ie, hepatotoxicity), which led to the development of geldanamycin analogs, particularly analogs that derivatization at position 17:Geldanamycin is a benzoquinone ansamycin antibiotic that binds to Hsp90 (Heat Shock Protein 90) and inhibits its function. Hsp90 proteins play an important role in regulating the cell cycle, cell growth, cell survival, apoptosis, angiogenesis, and oncogenesis.
Geldanamycin was originally discovered in the organism Streptomyces hygroscopicus. [1] There is a macrocyclic polyketide that is synthesized from a type I polyketide synthase. The genes, Gela, yellow, and GELC for polyketide synthase encoding. The PKS is first loaded with 3-amino-5-hydroxybenzoic acid (AHBA). It then uses malonyl-CoA, methylmalonyl-CoA and methoxymalonyl CoA to synthesize the precursor Progeldanamycin. [2] This precursor is subjected to several enzymatic and non-enzymatic adaptation to the active molecule geldanamycin, which catalyze hydroxylation include o-methylation, carbamoylation, and generate oxidation. [3]
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