Abstract
Geldanamycin and the closely related herbimycins A, B, and C are benzoquinone-type ansamycins with antitumoral activity. They are produced by Streptomyces hygroscopicus var. geldanus, Streptomyces lydicus and Streptomyces autolyticus among other Streptomyces strains. Geldanamycins interact with the Hsp-90 chaperone, a protein that has a key role in tumorigenesis of human cells. Geldanamycin is a polyketide antibiotic and the polyketide synthase contain seven modules organized in three geldanamycin synthases genes named gdmAI, gdmAII, and gdmAIII. The loading domain of GdmI activates AHBA, and also related hydroxybenzoic acid derivatives, forming geldanamycin analogues. Three regulatory genes, gdmRI, gdmRII, and gdmRIII were found associated with the geldanamycin gene cluster in S. hygroscopicus strains. GdmRI and GdmRII are LAL-type (large ATP binding regulators of the LuxR family) transcriptional regulators, while GdmRIII belongs to the TetR-family. All three are positive regulators of geldanamycin biosynthesis and are strictly required for expression of the geldanamycin polyketide synthases. In S. autolyticus the gdmRIII regulates geldanamycin biosynthesis and also expression of genes in the elaiophylin gene cluster, an unrelated macrodiolide antibiotic. The biosynthesis of geldanamycin is very sensitive to the inorganic phosphate concentration in the medium. This regulation is exerted through the two components system PhoR-PhoP. The phoRP genes of S. hygroscopicus are linked to phoU encoding a transcriptional modulator. The phoP gene was deleted in S. hygroscopicus var geldanus and the mutant was unable to grow in SPG medium unless supplemented with 5 mM phosphate. Also, the S. hygroscopicus pstS gene involved in the high affinity phosphate transport was cloned, and PhoP binding sequences (PHO boxes), were found upstream of phoU, phoRP, and pstS; the phoRP-phoU sequences were confirmed by EMSA and nuclease footprinting protection assays. The PhoP binding sequence consists of 11 nucleotide direct repeat units that are similar to those found in S. coelicolor Streptomyces avermitilis and other Streptomyces species. The available genetic information provides interesting tools for modification of the biosynthetic and regulatory mechanisms in order to increase geldanamycin production and to obtain new geldanamycin analogues with better antitumor properties.
Highlights
Antitumor Activity of Geldanamycin and its DerivativesGeldanamycin and the closely related herbimycins A, B, and C are benzoquinone-type ansamycins [1] with antitumoral activity [2,3] (Figure 1A)
These compounds are produced by different strains of S. hygroscopicus, Streptomyces lydicus, and by Streptomyces autolyticus, and gene clusters for geldanamycin have been found in other Streptomyces strains (Table 1)
Other genes for amino-5-hydroxybenzoic acid (AHBA) biosynthesis have been cloned in S. hygroscopicus 17997 by He et al [19], but except the amino dehydroquinate synthase were not located in the geldanamycin cluster described by Rasher et al [18]
Summary
Geldanamycin and the closely related herbimycins A, B, and C are benzoquinone-type ansamycins [1] with antitumoral activity [2,3] (Figure 1A). Major interest is as potent antitumor agents due to their ability to interact with the Hsp-90 chaperone geldanamycin and the herbimycins were discovered as weak antifungal and antibacterial antibiotics complex in human cells [7,8]. The members of the Hsp-90 chaperone family play an important role in [4,5,6] but their major interest is as potent antitumor agents due to their ability to interact with the theHsp-90 tumorigenesis process in humans. Both geldanamycin and the herbimycins have potent antitumor chaperone complex in human cells [7,8].
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