Identification of 4,5-Dihydro-4-hydroxygeldanamycins As Shunt Products of Geldanamycin Biosynthesis

2012 ◽  
Vol 75 (8) ◽  
pp. 1480-1484 ◽  
Author(s):  
Ting Li ◽  
Siyang Ni ◽  
Changhong Jia ◽  
Hongyuan Wang ◽  
Guizhi Sun ◽  
...  
Keyword(s):  
Geldanamycin Biosynthesis

scholarly journals Regulation of Geldanamycin Biosynthesis by Cluster-Situated Transcription Factors and the Master Regulator PhoP

Antibiotics ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 87 ◽  
Author(s):  
Juan F. Martín ◽  
Angelina Ramos ◽  
Paloma Liras
Keyword(s):  
Gene Cluster ◽  
Polyketide Synthase ◽  
Direct Repeat ◽  
Phosphate Transport ◽  
Streptomyces Avermitilis ◽  
Antitumoral Activity ◽  
Streptomyces Species ◽  
Repeat Units ◽  
Expression Of Genes ◽  
Geldanamycin Biosynthesis

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.

scholarly journals Identification of 6-demethoxy-6-methylgeldanamycin and its implication of geldanamycin biosynthesis

2013 ◽  
Vol 67 (2) ◽  
pp. 183-185 ◽  
Author(s):  
Siyang Ni ◽  
Bingya Jiang ◽  
Linzhuan Wu ◽  
Yiguang Wang ◽  
Hongxia Zhou ◽  
...  
Keyword(s):  
Geldanamycin Biosynthesis

scholarly journals 17-O-demethylreblastatin, a subnormal intermediate in geldanamycin biosynthesis

2011 ◽  
Vol 65 (2) ◽  
pp. 79-82
Author(s):  
Changhong Jia ◽  
Linzhuan Wu ◽  
Siyang Ni ◽  
Hongyuan Wang ◽  
Xin Liu ◽  
...  
Keyword(s):  
Geldanamycin Biosynthesis

Regulatory Genes of Geldanamycin Biosynthesis

2008 ◽  
Vol 24 (5) ◽  
pp. 717-722 ◽  
Author(s):  
W HE ◽  
J LEI ◽  
Y LIU ◽  
Y WANG
Keyword(s):  
Regulatory Genes ◽  
Geldanamycin Biosynthesis

scholarly journals Insights into the Biosynthesis of the Benzoquinone Ansamycins Geldanamycin and Herbimycin, Obtained by Gene Sequencing and Disruption

2005 ◽  
Vol 71 (8) ◽  
pp. 4862-4871 ◽  
Author(s):  
Andreas Rascher ◽  
Zhihao Hu ◽  
Greg O. Buchanan ◽  
Ralph Reid ◽  
C. Richard Hutchinson
Keyword(s):  
Gene Cluster ◽  
Polyketide Synthase ◽  
Gene Clusters ◽  
Biosynthetic Gene Cluster ◽  
System A ◽  
Antitumor Properties ◽  
Geldanamycin Biosynthesis ◽  
Tailoring Enzymes ◽  
Modular Polyketide Synthase ◽  
Chaperone Complex

ABSTRACT Geldanamycin and the closely related herbimycins A, B, and C were the first benzoquinone ansamycins to be extensively studied for their antitumor properties as small-molecule inhibitors of the Hsp90 protein chaperone complex. These compounds are produced by two different Streptomyces hygroscopicus strains and have the same modular polyketide synthase (PKS)-derived carbon skeleton but different substitution patterns at C-11, C-15, and C-17. To set the stage for structural modification by genetic engineering, we previously identified the gene cluster responsible for geldanamycin biosynthesis. We have now cloned and sequenced a 115-kb segment of the herbimycin biosynthetic gene cluster from S. hygroscopicus AM 3672, including the genes for the PKS and most of the post-PKS tailoring enzymes. The similarities and differences between the gene clusters and biosynthetic pathways for these closely related ansamycins are interpreted with support from the results of gene inactivation experiments. In addition, the organization and functions of genes involved in the biosynthesis of the 3-amino-5-hydroxybenzoic acid (AHBA) starter unit and the post-PKS modifications of progeldanamycin were assessed by inactivating the subclusters of AHBA biosynthetic genes and two oxygenase genes (gdmM and gdmL) that were proposed to be involved in formation of the geldanamycin benzoquinoid system. A resulting novel geldanamycin analog, KOS-1806, was isolated and characterized.

The Missing C-17 O-Methyltransferase in Geldanamycin Biosynthesis

2011 ◽  
Vol 13 (14) ◽  
pp. 3726-3729 ◽  
Author(s):  
Min Yin ◽  
Tao Lu ◽  
Li-Xing Zhao ◽  
Yihua Chen ◽  
Sheng-Xiong Huang ◽  
...  
Keyword(s):  
Geldanamycin Biosynthesis
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