The biosynthetic gene cluster for the microtubule-stabilizing agents epothilones A and B from Sorangium cellulosum So ce90

Molnár, István; Schupp, Thomas; Ono, M.; Zirkle, RE; Milnamow, M; Nowak-Thompson, Brian; Engel, Nathalie; Toupet, Christiane; Stratmann, Ansgar; Cyr, DD; Görlach, Jörn; Mayo, JM; Hu, Anren; Goff, Stephen A.; Schmid, Jochen; Ligón, James M.

doi:10.1016/s1074-5521(00)00075-2

Cited by 295 publications

(237 citation statements)

References 75 publications

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“…Ixabepilone (Ixempra; Bristol-Myers Squibb), an analogue of epothilone B, has been recently approved in the treatment of breast cancer 165 . The biosynthetic gene clusters of epothilones have been widely studied 166,167 . Recently, a 56 kb epothilone biosynthetic gene cluster was reassembled using unique restriction sites (which allowed for future module interchangeability) in the guanine-and cytosine-rich host Myxococcus xanthus 168 .…”

Section: Applyingmentioning

confidence: 99%

The re-emergence of natural products for drug discovery in the genomics era

Harvey

Edrada-Ebel

Quinn

2015

Nat Rev Drug Discov

2,113

1,410

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Natural products have been a rich source of compounds for drug discovery. However, their use has diminished in the past two decades in part because of technical barriers to screening natural products in high-throughput assays against molecular targets. Here, we review advances in chemical techniques for the isolation and structural elucidation of natural products that have reduced these technological barriers. We also assess the use of genomic and metabolomic approaches to augment traditional methods of studying natural products, and highlight recent examples of natural products in antimicrobial drug discovery and as inhibitors of protein protein interactions. The growing appreciation of functional assays and phenotypic screens may further contribute to a revival of interest in natural products for drug discovery.

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Section: Applyingmentioning

confidence: 99%

The re-emergence of natural products for drug discovery in the genomics era

Harvey

Edrada-Ebel

Quinn

2015

Nat Rev Drug Discov

2,113

1,410

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show abstract

“…An analysis of conserved catalytic motifs in the related methyltransferases shows that none of the metazoan FASs contains an intact set of catalytic residues, in agreement with the observation that these enzymes do not methylate their products and are not SAM-dependent. However, in related fungal and bacterial polyketide synthases, intact homologues of this domain are found in equivalent positions and are leading to the production of (partially) methylated products (Edwards et al 2004 ;Fujii et al 2005 ;Molnar et al 2000). The significance of the yME domain for animal FAS remains unclear ; it is probably a remnant from an evolutionary precursor multienzyme producing branched fatty acids or polyketides, and it may still play a steric or stabilizing role for the overall functioning of the enzyme.…”

Section: Domain Structuresmentioning

confidence: 99%

Structure and function of eukaryotic fatty acid synthases

Maier

Leibundgut

Boehringer

et al. 2010

Quart. Rev. Biophys.

123

127

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Abstract. In all organisms, fatty acid synthesis is achieved in variations of a common cyclic reaction pathway by stepwise, iterative elongation of precursors with two-carbon extender units. In bacteria, all individual reaction steps are carried out by monofunctional dissociated enzymes, whereas in eukaryotes the fatty acid synthases (FASs) have evolved into large multifunctional enzymes that integrate the whole process of fatty acid synthesis. During the last few years, important advances in understanding the structural and functional organization of eukaryotic FASs have been made through a combination of biochemical, electron microscopic and X-ray crystallographic approaches. They have revealed the strikingly different architectures of the two distinct types of eukaryotic FASs, the fungal and the animal enzyme system. Fungal FAS is a 2Á6 MDa a 6 b 6 heterododecamer with a barrel shape enclosing two large chambers, each containing three sets of active sites separated by a central wheel-like structure. It represents a highly specialized micro-compartment strictly optimized for the production of saturated fatty acids. In contrast, the animal FAS is a 540 kDa X-shaped homodimer with two lateral reaction clefts characterized by a modular domain architecture and large extent of conformational flexibility that appears to contribute to catalytic efficiency.

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“…The phlE gene, located at the 39 end of the phlACBD operon in P. fluorescens strains (Bangera & Thomashow, 1996Delany, 1999) encodes a putative transmembrane permease with 12 predicted transmembrane segments (TMS) (Bangera & Thomashow, 1999 transporter mediating resistance to a range of structurally dissimilar drugs (Paulsen & Sukurray, 1993;Yoshida et al, 1990). PhlE also has structural similarity with integral membrane proteins associated with resistance which are encoded within clusters responsible for polyketide biosynthesis (Brautaset et al, 2000; Fernandez-Moreno et al, 1991;Guillfoile & Hutchinson, 1992;Marger & Saier, 1993;Molnar et al, 2000). It has been reported that phlE mutants produce less PHL than the parent strain (Bangera & Thomashow, 1996.…”

Section: Introductionmentioning

confidence: 99%

The putative permease PhlE of Pseudomonas fluorescens F113 has a role in 2,4-diacetylphloroglucinol resistance and in general stress tolerance

et al. 2004

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2,4-Diacetylphloroglucinol (PHL) is the primary determinant of the biological control activity of Pseudomonas fluorescens F113. The operon phlACBD encodes enzymes responsible for PHL biosynthesis from intermediate metabolites. The phlE gene, which is located downstream of the phlACBD operon, encodes a putative permease suggested to be a member of the major facilitator superfamily with 12 transmembrane segments. PhlE has been suggested to function in PHL export. Here the sequencing of the phlE gene from P. fluorescens F113 and the construction of a phlE null mutant, F113-D3, is reported. It is shown that F113-D3 produced less PHL than F113. The ratio of cell-associated to free PHL was not significantly different between the strains, suggesting the existence of alternative transporters for PHL. The phlE mutant was, however, significantly more sensitive to high concentrations of added PHL, implicating PhlE in PHL resistance. Furthermore, the phlE mutant was more susceptible to osmotic, oxidative and heat-shock stresses. Osmotic stress induced rapid degradation of free PHL by the bacteria. Based on these results, we propose that the role of phlE in general stress tolerance is to export toxic intermediates of PHL degradation from the cells. INTRODUCTIONMany Pseudomonas fluorescens strains produce 2,4-diacetylphloroglucinol (PHL) (Bangera & Thomashow, 1996;Boruah & Kumar, 2002;Nowak-Thompson et al., 1994;Reddi & Borovkov, 1970; Sharifi-Tehrani et al., 1998). This phenolic molecule has broad-spectrum antifungal (Levy et al., 1992;Schoonbeek et al., 2002;Tomas-Lorente et al., 1989;Weller & Cook, 1983), antibacterial (Levy et al., 1992), antihelminthic (Bowden et al., 1965; Harrison et al., 1993) and phytotoxic (Keel et al., 1992;Reddi et al., 1969) activities. PHL is the primary determinant of biological control by P. fluorescens F113 (Shanahan et al., 1992). Synthesis of PHL is directed by the phlACBD genes, which are believed to constitute an operon (Bangera & Thomashow, 1996Delany, 1999). PhlD shows structural similarities with plant chalcone synthase, also called polyketide synthase type III, and is necessary but not sufficient for the synthesis of monoacetylphloroglucinol (MAPG) (Bangera & Thomashow, 1999). PhlA, PhlC and PhlB are necessary and sufficient for the transacetylation of MAPG to produce PHL (Bangera & Thomashow, 1999;Shanahan et al., 1992). The available data strongly suggest that PhlA, PhlC, PhlB and PhlD function in a multienzyme complex (Bangera & Thomashow, 1999;Delany, 1999). Expression of the phlACBD operon is subject to complex regulation (Aarons et al., 2000;Abbas et al., 2002;Bangera & Thomashow, 1999;Chou et al., 1993;Corbell & Loper, 1995;Delany, 1999; Delany et al., 2000;Duffy & Defago, 1999;Schnider-Keel et al., 2000). In addition, PHL is an autoregulator, positively influencing its own biosynthesis (Abbas et al., 2002;Schnider-Keel et al., 2000).Micro-organisms have developed various ways to resist the toxic effects of the secondary metabolites they produce. These mechanisms include expo...

show abstract

The biosynthetic gene cluster for the microtubule-stabilizing agents epothilones A and B from Sorangium cellulosum So ce90

Cited by 295 publications

References 75 publications

The re-emergence of natural products for drug discovery in the genomics era

The re-emergence of natural products for drug discovery in the genomics era

Structure and function of eukaryotic fatty acid synthases

The putative permease PhlE of Pseudomonas fluorescens F113 has a role in 2,4-diacetylphloroglucinol resistance and in general stress tolerance

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