Polyethers biosynthesis

Classical feeding experiments with both stable and radioactive isotopic labels (7) enabled the biosynthetic origin of the polyethers to be elucidated and for a general stereochemical model to be proposed (1). More recent work on this class of compounds has focused on a genetic approach, and unusual and interesting genes specific to polyether biosynthesis have been isolated from these clusters. 

For a review on polyether biosynthesis (as well as polyketides and mixed NRPS/PKS metabolites) Hill AM. The biosynthesis, molecular genetics and enzymology of the polyketide-derived metabolites. Nat. Prod. Rep. 2006 23 256-320. 

For a review on polyether biosynthesis in dinoflagellates Rein KS, Snyder RV. The biosynthesis of polyketide metabolites by dinoflagellates. Adv. Appl. Microbiol. 2006 50 93-125. 

In 1983, Cane et al. postulated that polyether biosynthesis takes place as a two step process. The first of these steps was proposed to be the enzymatically polyepoxidation of an acyclic hydroxypolyene precursor, and the second comprised a cascade of intramolecular epoxide ring openings with formation of the polyether frame work. [1] For monensin A... 

First, it plays a decisive role in ether and polyether biosynthesis and there are indeed two routes available to transform epoxides into cyclic ethers. With both, unfortunately, we have to worry about regioselectivity [95]. 

Acyclic stereocontrol has been a striking concern in modern organic chemistry, and a number of useful methods have been developed for stereoregulated synthesis of conformationally nonrigid complex molecules such as macrolide and polyether antibiotics. Special attention has therefore been paid to the aldol reaction because it constitutes one of the fundamental bond constructions in biosynthesis. 

Another cationic-cationic domino reaction which follows the way of biosynthesis is used by Koert et al for the synthesis of the whole left part of the polyether etheromydn.1141 The starting step is an add catalyzed cyclization of a diepoxide to give a bistetrahydrofuran with creation of three new oxa-cycles in over 30 % yidd. 

Robinson JA (1991) Chemical and biochemical aspects of polyether-ionophore antibiotic biosynthesis. Prog Chem Org Nat Prod 58, 1-81. 

The formation of the six-membered ether ring via epoxy ester-ortho ester cyclic ether rearrangement supports the hypothesis that epoxy ester-ortho ester cyclic ether rearrangement may be involved in the biosynthesis of ladder-type marine polyether toxins. This reaction represents a biomimetic preparation of medium ring cyclic ethers. 

Rearrangement of the epoxy ester 317 affords a 1 1 mixture of the tetrahydropyran 318 and a steroidal tetra-hydrofuran by-product. This methodology offers a new hypothesis regarding the biosynthesis of polyether natural... 

Small heterocycles are of interest in view of their high reactivity and role in biosynthesis. Moreover, for the three-membered ring with an oxygen atom, the ease of ring cleavage creates conditions for polycondensations and heterocyclizations. The former give perfluorinated polyethers with a broad spectrum of practical applications, and the latter affords various heterocyclic compounds. 

C-labelled propionates double-labelled with deuterium or fluorine have been needed to study the stereochemistry of the chain elongation steps in the biosynthesis of polyether antibodies75. NMR spectroscopy allows one to identify the stable isotope-labelled positions in these compounds, thus avoiding a chemical degradation76. 

Gallimore, A. R. Spencer, J. B. Stereochemical uniformity in marine polyether ladders - implications for the biosynthesis and structure of maitotoxin, Angew. Chem. Int. Ed. 2006, 45, 4406-4413. 

The question of oxidative cyclization versus a polyepoxide cascade in the biosynthesis of polyether natural products has been reviewed <1995AGE298>. Enzymatic domino reactions involving epoxide intermediates have been reviewed <2001CSR332>. The DNA-damaging activity of epoxides and other oxidized species has been examined using chemical models <1995ACR289>. 

Polyketide Biosynthesis, Enediyne Polyketides Polyketide Biosynthesis, Aromatic Polyetides Polyketide Biosynthesis, Modular Polyketide Synthases Polyketide Biosynthesis, Polyethers Polyketides as Drugs... 

This review covers the biosynthesis of terrestriai and marine polyethers and discusses their biologic properties and the molecular genetics and enzymology of the proteins responsible for their formation. The biosynthesis of monensin, nanchangmycin, nonactin, and the marine polyether ladders are discussed in detail. Novel enzymes found only in type I polyketide polyether gene clusters that are responsible for the epoxidation and cyclization of polyene biosynthetic intermediates are described. The macrotetrolide biosynthetic gene cluster, which is an ACP-less type II polyketide synthase that functions noniteratively is reviewed. 

The first polyether antibiotic to be isolated was nigericin 1 in 1951. By 1983, more than 70 terrestrial polyether antibiotics had been reported and Cane et al. (1) had proposed a unified stereochemical model to account for their biosynthesis, including the polyene-polyepoxide model of polyether formation. It took almost 20 years for the first polyether gene cluster to be reported (2). In contrast, the first marine polyethers were reported in 1981, and a model to explain the biosynthesis of marine polyether ladder compounds was proposed in 2006 (3) no genetic information is available currently for the marine polyethers. 

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