Macrolide polyketide

Schell U, Haydock SF, Kaja AL et al (2008) Engineered biosynthesis of hybrid macrolide polyketides containing D-angolosamine and D-mycaminose moieties. Org Biomol Chem 6 3315-3327... 

Purified DEBS 1-TE has also been used to investigate another interesting aspect of polyketide biosynthesis the control of stereochemistry. As noted by W. D. Celmer in 1965, the macrolide polyketides (the class of complex polyketide to which erythromycin belongs) have the same absolute configuration at all comparable stereocenters (Fig. 12) [40,41], These homologies suggest that there exists... 

Schell U, Haydock SF, Kaja AL, Carletti I, Lill RE, Read E, Sheehan LS, Low L, Fernandez MJ, Grolle F, McArthur HA, Sheridan RM, Leadlay PF, Wilkinson B, Gaisser S (2008) Engineered Biosynthesis of Hybrid Macrolide Polyketides Containing D-Angolosamine and D-Mycaminose Moieties. Org Biomol Chem 6 3315... 

There has been very little experimental work conducted with natural products from the phylum Bryozoa. The family of bryostatins, macrolide polyketides isolated by Pettit from the bryozoan Bugula neritina, is certainly of greatest significance in terms of biomedical potential [92]. Bryostatin 1 (57) exhibits selective activity against B-cell lymphomas and leukemias, [93] and directly stimulates bone marrow progenitor cells to form colonies that functionally activate neutrophils [94]. Additionally, bryostatin 1 activates protein kinase C [95] and has immunomodulatory activity both in vitro and in vivo [96]. In combination with the vinca alkaloid vincristine, bryostatin 1 inhibits the growth of lymphoma cells without adverse effects on bone marrow cells [97]. 

As the source for the family of novel tetracyclic macrolide polyketides, the spinosyns [21, 22] were found to be secondary metabolites of the soil bacterium actinomycete Saccharopolyspora spinosa [23, 24]. The spinosyn biosynthetic gene cluster has been cloned from S. spinosa and sequenced, and the results have been used to formulate a proposed biosynthetic pathway [25] (Chapter 29.3). 

Role of polyketide synthases in biosynthesis of some heterocycles, in particular macrolides 97CRV2465. 

There are at least three types of PKS. Type I PKSs catalyze the biosynthesis of macrolides such as erythromycin and rapamycin. As modular enzymes, they contain separate catalytic modules for each reaction catalyzed sequentially in the polyketide biosynthetic pathway. Type II PKSs have only a few active sites on separate polypeptides, and the active sites are used iteratively, catalyzing the biosynthesis of bacterial aromatic polyketides. Type III are fungal PKSs they are hybrids of type I and type II PKSs [49,50]. 

Yoon, Y.J., Beck, B.J., Kim, B.S. et al. (2002) Generation of multiple bioactive macrolides by hybrid modular polyketide synthases in Streptomyces venezuelae. Chemistry Biology, 9, 203-214. 

Ikeda, H., Nonomiya, T., Usami, M. et aL (1999) Organization of the biosynthetic gene cluster for the polyketide anthelmintic macrolide avermectin in Streptomyces avermitilis. Proceedings of the National Academy of Sciences of the United States of America, 96, 9509-9514. 

RAWLINGS, B.J., Biosynthesis of polyketides (other than actinomycete macrolides), Nat. Prod. Rep., 1999,16,425-484. 

General Procedure for the Silylformaltion/Sakurai Allylation. Synthesis of Polyol Fragments for Polyketide and Macrolide Synthesis. In a magnetically stirred stainless-steel Parr bomb the substrate (1 eq) is dissolved in benzene. The solution is cooled to - 78 °C until frozen. Rh(acac)(CO)2 (3 mol %) is then added and the Parr bomb is assembled and pressurized with CO (60 bar) and vented. This purge is repeated twice and the Parr bomb is pressurized with CO (60 bar) at - 78 °C. The apparatus is then immersed in an oil bath and heated at 60 °C for 22-24 h. After cooling to 0 °C, the bomb is vented. The solution... 

Jung WS, Lee SK, Hong JSJ, Park SR, Jeong SJ, Han AR, Sohng JK, Kim BG Choi CY, Sherman DH, Yoon YJ. (2006) Heterologous expression of tylosin polyketide synthase and production of a hybrid bioactive macrolide in Streptomyces venezuelae. Appl Microbiol Biotechnol 72 763-769. 

Overall, however, the immensity of temperate land corresponds to a most various secondary metabolic production, different from that of tropical land. The most renowned alkaloids belong to the morphine class (Chart 6.2.A1), and, in combination with isoprenoids, to the ergot and triterpene classes (Chart 6.2. A2). Prominent in the peptides are the cyclosporins (the first of which was isolated from a fiingus collected in Norway), streptogramins, and P-lactams (Chart 6.2.P). The isoprenoids are represented by pyrethrin monoterpenes, cedrane sesquiterpenes, ginkgolide and taxane diterpenes, ophiobolane sesterterpenes, and arborane and amyrin-like triterpenes (Chart 6.2.1). In the polyketides, epothilones, recently discovered from Myxobacteria, and the long known rapamycin, are two prominent classes of macrolides (Chart 6.2.FA/PO/C). 

The macrolide systems described above are produced by formation of an intramolecular ester or amide linkage, utilizing appropriate functionalities in the growing polyketide chain. Macrolide formation does not always occur, and similar acetate-propionate precursors might also be expected to yield molecules which are essentially linear in nature. Good examples of such molecules... 

Another important class of anti-infective natural products introduced in recent years is the avermectins, polyketide-derived macrolides that were originally isolated from several species of Streptomyces. The major drug in this class, ivermectin, was originally developed to treat and control nematodes and parasites in livestock. In recent years, however, the potential of ivermectin for the treatment of human disease has also been realized, and it is now used to treat onchocerciasis (river blindness), a disease that afflicts 40 million people worldwide (De Smet, 1997). 

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