Antibiotics polyketides

Concepmally similar, although mechanistically distinct, is Vgb, a class B streptogramin inactivating enzyme. Strep-togramins consist of two distinct structural classes of antibiotics polyketide-peptide hybrids (type A streptogramins) and cychc... 

Oxytetracycline is an antibiotic polyketide synthesized by the bacterium Saccharopolyspora erythraea. 

A reiterative application of a two-carbon elongation reaction of a chiral carbonyl compound (Homer-Emmonds reaction), reduction (DIBAL) of the obtained trans unsaturated ester, asymmetric epoxidation (SAE or MCPBA) of the resulting allylic alcohol, and then C-2 regioselective addition of a cuprate (Me2CuLi) to the corresponding chiral epoxy alcohol has been utilized for the construction of the polypropionate-derived chain ]R-CH(Me)CH(OH)CH(Me)-R ], present as a partial structure in important natural products such as polyether, ansamycin, or macro-lide antibiotics [52]. A seminal application of this procedure is offered by Kishi s synthesis of the C19-C26 polyketide-type aliphatic segment of rifamycin S, starting from aldehyde 105 (Scheme 8.29) [53]. 

From the cultures of streptomycetes were isolated anthacyclinones like aklavi-none. Various aromatic polyketide antibiotics produced by fungi and bacteria have quinoid structures, for example, doxorubicin, rhodomycin, and actinorhodin. ... 

Schneider, G., Enzymes in the biosynthesis of aromatic polyketide antibiotics, Curr. Opin. Struct. Biol., 15, 629, 2005. 

Fischbach, M.A. and Walsh, C.T. (2006) Assembly-line enzymology for polyketide and nonribosomal peptide antibiotics logic, machinery, and mechanisms. Chemical Reviews, 106, 3468—3496. 

Baltz, R.H. (2006) Molecular engineering approaches to peptide, polyketide and other antibiotics. Nature Biotechnology, 24, 1533. 

Hutchinson, C.R. and Fujii, I. (1995) Polyketide synthase gene manipulation a structure-function approach in engineering novel antibiotics. Annual Review of Microbiology, 49, 201. 

Walsh, C.T. (2004) Polyketide and nonribosomal peptide antibiotics modularity and versatility. Science, 303, 1805. 

McDaniel, R., Welch, M. and Hutchinson, C.R. (2005) Genetic approaches to polyketide antibiotics. Chemical Reviews, 105, 543. 

Marsden, A.F., Wilkinson, B., Cortes, J. et al. (1998) Engineering broader specificity into an antibiotic-producing polyketide synthase. Science, 279, 199. 

Petkovic, H., Lill, R.E., Sheridan, R.M. et al. (2003) A novel erythromycin, 6-desmethyl erythromycin D, made by substituting an acyltransferase domain of the erythromycin polyketide synthase. The Journal of Antibiotics, 56, 543. 

BANGERA, M.G., THOMASHOW, L.S., Identification and characterization of a gene cluster for the synthesis of the polyketide antibiotic 2,4-diacetylphloroglucinol from Pseudomonas fluorescens Q2-87, J. Bacteriol., 1999,181,3155-3163. 

Aldol reactions are among the most prominent and most frequently applied transformations, since they build up polyketide fragments of important biologically active compounds such as antibiotics and antitumor compounds. 

Takano E, Kinoshita H, Mersinias V, Bucca G, Hotchkiss G, NihiraT, Smith G, Bibb M, Wohlleben W, Ghater KE, A bacterial hormone (the SGBl extracellular signalling system) directly controls an antibiotic pathway-specific regulator in the cryptic type I polyketide biosynthetic cluster oiStreptomyces coelicolor A5 2), Mol Microbiol 56 465 79, 2005. 

A further natural product inhibitor is mithramydn A, a structurally complex anticancer antibiotic. Mithramycin A is a member of a group of aureolic add-type polyketides that are produced by the soil bacterium Streptomyces argillaceus [94]. 

The polyketides are a large family of bio synthetically related NPs, some of which have very great pharmaceutical value (polyketide sales total about 10 billion annually, see also Chapter 7). Some antibiotics (erythromycin, monensin, rifamycin), immunosuppressants (rapamycin), antifungal substances (amphotericin), antiparasitic (aver-mectin) and anticancer drugs (doxorubicin) are polyketides. The term polyketide refers to the fact that the basic carbon skeleton is not a simple hydrocarbon chain as in the case of fatty acids but is a series of linked keto groups in sequence (Figure 3.6). The first phase of this pathway, the generation of carbon skeleton diversification. 

In 1997 (-)-callystatin A (Fig. 1.2.2), a potent cytotoxic polyketide, was isolated from the marine sponge Callyspongia truncata and structurally elucidated by Ko-bayashi et al. [20] shortly afterward its absolute configuration was confirmed by the same authors by total synthesis [21]. The structure of (-)-callystatin A shows a polypropionate chain and a lactone ring connected to each other by two diene systems separated by two sp carbon atoms (Fig. 1.2.2). Since this arrangement is structurally related to several antitumor antibiotics and due to the fact that only very small amounts can be isolated from natural sources, callistatin A has been... 

A second enzyme (of mass 100 kDa) is needed for activation of phenylalanine. It is apparently the activated phenylalanine (which at some point in the process is isomerized from l- to D-phenylalanine) that initiates polymer formation in a manner analogous to that of fatty acid elongation (Fig. 17-12). Initiation occurs when the amino group of the activated phenylalanine (on the second enzyme) attacks the acyl group of the aminoacyl thioester by which the activated proline is held. Next, the freed imino group of proline attacks the activated valine, etc., to form the pentapeptide. Then two pentapeptides are joined and cyclized to give the antibiotic. The sequence is absolutely specific, and it is remarkable that this relatively small enzyme system is able to carry out each step in the proper sequence. Many other peptide antibiotics, such as the bacitracins, tyrocidines,215 and enniatins, are synthesized in a similar way,213 216 217 as are depsipeptides and the immunosuppresant cyclosporin. A virtually identical pattern is observed for formation of polyketides,218 219 whose chemistry is considered in Chapter 21. 

Figure 21-10 Some important polyketide antibiotics and plant defensive compounds.

Figure 21-11 Catalytic domains within three polypeptide chains of the modular polyketide synthase that forms 6-deoxyerythronolide B, the aglycone of the widely used antibiotic erythromycin. The domains are labeled as for fatty acid synthases AT, acyltransferase ACP, acyl carrier protein KS, 3-ketoacyl-ACP synthase KR, ketoreductase DH, dehydrase ER, enoylreductase TE, thioesterase. After Pieper et al.338 Courtesy of Chaitan Khosla.

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