Biosynthetic pathways polyketide

The overall biosynthetic pathway to the tetracychnes has been reviewed (74). Studies (75—78) utilising labeled acetate and malonate and nmr analysis of the isolated oxytetracycline (2), have demonstrated the exclusive malonate origin of the tetracycline carbon skeleton, the carboxamide substituent, and the folding mode of the polyketide chain. Feeding experiments using [1- 02] acetate and analysis of the nmr isotope shift effects, led to the location of... 

Quinones represent a very large and heterogeneous class of biomolecules. Three major biosynthetic pathways contribute to the formations of various quinones. The aromatic skeletons of quinones can be synthesized by the polyketide pathway and by the shikimate pathway. The isoprenoid pathways are involved in the biosynthesis of the prenyl chain and in the formation of some benzoquinones and naphthoquinones. ... 

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]. 

Recently, a new polyketide biosynthetic pathway in bacteria that parallels the well studied plant PKSs has been discovered that can assemble small aromatic metabolites.8,9 These type III PKSs10 are members of the chalcone synthase (CHS) and stilbene synthase (STS) family of PKSs previously thought to be restricted to plants.11 The best studied type III PKS is CHS. Physiologically, CHS catalyzes the biosynthesis of 4,2, 4, 6 -tetrahydroxychalcone (chalcone). Moreover, in some organisms CHS works in concert with chalcone reductase (CHR) to produce 4,2 ,4 -trihydroxychalcone (deoxychalcone) (Fig. 12.1). Both natural products constitute plant secondary metabolites that are used as precursors for the biosynthesis of anthocyanin pigments, anti-microbial phytoalexins, and chemical inducers of Rhizobium nodulation genes.12... 

C domains can display functions that deviate from typical amide bond formation. Several C domains are postulated to act as ester synthases, catalyzing ester formation instead of amide formation. NRPS modules containing C domains that display this activity are present in the biosynthetic pathways for the kutznerides, cryptophycins, " cereulide, valinomycin, hectochlorin, and beauvericin. Each of these C domains likely utilizes a PCP-bound a-hydroxyl acceptor in the condensation reaction. Another NRPS C domain that catalyzes ester bond formation is involved in the biosynthesis of the polyketide-derived mycotoxins known as the fiimonisins. Du and coworkers have shown that a recombinant PCP-C didomain of an NRPS involved in the biosynthetic pathway of the fnmonisins can catalyze ester bond formation between hydroxyfumonisins and the A-acetylcysteamine thioester of tricarballylic acid, even though PCP-bound tricarballylic acid is not... 

During their studies on OTA biosynthetic pathway genes, O Callaghan et al. (2003) did not only clone a polyketide synthase from A. ochraceus but cloned and sequenced several more differentially expressed cDNA fragments of yet unassigned origin from typical producers of OTA. Based on that work. University College Cork (Ireland) filed worldwide (WO 2004/072224 A2) as well as European (EP 1 592 705 A2)... 

Motivated by the value of these natural products, there has been much research focused on developing guidelines for engineering polyketide synthases to generate natural and novel polyketides [445,446], Additionally, manipulation of the biosynthetic pathways of microbial polyketides through engineering permits the biosynthesis of bioactive polyketides not generated naturally [447,448],... 

Figure 1.37 Proposed biosynthetic pathway of curcuminoids in tumeric. Enzyme abbreviations CCOMT, caffeoyl-CoA O-methyltransferase 4CL, 4-coumarate CoA ligase CST, shikimate transferase CS3 H, p-coumaroyl 5-O-shikimate 3 -hydroxylase OMT, O-methyltransferase PKS, polyketide synthase. [Adapted from Ramirez-Ahumada et al. (2006)]...

Two epimeric amino alcohols, 2(5)-aminotetradeca-5,7-dien-3(5)- and -3(/ )-ol (305 and 306) were isolated from a sponge from Papua New Guinea (Xestospongia sp.) (248). The absolute stereochemistry was disclosed by degradation to L-alanine, and these amino alcohols (305 and 306) were suggested to be biosynthesized from fatty acids and alanine. Compounds 305 and 306 show antimicrobial activity. Rhizochalin (307) was isolated from the Madagascan sponge Rhizochalina incrustata as an antimicrobial constituent (349). The biosynthetic pathway for 307 is unknown but is conventionally believed to be derived from alanine and a polyketide precursors). 

Metabolites of the phylum Porifera account for almost 50% of the natural products reported from marine invertebrates. Of the 2609 poriferan metabolites, 98% are derived from amino acid, acetogenin, or isoprenoid pathways. Isoprenoids account for 50% of all sponge metabolites, while amino acid and polyketide pathways account for 26% and 22%, respectively. A significant number of sponge metabolites appear to be derived from mixed biosynthetic pathways. Most structures reported containing carbohydrate moieties were glycosides. 

Similar to other natural products, phytotoxins are classified on the basis of their structural types considering their biosynthetic pathways. Among various phytotoxin families, polyketides including aromatic and reduced polyketides, peptides including diketopiperazines, and terpenes are most frequently described in the literature. In this section, representative phytotoxins that are well-characterized biosynthetically and physiologically will be introduced. 

Extracts of Pterogorgia anceps contain a fraction enriched in ancepsenolide metabolites of the polyketide class, one of which (134) is individually deterrent in shipboard assays with T. bifasciatum 0 This last study illustrates that chemical defense mechanisms in gorgonians do not solely rely on the terpenoid biosynthetic pathway. 

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