Natural products, polyketide

Cytochrome P450 enzymes have been the subject of a number of recent reviews in which their mechanism and scope of action are covered in much detail [1, 6, 10, 11]. The reader is referred to these articles for a more thorough account of the mechanism and reactivity of cytochrome P450 enzymes, while we present a few representative examples of cytochrome P450-catalyzed epoxidation below. The enzymes we chose are all involved in the biosynthesis of polyketide natural products. Polyketides are a large, structurally diverse family of compounds and have provided a wealth of therapeutically useful drugs and drug leads. 

Chalcone synthase (CHS), the first plant natural product polyketide synthase (PKS) to be characterized at the molecular level (39), catalyzes the condensation of 4-coumaroyl-CoA with three molecules of malonyl-CoA to afford naringenin chalcone, a precursor of the major classes of plant flavonoids. The cloning of a novel type III pentaketide chromone synthase (PCS) from aloe (Aloe arborescens, Liliaceae) rich in aromatic polyketides, especially quinones such as aloe-emodin and emodin, resulted in... 

The emphasis of this review is placed on two structural classes of natural products polyketides and nonribosomal peptides (NRPs). The MS of these biosynthetic pathways is most advanced and will be covered in detail. In the following sections we will describe the current methods and applications used to study the biosynthetic pathways of natural products and provide a glimpse into upcoming techniques. In addition, a brief introduction to experimental design using high-end MS to study the biosynthesis of other natural metabolites, such as ribosomally encoded pathways and cofactors, is described. 

Because they often function as virulence factors, the enzymes involved in siderophore biosynthesis are potential targets for developing antimicrobial strategies. The mechanisms of siderophore biosynthesis follow the same fundamental biosynthetic logic involving similar protein machinery, which we describe in greater detail in Chapter 5 for fatty acid biosynthesis. It is also used in the microbial biosynthesis of many important natural products polyketides and peptides (including many antibiotics). Essentially, as is illustrated in Fig. 4.20, for enterobactin, it involves... 

Gates, R Reather, J. Staunton, J. Accurate-Mass MSn Studies of Natural Products (Polyketides) by ESI-FT-ICR Mass Spectometry, in Proceedings of the 47th ASMS Conference on Mass Spectrometry and Allied Topics, Dallas, Texas, June 13-17, 1999. 

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]. 

These mesylates, in turn, can be converted to enantioenriched allenyltin, zinc, and indium reagents which add to aldehydes with excellent diastereo-and enantioselectivity to afford either syn- or anti-homopropargylic alcohols or allenylcarbinols (eq 2, 3, and 4).3 4 Adducts of this type serve as useful intermediates for the synthesis of polyketide and hydrofuran natural products.5... 

Until recently no enzymes able to produce olivetol-like compounds have been isolated. In an article by Puna et al., polyketide III enzymes were responsible for the formation of phenohc lipid compound [34], a natural product group that ohvetol belongs to. Although the biosynthesized compounds contained a longer chain, which increased over time, the study supported the hypothesis of olivetohc acid production by a polyketide III synthase. Further studies on the genetic and protein level are essential to elucidate the mode of mechanism by which olivetohc acid is formed in C. sativa. 

These reagents exhibit reagent control of stereoselectivity and have proven to be very useful in stereoselective synthesis of polyketide natural products, which frequently contain arrays of alternating methyl and oxygen substituents.44... 

Leighton and coworkers [217] have also used this approach to develop efficient strategies for the synthesis of polyketide-derived natural products [218]. A main motif of these compounds is a skipped polyol structure, as in 6/2-94 this can easily be prepared by a novel Rh-catalyzed domino reaction of a diallylsilyl ether in the presence of CO, followed by a Tamao oxidation [219]. Thus, reaction of, for example, the silane 6/2-93, which is readily prepared from the corresponding ho-... 

Staunton, J. and Weissman, K.J. (2001) Polyketide biosynthesis a millennium review. Natural Product Reports,... 

McDaniel, R., Thamchaipenet, A., Gustafsson, C. et al. (1999) Multiple genetic modifications of the erythromycin polyketide synthase to produce a library of novel unnatural natural products. Proceedings of the National Academy of Sciences of the United States of America, 96, 1846. 

Kopp, F. and Marahiel, M.A. (2007) Macrocyclization strategies in polyketide and nonribosomal peptide biosynthesis. Natural Product Reports, 24, 735. 

Kealey, J.T., Liu, L., Santi, D.V. et al. (1998) Production of a polyketide natural product in nonpolyketide-producing prokaryotic and eukaryotic hosts. Proceedings ofthe National Academy of Sciences ofthe United States of America, 95, 505—509. 

In this chapter, we will introduce an exciting class of natural product biosynthetic enzymes, the modular synthases, as well as their associated enzyme partners. We will discuss the use of metabolic engineering as a tool for small-molecule discovery and development, both through directed fermentation and combinatorial biosynthesis. In addition, we will review six classes of partner enzymes involved in the modification of polyketide (PK) and nonribosomal peptide (NRP) natural products. We believe that these enzymatic transformations hold great opportunities for synthetic chemists and will serve as the foundation for a new trend in both discovery and process chemistry. 

Du, L., Sanchez, C. andShen, B. (2001) Hybrid peptide—polyketide natural products biosynthesis and prospects toward engineering novel molecules. Metabolic Engineering, 3 (1), 78—95. 

Moore, B.S. and Hertweck, C. (2002) Biosynthesis and attachment of novel bacterial polyketide synthase starter units. Natural Product Reports, 19 (1), 70-99. 

A stereoselective total synthesis of erythronolide A, using two Mg/z-mediated cycloadditions of nitrile oxides has been described. Of broader significance, the strategy not only facilitates the synthesis of specific polyketide targets (i.e., natural products) but also opens up new possibilities for the preparation of nonnatural analogs (482). 

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... 

FUJII, I., Polyketide biosynthesis in filamentous fungi. In Comprehensive Natural Products Chemistry, Vol. 1, Polyketides and Other Secondary Metabolites Including Fatty Acids and Their Derivatives (U. Sankawa ed.), Elsevier, Amersterdam, 1999, pp. 409-441. 

The second largest class of compounds reported from macroalgae is the polyketides, which comprise approximately a quarter of known algal compounds (Blunt et al. 2007). Polyketides are polymers of acetate (C2) and occasionally propionate (C3) and are very similar to fatty acids in their biosynthetic origin. Polyketides can be found in plants, animals, bacteria, and fungi. With a range of activities as broad as their structures, the polyketides are a diverse family of natural products classified based upon the polyketide synthases (PKSs) responsible for their biosynthesis, primarily type I and type II. 

Microalgae produce many potent natural products in the form of complex polycyclic polyethers, a type of polyketide. The ladder-like polyether brevetoxin B (Fig. 1.8a) (Lin et al. 1981) is representative of a host of such toxins, which include cigua-toxin (Scheuer et al. 1967), yessotoxin (Murata et al. 1987), maitotoxin (Murata et al. 1993), gambieric acids (Murata et al. 1992), and azaspiracid (Satake et al. 1998). Brevetoxin B, one of the causitive agents of red tide poisoning, can be isolated from... 

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