Polyketides groups

The ansa-chain of the ansamycins streptovaricins (4), rifamycins (263), geldanamycin (4), and herbimycin (32) has been shown to be polyketide in origin, being made up of propionate and acetate units with the 0-methyl groups coming from methionine. The remaining aromatic C N portion of the ansamacroHdes is derived from 3-amino-5-hydroxybenzoic acid (264—266) which is formed via shikimate precursors. Based on the precursors of the rifamycins and streptovaricins isolated from mutant bacteria strains, a detailed scheme for the biosynthesis of most of the ansamacroHdes has been proposed (95,263). 

Biosynthetic studies using acetate (Ac), propionate (Pr), and butyrate (Bu) revealed the polyketide nature of aurodox which has the composition Pr(Ac)g for the goldinamine skeleton C-7 to C-25 and the composition Bu(Ac) for the C-27 to C-39 carbon chain of goldinonic acid. In contrast to the methyl branch at C-8, those at C-19 and C-21 are methionine-derived as are all remaining methyl groups (52,53). The biogenetic origin of the pyridone moiety is not clear. 

The biosynthesis of two major classes of red tide toxins, saxitoxin analogs and brevetoxins, have been studied. It was shown that saxitoxin is biosynthesized from arginine, acetate, and methionine methyl group. Brevetoxins were shown to be unique polyketides, which are probably biosynthesized from dicarboxylic acids. Some details of the biosynthetic mechanism have been elucidated. 

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. 

An unusual class of heterocydes are polyketide-derived macrodiolide natural produds. The groups of Porco and Panek have recently shown that stereochemically well-defined macrodiolides of this type can be obtained by cyclodimerization (transesterification) of non-racemic chiral hydroxy esters (Scheme 6.154) [301]. Preliminary experiments involving microwave irradiation demonstrated that exposing dilute solutions of the hydroxy ester (0.02 m) in chlorobenzene to sealed-vessel microwave irradiation conditions (200 °C, 7 min) in the presence of 10 mol% of a distannoxane transesterification catalyst led to a 60% isolated yield of the 16-mem-bered macrodiolide heterocycle. Conventional reflux conditions in the same solvent (0.01 m in the hydroxy ester) provided a 75% yield after 48 h at ca. 135 °C. 

Members of the CHS/STS family of condensing enzymes are relatively modest-sized proteins of 40-47 kDa that function as homodimers. Each enzyme typically reacts with a cinnamoyl-CoA starter unit and catalyzes three successive chain extensions with reactive acetyl groups derived from enzyme catalyzed decarboxylation of malonyl-CoA.11 Release of the resultant tetraketide together with or prior to polyketide chain cyclization and/or decarboxylation yields chalcone or resveratrol (a stilbene). Notably, CHS and STS catalyze identical reactions up to the formation of the intermediate tetraketide. Divergence occurs during the termination step of the biosynthetic cascade as each tetraketide intermediate undergoes a distinct cyclization reaction (Fig. 12.2). 

Posttranslational modifications can be broken down into two main classes those that are reversible and those that are irreversible. Included in the large group of reversible posttranslational modifications are phosphorylation, acetylation, and disulfide formation. Irreversible posttranslational modifications include peptide bond cleavage as in intein splicing also irreversible is the introduction of a phosphopantetheinyl group during fatty acid, polyketide, and nonribosomal peptide biosyntheses. The current debate is whether to classify lysine N-methylation as reversible or irreversible. Recently, there have been reports of lysine demethylases. ... 

Scheme 6.26. Construction of polyketide building blocks by sequential directed stereoselective hydroformylation and directed cuprate addition with the aid of the reagent-directing o-DPPB group. (o-DPPB = ortho-diphenylbenzoylphosphanyl, DME = dimethoxyethane)...

Certainly of genuine origin is anachelin, a strange compound whose biosynthesis requires inter alia steps from the peptide and polyketide paths. It exists in an open (anachelin H, Fig. 3, (10)) and two cyclic forms arising from an interaction of the carbonyl group of the salicylic acid residue with one of the neighboring... 

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