Pentaketides

Pentaketides are formed from five acetate/malonate units. Commonly compounds of type (3,53) are produced which are further modified as for the tetraketides in ways which include aromatic ring scission. A simple modification is in the formation of isocoumarins [as 3.58)], Citrinin (3.57) is believed to be derived via 3.56) [39]. 

Many of the structural variations found in aromatic fungal metabolites that are tetraketides are also found in the pentaketides that are biosynthesized by Penicillium and Aspergillus species. Several fungal metabolites have a carbon skeleton that is derived from acetylorsellinic acid. This compoimd is itself a metabolite of Penicillium brevi-compactum. Cyclization of acetylorsellinic acid 

Daldinia concentrica [3.5 x 10 % fresh fungus 1% by spectroscopic assay] (75), (76), Hypoxylonfuscum [0.5%, dried fungus] (339) 

Bulgaria inquinans (210), Daldinia concentrica (14,15,16,19), Hypoxylon fuscum (339), H. sclerophaeum var. microspora (713) 

Bulgarhodin (266) formed a tetra-acetate (268) which is believed to be a derivative of the ortho-qmnonoid tautomer (267) of the pigment. 

Neither bulgarhodin nor bulgarein is the same as the crystalline pigment bulgariin isolated from B. inquinans by Zopf (755). 

The close relationship of Bulgaria and Daldinia with Hypoxylon in the Xylariaceae is illustrated by the occurrence in some Hypoxylon species of perylenequinones and their relatives (Table 22). The structure of hypoxylone (269), the main pigment of the dark purple carpophores of Hypoxylon sclerophaeum collected in French Guyana, followed from analysis of the and C-n.m.r. spectra and comparison with model systems 107). The naphthyl-naphthoquinone structure of hypoxylone suggests oxidative coupling between naphthalene-1,8-diol (258) and naphthalene-1,4,5-triol. 

Polyketides of this group are either monocyclic compounds, e.g., eugenone, Ceratocystis toxins, or bicyclic substances, e.g., citrinin, and possess a six-mem-bered carbocyclic ring. Compounds with seven-membered rings (tropoplones, e.g., sepedonin) also occur in nature. 

Polyketides of this type are built in molds, e.g., Aspergillus and Penicillium. Biosynthesis 

There are several possibilities for the cyclization of the corresponding polyketo acid (Figs. 75 and 76). Transformation of the cyclic compounds is common. Of special interest is the ring enlargement during the formation of tropolones (Fig. 77). 

The C-atoms marked by b are derived from the methyl group of L-methionine 

Fig 76. Formation of polyketide-derived coumarins of the eugenone type 

Incorporation studies with singly and doubly labelled [ C]acetates have confirmed that the dihydroisocouroarin moiety of 

C-labelling studies on aspyrone (20) have appeared.Asperlactone (21) is a co-metabolite of aspyrone in 

meIleus and has the same carbon skeleton. Computer-aided re- 

Diplodia macrospora, has been studied, using C-labelled acetates 

These are consistent with formation of sclerin (27) via ring 

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Aloe (Aloe arborescens) is a medicinal plant rich in aromatic polyketides such as pharmaceutically important aloenin (a hexaketide pyrone), aloesin (a heptaketide chromone), and barbaloin (an octaketide anthrone) (Fig. 4a). Pentaketide chromone synthase (PCS) and octaketide synthase (OKS) are novel plant-specific type III PKSs, which were obtained from the aloe plant by RT-PCR cloning using degenerate oligonucleotide primers based on the conserved sequences of known CHS enzymes [30-33]. The deduced amino acid sequences of PCS and OKS are 91% identical (368/403), and show 50-60% identity to those of other CHS superfamily type III PKSs of plant origin OKS shares 60% identity (240/403) with CHS from... 

Abe I, Utsumi Y, Oguro S, Morita H, Sano Y, Noguchi H (2005) A plant Type III polyketide synthase that produces pentaketide chromone. J Am Chem Soc 127 1362-1363... 

Morita H, Kondo S, Oguro S, Noguchi H, Sugio S, Abe I, Kohno T (2007) Structural insight into chain-length control and product specificity of pentaketide chromone synthase from Aloe arborescens. Chem Biol 14 359-369... 

Concentrate now on the biosynthesis of scytalone in the first problem. You should have identified it as a pentaketide. Now consider how many different ways the pentaketide chain might be folded to give scytalone. 

Using precursor-directed biosynthesis, Boddy et a/. were able to effectively reconstitute epothilone biosynthesis in E. coli. A pentaketide NAC thioester intermediate... 

Several important chalcone synthase-related PKSs have recently been discovered in bacteria. 21 RppA is a Type III PKS that synthesizes 1,3,6,8-tetrahydroxynaph-thalene (THN) from five malonyl-CoAs in Streptomyces griseusf RppA specifically cyclizes the pentaketide intermediate via two intramolecnlar condensations to yield the bicyclic THN. The crystal stractnre of a closely related THN synthase (THNS) from S. coelicolor was recently determined, uncovering the presence of a second active-site cysteine that stablizes the growing polyketide and prevents aberrant cyclization of the highly reactive pentaketide. ... 

FIGURE 3. (A) Crystal structure of pentaketide chromone synthase with a bound CoA in the active site (2D3M, Plate II). (B) The active site showing part of the bound CoA and the three catalytically significant side chains. The Cys side chain is oxidized to —S02 in the crystal structure (Plate III). The reduced —SH group of Cysl77 is needed for catalysis... 

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... 

Possible pentaketide precursor with a m onate starter unit... 

CHS-related enzymes are also found in microorganisms and appear to be responsible for the formation of the pentaketide 1,3,6,8-tetrahydroxynaphthalene (10) in Streptomyces griseusP While flavonoids are widely distributed in plants, chlorflavonin (72) has been isolated from the frmgus Aspergillus candicusP although nothing is currently known of the nature of the associated synthase. 

Penicillic acid provides an example of a simple tetra-ketide whose aromatic ring is cleaved and cyclized, as shown by experiments with [l,2- C2]-acetate (Fig. 4). On the other hand, the pentaketide citrinin is the result of the cyclization of a linear polyketide chain wherein... 

Acetate is also a precursor of several groups of alkaloids in the form of a polyketide chain that interacts with an unknown nitrogen source (as in the terpene alkaloids). Examples of acetate-derived alkaloids are coniine—the toxic principle of Conium maculatum, pinidine—from several Pinus species, and the naphthy-lisoquinoline alkaloids (e.g., ancistrocladine)—showing antimalarial and anti-HIV activity. The latter alkaloids are apparently derived from the oxidative coupling of two pentaketide units. Huperzine A, currently in clinical trials for the treatment of Alzheimer s disease and isolated from the club moss (Serrata huperzia), is derived from a polyacetate precursor (Fig. 46). 

An exercise in the folding of the polyketide chain to make a simple pentaketide. 

Three previously unknown pentaketides, (+)-formylanserinone B 51, (-)-epoxyserinone A 52, and (+)-epoxyserinone B 53, along with two constituents, hydroxymethylanserinone B 54 and deoxyanserinone B 55,... 

Two new 10-membered macrolides, modiolides A 205 and B 206, and a new linear pentaketide, modiolin 207, were isolated from the culture broth of fungus Paraphaeosphaeria sp. (N-119), which was separated from a marine horse mussel. Both compounds 205 and 206 showed antibacterial activity against Micrococcus luteus (MIC value 16.7 pg mL ) and anti-fungal activity against Neurospora crassa (MIC value 33.3 pg mL ). 

Neirgenicin (136) is an antibiotic isolated from Nocardia argentinemis. In the biosynthetic studies of nargenidn (136) a pentaketide precursor (133) was incorporated into 136 without modification of the stereochemistry and E-olefine via cis decaline system (135). The incorporation of the tetraene precursor (134) indicates that the decaline system (135) would be generated by the enzymatic Diels-... 

Feeding studies to Nocardia argentine sis with - C labelled NAC thioesters of di-, tri-, tetra- and pentaketide intermediates demonstrated regiospecific incorporations into nargenicin 37 (Scheme 18) which are consistent with an intramolecular Diels-Alder cyclisation of a linear nonaketide intermediate (Scheme 19) [72,73]. 

The insect pathogenic filamentous fimgus Beauveria bassiana makes the 2-pyridone tenellin 19 (Figure 7) in high yield. Feeding studies established that tenellin is derived from tyrosine (or phenylalanine) and a pentaketide (23). 

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