Orsellinic acid biosynthesis

Similar stereochemical studies have also been conducted on the orsellinic acid synthase from Penicillium cyclopium, a multisubunit enzyme composed of a 130 kDa protein [129, 130]. The catalytic cycle of this PKS is identical to the 6-MSAS cycle, except that it lacks any ketoreduction or dehydration reactions. Unlike 6-MSAS, enolizations occurring during orsellinic acid biosynthesis are not stereospecific. 

Tetraacetic acid (or a biological equivalent) is suggested as an intermediate in the biosynthesis of phenolic natural products. In the laboratory, it can be readily converted to orsellinic acid. Suggest a mechanism for this reaction under the conditions specified. 

The orsellinic acid derivative lasiodiplodin 84 and its de-O-methyl congener are found, i.a., in the roots of Arnebia euchroma, a plant which is used in traditional Chinese medicine. These compounds elicit diverse biological responses as inhibitors of prostaglandin biosynthesis, cyctotoxic agents, and plant growth regulators. 

In 1907, Collie proposed that polymers of ketene (CH2=C=O) might be precursors of such compounds as orsellinic acid, a common constituent of lichens. The hypothesis was modernized in 1953 by Birch and Donovan, who proposed that several molecules of acetyl-CoA are condensed (Eq. 21-19) but without the two reduction steps required in biosynthesis of fatty acids (Fig. 17-12).329 As we now know they were correct in assuming that the condensation occurs via malonyl-CoA and an acyl carrier group of an enzyme. The resulting p-polyketone can react in various ways to give the large group of compounds known as polyketides. 

Merely by writing ketones instead of phenols and doing one disconnection corresponding to a simple carbonyl condensation, we have reached a possible starting material which is a typical acyl polymalonate product without any reductions. This is what polyketides are. The fatty acids are assembled with full reduction at each stage. Polyketides are assembled from the same process but without full reduction indeed, as the name polyketide suggests, many are made without any reduction at all. This is the biosynthesis of orsellinic acid. 

As the polyketide chain is built up, any of the reductions or eliminations from fatty acid biosynthesis can occur at any stage. The simple metabolite 6-methyl salicylic acid (6-MSAJ is made in the microorganism Penicillium patulum, and it could come from the same intermediate as orsellinic acid with one reduction,... 

Penicillic acid (82 in Figure 17) is a toxic compound produced by many Penicillum and some Aspergillus species.166 It is biosynthesized from orsellinic acid through the pathway shown in Figure 17.167 A candidate of a gene encoding a PKS for penicillic acid biosynthesis was obtained from A. ochraceus 6t... 

Cell-free systems capable of in vitro synthesis of 6-methylsalicylic acid (6-MS A) and a related tetraketide, orsellinic acid, were developed long before the advent of recombinant DNA technologies in the field of natural product biosynthesis [113-115] (Fig. 5). Since then, the biosynthetic mechanisms and molecular recognition features of 6-methylsalicylic acid synthase (6-MSAS) have been extensively studied. 6-MSAS initiates synthesis with an acetyl group derived from acetyl Co A, extends the polyketide chain to a tetraketide via three decar-boxylative condensations of malonyl CoA-derived extender units, and uses NADPH to specifically reduce one of resulting carbonyls to a hydroxyl group. In its natural producer, Penicillium patulum, the product, 6-MSA is subsequently glycosylated to form the antibiotic patulin [116]. 

The tetraketide orsellinic acid 1 is the simplest tetraketide, which requires no reductions during its biosynthesis. One of the first discovered fungal PKS, orsellinic acid synthase (OSAS)... 

No discussion of studies on the stereochemical outcome of polyketide biosynthesis would be adequate without mention of the seminal studies of Jordan and Spencer [56-58] using chiral malonates to determine the stereospecificity of the elimination and enolisation reactions occurring during 6-MSA (66, R = H) and orsellinic acid (66, R = OH) biosynthesis. Early experiments by Abell and... 

CijHigOg, Mr 374.35, prisms, mp. 195 C, yellow color with KOH and p-pheny lenediamine, soluble in benzene and chloroform. A. is a depside with antibiotic properties occurring in many lichens (e.g in Hypogymnia physodes and Lecanora atra). The biosynthesis proceeds via acetyl-CoA and orsellinic acid. 

Examples of P. are Tetra clines (see), Griseofulvin (see), Macrolide antibotics (see), Cydoheximide (see), and various fungal products such as orsellinic acid, 6-methylsalicylic acid and cyclopaldic add. [ The Biosynthesis of Acetate-Derived Phenols (Polyketides) by N.M.Packter pp. 535-570, in The Biochemistry of Plants, V6I4, 1980 (Edit. P.K. Stumpf), Academic Press S.Sahpaz et al. Phytochemistry 42 (1996) 103-107]... 

CYP248A1 (Cal02) Micromonospora echi-nospora (or purpurea) 3BUJ Orsellinic acid hydroxylase in cali-cheamicin biosynthesis [230]... 

Comparison of the illustrated pathway to 3.5) (Scheme 3.2 cf. Scheme 3.4) with that of fatty acid biosynthesis (Section 1.1.2 Scheme 1.2) indicates that a clear distinction between them is achieved by the absence of a reductase in polyketide formation, i.e. oxygen atoms of acetate are retained in polyketide metabolites. In the case of orsellinic acid 3.4), in particular, results of experiments with [ Ojacetate established this to be correct [10]. It should be noted, however, that universal retention of acetate oxygen through the poly-jS-keto-acyl-CoA to the final metabolite is not observed. One is missing, for example, in 6-methylsalicyclic acid 3.14) and several in curvularin 3.87). (See, especially. Section 3.9 for what appear to be polyketides formed with varying levels of oxidation and dehydration corresponding to the steps illustrated in Scheme 1.2, Section 1.1.2.)... 

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