6- methylsalicylic acid polyketide biosynthesis

Monodictyphenone has been previously isolated from a marine fungus Monodictys putredinis as well as an engineered strain of A mdidans. This strain of A. nidulans expressed the (3area lozoyensis polyketide synthase gene involved for 6-methylsalicylic acid (15) biosynthesis, and the authors could not determine whether the monodictyphenone produced in addition to 6-methydsalicylic acid was due... 

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]. 

Aromatic biosynthesis, aromatizatioa biosynthesis of compounds containing the benzene ring system. The most important mechanisms are 1. the shi-kimate/chorismate pathway, in which the aromatic amino acids, L-phenylalanine, L-tyrosine and L-trypto-phan, 4-hydroxybenzoic acid (precursor of ubiquinone), 4-aminobenzoie acid (precursor of folic acid) and the phenylpropanes, including components of lignin, cinnamic acid derivatives and flavonoids are synthesized and 2. the polyketide pathway (see Polyke-tides) in which acetate molecules are condensed and aromatic compounds (e.g. 6-methylsalicylic acid) are synthesized via poly-fl-keto acids. Biosynthesis of flavonoids (e.g. anthocyanidins) can occur by either pathway. 

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]... 

Formation of a polyketide involves condensation of acetyl-CoA with the appropriate number of malonyl-CoA units, modification of the completed poly-j3-ketone where required, and release of the product in stable form, as, for example, in 6-methylsalicylic acid biosynthesis (Scheme 3.4). The whole sequence occurs enzyme-bound, without release, or acceptance, of intermediates externally. Thus probing of the biosynthetic sequence by normal feeding experiments with possible intermediates fails. Instead, very properly, information is gained in different ways by working with the actual enzymes involved. The biosynthesis of several polyketides has been explored in this way, and most extensively that of 6-methylsalicyclic acid 3.14) [14-17]. 

The biosynthesis of patulin (10) has been studied extensively, since the molecule represents a relatively simple model system in which to examine the detailed enzymology of polyketide biosynthesis. Patulin is biosynthesized by the fungus Penicillium patulum via an oxidative pathway from 6-methylsalicylic acid (188) which is synthesized from acetyl-CoA and malonyl-CoA. The major pathway from (188) and the biosynthetic relationships of the phenolic secondary metabolites of P. patulum are... 

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