Penicillium patulum, patulin

Patulin is an excellent example of an acetate-derived structure synthesized from an aromatic substrate via oxidative cleavage and subsequent modifications (Figure 3.44). Patulin is a potent carcinogen produced by Penicillium patulum, a common contaminant on apples. If mould-infected apples find their way into food products, e.g. 

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]. 

Two interesting metabolites of Penicillium patulum are patulin and penicillic acid. Their biosynthesis involves the cleavage of an aromatic ring. These substances are mycotoxins and their activity in this context is discussed in Chapter 9. 

Polyketides 6-Methylsalicylic acid, patulin (D 3.3.1) Penicillium patulum A, B... 

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... 

Scott, A. L, and L. Beadling Biosynthesis of Patulin. Dehydrogenase and Dioxygenase Enzymes of Penicillium patulum. Bioorganic Chem. 3, 281 (1974). 

Patulin (52X Although the conversion of 6-methylsalicylic acid (51) into patulin (52) by Penicillium patulum was known, the nature of the aromatic intermediates on the pathway to the lactone was obscure. The discovery of several phenolic co-metabolites, m-cresol (53a R = H), m-hydroxybenzyl alcohol (54), and toluquinol (55) in this organism suggested that (53) is a likely intermediate, as shown in Scheme IS. Administration of 3-methyl[2,4,6- H3]phenol (53b R = H) to P. patultim afforded an enriched patulin. The [M + 2)... 

Tanenbaum, S. W., and E. W. Bassett The biosynthesis of patulin. I. Related aromatic substances from Penicillium patulum, strain 2159 A II, the general physiology of several strains of P. patulum. Biochim. et Biophys. Acta 28, 21, 247 (1958b). 

The microbial culprit organisms found to produce this environmental toxin are mostly Penicillium, Aspergillus, and Byssochlamys species (286-288) including P. patulum (289), P. urticae (290), P. claviforme (291), and P. expansum (292). While patulin (348) possesses antibiotic properties (293), it has not been investigated fully in this respect due to its toxic effects against mammals and plants (294). The chemical identity of patulin (348) was proposed initially incorrectly in 1948 (295), with the structure corrected by Woodward and Singh the following year to the structure shown (348, Fig. 7.1). 

The ylidenebutenolide patulin (10) occupies a somewhat special place in organic chemistry. This structurally simple molecule, which is produced by the mold Penicillium urticae (synonym, P,patulum, P.flexuosum) was isolated independently by several groups of workers during the early 1940 s. It aroused immediate and widespread interest because of its potent antibiotic properties, but this interest evaporated almost as... 

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