Griseofulvin biosynthesis

It iaterferes with the synthesis of the hyphal walls, the biosynthesis of nucleic acids, and the synthesis of chitin. The iateraction with microtubules has also been described. The sensitivity of a cell seems to depend particularly on the abiUty to form griseofulvin—nucleic acid complexes. Further information concerning griseofulvin is available (21). 

Griseofulvin is biosynthetically manufactured by elaboration with Penicillium griseofulvum and related strains of Penicillia. The biosynthesis has been the subject of numerous chemical and biological studies, the latest of which is given by Harris, et. al. (9) Figure 10. Other proposed biosynthetic pathways are discussed. 

ABSTRACT Fermentation of produced strains, purification, isolation and biosynthesis of griseofulvin are described. Metabolites similar to griseofulvin (precursors, side products of biosynthesis, etc.) are also discussed. Most important fungal metabolites containing halogen atoms are included in the second part of the review. In brief, metabolites are included that were discovered and isolated in 1995 and later. Pharmacological properties are only described when referred to in the original papers. 

Similarly to the biosynthesis of tetracyclines, even here the bromo analog was produced by simply substituting KBr for KCl in the medium [25], Deuterated griseofulvin has been obtained by cultivation of P. janczewskii in culture medium with D2O. 

A. are chemically heterogeneous Important components include amino acids, often nonproteogenic D-amino acids (e.g. in gramicidin), acetate/malonate units (griseofulvin, tetracycline), sugars and sugar derivatives (streptomycin), tetracyclic triterpenes (fusi-dinic acid, helvolinic acid, cephalosporin P,). There are also many Nucleoside A. (see). A. act by various mechanisms Many interfere with protein biosynthesis, but others, e.g. penicillin, inhibit cell wall synthesis in bacteria. 

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]... 

Fig. 4.38 Spirocyclization catalyzed by cytochrome P450 GstF in the biosynthesis of a precursor of the antibiotic griseofulvin showing the probable diradical intermediate involved in the coupling reactions... 

In the biosynthesis of griseofulvin the polyketo acid I cyclizes to the benzo-phenone derivative II, which is methylated (C 3.3) and chlorinated (C 2.4.2). Attack of a phenol oxidase (C 2.3.1) or peroxidase (C 2.4.1) yields a biradical which is the key intermediate in the closure of the O-heterocyclic ring. 

XXXVI. The latter could be synthesized from 7 molecules of acetate, with malonyl coenzyme A as an intermediate as it is in the synthesis of fatty acids. 0-Methylation and the introduction of a chlorine atom into the carbon skeleton would be required to yield XXXV. But the biosynthesis of the skeleton itself appears to be independent of the process of chlorination, for dechlorogriseofulvin has been isolated from culture fluids of Penicillium griseofulvum and Penicillium janczewskii, and the bromo analogue of griseofulvin may be formed when chloride in the culture medium is replaced by bromide . ... 

Miscellaneous antibiotics - Griseofulvin. the sideromycins and novobiocin known to affect varied processes in bacteria. can be included in this group. Also to be included are a number of antibiotics such as hadacidin. psicofuranine. tubercidin, toyocamycin. sangivamycin. azasering. diazo-oxo-norleucine (DON), cordycepin and mycophenolic acid known to block biosynthesis of some nucleic acid precursors. ... 

Figure 5.2 The hypothesis for the biosynthesis of the antibiotic griseofulvin using sodium [lJ C]acetate. The black dots in the supposed intermediatepolyketide and the product indicate which carbon atoms should be labelled...

The biosynthesis of the skeletons of many natural products by head to tail linkage of acetate-malonate units is firmly estabhshed (Birch, 1962 Richards and Hendrickson, 1964). Two possible mechanisms (see Fig. 1) for the cyclization of the intermediate linear S-polyketomethylene chain have been discussed. Acetylphloroglucinol (Fig. 1, VII) and orsellinic acid (Fig. 1, VI) can be derived by internal Claisen and aldol condensation respectively of 3)5,7-trioxooctanoic acid, probably as its coenz3mie-A ester. The alternative aldol condensation leads to 3>5 dihydroxyphenylacetic acid (Fig. 1, V). Considerable academic interest in the biosynthesis of griseofulvin arises from the observation that its formation from a linear polyketomethylene chain of seven acetate-malonate units could involve both types of condensation. 

Fig. 2. Biosynthesis of griseofulvin. Denotes atom derived from COgH of an acetate unit. —> Denotes established fungal conversion. - > Denotes hypothetical pathway...

Following the identification of the benzophenones (Fig. 2, IX, X and XII) as metabolic products of P. patulum, the reasonable and attractive hypothesis was advanced that griseofulvin biosynthesis proceeded by the pathway acetate-malonate -> (VIII) -> (IX) (X) -> (XII) (XIV) -> (XI) -> (I R = Cl) it received some support from the fact that the reactions (XII) -> (XIV) -> (XI) and (XI) -> (I R = Cl) had already been achieved in vitro by oxidative phenol radical coupling and stereospecific selective catal)d ic reduction respectively for review see Grove (1964). 

There is evidence (Rhodes et al, I96I) from the isolation of compounds (X) and (XII) that chlorination takes place at the benzophenone step of the P. patulum fermentation, and, indeed, is a key reaction in griseofulvin biosynthesis in shake culture. It may be noted however, that chlorination of a grisan intermediate apparently occurs in the biogenesis of geodin (Rhodes et aL, 1962). 

Birch, A. J., R. A. Massy-Westropp, and R. W. Rickards Studies in relation to biosynthesis. Part XIII. Griseofulvin. J. Chem. Soc. 1958b, 360. 

Rhodes, A. Griseofulvin Production and biosynthesis. Progr. Ind. Microbiol. 4, 167 (1963). 

Semkina, L. E., N. N. Mustafova, and V. K. Grekova Growth and development peculiarities of Penicillium nigricans in submerged griseofulvin biosynthesis. Antibiotiki 8, 701 (1963). 

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