Penicillium cyclopium

The first organism reported to produce poly(L-malic acid) was Penicillium cyclopium [7]. An amount of 2.6-... 

Penicillic acid (Figure 3.45), another micro-bially produced food contaminant with carcinogenic properties, is synthesized by cultures of Penicillium cyclopium and P. baarnense, and also features oxidative ring fission of an aromatic compound. This time orsellinic acid (Figure 3.25) is a precursor, and ring fission appears to proceed via a quinone, which is the result of decarboxylation, oxidation, and methylation reactions. Figure 3.45 also represents an over-simplistic rationalization of the ring fission process. 

Cyclopiazonic acid Penicillium cyclopium Wheat and other grains... 

Benzodiazepine Bases.—It is known that phenylalanine is an intact precursor for the benzodiazepine bases cyclopenin (124) and cyclopenol (125), via (122) and (123), in Penicillium cyclopium cultures.102 Examination of the stereochemical course of the necessary tritium loss from C-3 of the precursor amino-acid on formation of (124) has given a surprising result more than half of the tritium was... 

Cyclopenin and precursor alkaloids Penicillium cyclopium Westling" 5,7,18,47... 

Penicillium cyclopium Westling is renamed P. aurantiogriseum Dierckx. 

Fig. 12. Metabolic pathways leading to the biosynthesis of phenylalanine, anthranilic acid, and cyclopenin in Penicillium cyclopium (67). Symbols in parenthesis indicate observed feedback inhibition (-) or activation (-I-) of enzyme activities by L-amino acids. Number in circles (pkat/cm of mycelial area) represent either in vitro activities of the enzymes indicated or the rate of alkaloid formation in vivo. All data were measured after 7 days of growth in surface cultures. E 4-P, Erythrose 4-phosphate PEP, phosphoenolpyruvate DAHP, 3-deoxo-D-arabiuoheptuIosonic acid-7-phosphate InGP, inositol glycerophosphate SAM, 5-adeno ylmethionine.

Fig. 14. Overview of regulatory mechanisms acting at the level of transport and channeling of the alkaloid precursor phenylalanine in Penicillium cyclopium (60). (1) Under the influence of P-factor, the biosynthesis of vacuolar phenylalanine carriers is stimulated. (2) Above a threshold concentration, cellular methionine and cysteine inactivate vacuolar phenylalanine carriers. (3) Distinct concentrations of cellular ATP inhibit the efflux from the vacuole high levels of cytosolic amino acids stimulate efflux in the presence of sufficient ATP. (4) The vacuolar phenylalanine pool is most probably involved in triggering the expression of alkaloid metabolism. (5) In the idiophase, cyclopenin stimulates enzymes involved in the biosynthesis of phenylalanine.

Fig. 15. Transformation of cyclopenin-cyclopenol after an increase of membrane permeability by ATP limitation in cultures of Penicillium cyclopium (60). Growth conditions were as described in the legend to Fig. 9. After 7 days of growth 1 mmol/liter azide was added to the culture medium, causing a reduction of the cellular ATP level and thus increasing membrane permeability. (A) Disappearance of cyclopenin-cyclopenol from the medium and concomitant increase of viridicatin-viridicatol content in the culture (100= 1.4 (jrmol alkaloids/cm culture area). (B) Transformation of cyclopenin-cyclopenol present in the cells to viridicatin-viridicatol (100 = 0.24 p.mol al-kaloids/cm culture area).

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. 

Acetate incorporation can also be studied by tritium ( H) NMR. It is more sensitive to detection than C and its radioactivity can be used as a simultaneous monitor. A good signal-to-noise ratio has been obtained [25] from as little as 1 mCi of in penicillic acid (3), biosynthesised by Penicillium cyclopium. [ H]-I-Acetate (460 mCi) has been incorporated with 7% efficiency. Chemical shifts and coupling constants are predictable from H spectra and direct information about stereospecific hydrogen labelling can be obtained. 

Cyclopiazonic Acid.—a-Cyclopiazonic acid (93) is formed in Penicillium cyclopium from tryptophan via (91) and jS-cyclopiazonic add (92) (Scheme 5). Further... 

A similar stereochemical outcome to that observed for 6-MSA was found using orsellinate synthase isolated from Penicillium cyclopium [58]. The hydrogens retained at C-3 and C-5 of orsellinic acid (66, R=OH) are from opposite prochiral sites in malonate. This contrasts with a previous study [59] on... 

Pyrrolizidines compounds have been produced in connection with syntheses of other types of natural products. For example, Gensler and Hu prepared the dioxopyrrolizidine ester (46) as an intermediate in the synthesis of ( + )-slaframine, an indolizidine alkaloid obtained from cultures of Rhizoctonia leguminicola. The pyrrolidone ester (47), prepared from l-glutamic acid [Eq. (14)], was optically active, but the cyclized product, formed in quantitative yield from 47, was completely racemized. The synthesis of 2-acetyl-1,3-dioxopyrrolizidine (48) was carried out by Kruger and Arndt to assist with their investigations on model compounds aimed toward the total synthesis of a-cyclopiazonic acid, the main toxic principle of Penicillium cyclopium The spectra of the product (48) obtained in 30% overall yield was typical of an intramolecularly H-bonded enolized )S-... 

Alkaloid biosynthesis in Penicillium cyclopium, M. Luckner, J. Nat. Prod., 1980, 43, 21. 

Benzodiazepine Alkaloids.—Cyclopenin (49) and cyclopenol (50) are isolated from Penicillium cyclopium. Their biosynthesis would appear to involve one molecule of phenylalanine and one of anthranilic acid and indeed the biosynthetic pathway to viridicatin and viridicatinol in Penicillium viridicatum from these two amino-acids has (49) and (50) as intermediates. ... 

The fungal metabolite cyclopiazonic acid 1 (40) has been shown to derive from tryptophan, mevalonic acid, and acetate. The corresponding bis-seco-derivative (39) also gave an incorporation when administered to Penicillium cyclopium Westling and is, therefore, probably an intermediate.28... 

Cyclopiazonic Acid.—Cyclopiazonic acid (115) is formed in Penicillium cyclopium from mevalonate, tryptophan, and an acetate-derived C4 unit [heavy bonding... 

The only note dealing with quinoline derivatives of fungal origin is by way of confirming the well-known fact that viridicatin (3-hydroxy-4-phenyl-2-quinolone) is produced by Penicillium cyclopium ... 

In 1973, Abe and co-workers 193) isolated cyclopiazonic acid (130, a-CA), mp 245-246°C, cyclopiazonic acid imine (131), mp 277-278°C, and bissecode-hydrocyclopiazonic acid (132, p-CA), mp 168-169°C, from the combined extracts of mycelia and culture filtrates of Asp. versicolor. Cyclopiazonic acid was also isolated from Asp. flavus 194) and Asp. oryzae 195) by other groups. Penicillium cyclopium Westling 196) also produced the above metabolites as well as the intermediate, a-acetyl-7-(P-indolyl)methyltetramic acid (133), mp 164-165°C. Cyclopiazonic acid is known to cause acute toxicosis in ducklings and rats 197). 

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