Cyclopenine metabolism

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.

The benzodiazepine alkaloids are thoroughly excreted into the medium, thus keeping the cellular content of the hyphal cells very low. The alkaloid content cannot be substantially increased, even after artificial breakdown of membrane barriers. Permeabilization of hyphal cell membranes by lowering the ATP content (see above) is reversible by adding ATP or by allowing ATP net synthesis after removal of the metabolic inhibitors. Even if cyclopenin is present during such a permeabilization—reimpermeabilization cycle, the resealed cells do not... 

The enzymes involved in the alkaloid metabolism of P. ovoloplum become measurable during the transition from tne trophophase to the idiophase. The activity increase of cyclopeptine dehydrogenase, dehydrocyclopeptine ep-oxidase and cyclopenin m-hydioxylase is inhibited by 5-fluorouracil and cycloheximide, indicating that it depends on RNA and protein biosynthesis (7 - 9). Hence like many other secondary metabolic activities (cf, 2,... 

In contrast to the hyphal cells, which after their synthesis specialize with formation of the means necessary for alkaloid metabolism, with the conidiospores specialized cells are formed de novo. The conidia contain the enzymes of cyclopenin-cyclopenol biosynthesis as constitutive proteins (Fig. 5), Hence these enzymes are synthesized during cell division in the conidia-pro-ducing cells, the phialides. However, as with alkaloid biosynthesis in the hyphae in spite of optimum enzyme... 

Mohammed, Y. S. The structure of cyclopenin and cyclopenol, metabolic products from P. cyclopium and P. viridicatum Westling. Tetrahedron Letters 28, 1953... 

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