Radiolabeled verruculogen was detected in a wide range of body tissues 6 min after intravenous administration, but after a further 20 min it was mainly being excreted via the biliary route. In isolated liver perfusion, [14C]verruculogen was rapidly taken up by the liver and metabolized completely, principally to the related tremorgen TR-2 but also to a desoxy derivative of verruculogen. In addition, a smaller amount of an isomer of TR-2 was detected. These metabolic products were excreted in the bile.
14C-Labelled compound TR-2, a tremorgenic mycotoxin, was administered to Penicillium raistrickii in submerged fermentation. Half of the added radiolabel was taken up by the fungus during the 60 h incubation period and the secondary metabolites subsequently isolated, principally verruculogen but also fumitremorgin B, were found to be radiolabelled. The efficiency of biosynthetic incorporation of TR-2 into verruculogen within the mycelium was at least 35%, demonstrating for the first time an intermediary role for TR-2. Fumitremorgin B was also TR-2-derived but may not be an important intermediate in verruculogen biosynthesis.
Roquefortine and the penitrems were biosynthesised concurrently at an approximately equimolar rate by Penicillium crustosum after growth and sporulation. [14C]mevalonic acid was incorporated (15% efficiency) into the isoprenoid regions of the penitrem and roquefortine molecules to an extent consistent with their 6:1 molar ratio of isoprenoid components. [14C]penitrem A (specific activity, 3.4 X 10(2) mu Ci mmol-1) and 14C-penitrems B, C, and E readministered to young cultures were metabolically interconverted, indicating considerable metabolic flux, though generally directed towards penitrem A as the end product and suggesting a metabolic grid for the penitrem metabolites. Addition of bromide to the medium preferentially favored the production of bromo-analogs rather than the usual chloropenitrems.
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