Metabolic development and mitochondrial changes during cyclopiazonic acid production in Penicillium cyclopium

Abstract

During a study of cyclopiazonic acid (total α- and β-cyclopiazonic acids, CA) production by Penicillium cyclopium Westling, it was found that nitrogen depletion controlled the advent of secondary metabolism and that nitrate reduction was not rate-limiting. In concert with N depletion both tryptophan (Trp) biosynthesis and glucose catabolism fell. The rate of Trp production dropped to match the rate of CA biosynthesis. Glucose utilization varied between an early and late preference for the pentose cycle, with a mixture of pentose and Emden–Meyerhof pathways at an intermediate time. This pattern may well reflect the need for erythrose-4-phosphate in Trp biosynthesis. Additions of Trp caused a drop in CA production possibly because of repression of Trp synthetase. Exogeneous dimethylallylpyrophosphate (DMAPP) increased CA biosynthesis, while mevalonic acid had no effect which suggested a rate-limiting step between these two metabolites. These changes probably best fit Bu'Lock's hypothesis that secondary metabolism links fermentative and aerobic metabolism (ATP generation). In this case protein and polyisoprenoid biosynthesis, sugar utilization, and energy requirements would all be interlocked with the advent of secondary metabolism. The possible relationship between the observed metabolic changes and energy control were supported by electron-microscopic examination of the mitochondria in situ, when these ATP-generating organelles underwent major changes. Addition of ATP to the culture depressed CA production, as did excessive aeration. The metabolic regulator cAMP had no effect other than to increase autocatalysis.