Abstract

Although Penicillium brevicompactum is a widely used commercial strain for the manufacture of mycophenolic acid , there are few findings of Ca 2+ , Mn 2+ , and reactive oxygen species (ROS) interaction. Metal ions play a crucial role in physiological metabolism. Calcium, as the important second messenger , influences fungus growth , virulence, and stress responses. The concentration of cytosolic Ca 2+ was influenced by the Mn 2+ , which demonstrated the crosstalk between calcium and manganese. In the previous study, the crosstalk between calcium and ROS has been discovered and verified, which modified the secondary metabolism and enhanced the yield of MPA (Mycophenolic Acid). A higher concentration of Mn 2+ in the fermentation broth causes an increase in cytoplasmic Ca 2+ and ROS (Reactive Oxygen Species), enhancing the yield of MPA by about 20 % higher and disclosing the cascade regulation with the Mn 2+ , Ca 2+ , and ROS. To be more specific, the intracellular concentration of ROS at 6 mM Mn 2+ is about 1.5 times higher than that at 0.6 mM. Furthermore, we identify an Mn 2+ transport protein , designated as Pb–PHO, which shows 71.2 % identity to the inorganic phosphate transporter PHO84 (Q0CBJ6) from Aspergillus terreus . At the same time, the △Pb-pho exhibits damage to the cell wall integrity, while the OE-pho displays a more normal phenotype at high osmotic stress . The high-affinity Ca 2+ channel, Pb–CCH, is examined via knockdown to demonstrate the crosstalk between Mn 2+ and Ca 2+ . The results show that the addition of Mn 2+ remits the negative influence of pb-cch knockdown and the addition of Ca 2+ remits the negative influence of pb-pho knockdown, demonstrating the relationship between cytoplasmic Mn 2+ and Ca 2+ . Taken together, our results demonstrate the mechanism of a manganese-induced cascade of manganese-calcium-ROS and reveal a signal pathway-relative method to illustrate the manganese-induced increase of MPA production in P