The second messenger cyclic di-AMP (c-di-AMP) is essential for growth of many bacteria because it controls osmolyte homeostasis. c-di-AMP can regulate the synthesis of potassium uptake systems in some bacteria and it also directly inhibits and activates potassium import and export systems, respectively. Therefore, c-di-AMP production and degradation have to be tightly regulated depending on the environmental osmolarity. The Gram-positive pathogen Listeria monocytogenes relies on the membrane-bound diadenylate cyclase CdaA for c-di-AMP production and degrades the nucleotide with two phosphodiesterases. While the enzymes producing and degrading the dinucleotide have been reasonably well examined, the regulation of c-di-AMP production is not well understood yet. Here we demonstrate that the extracytoplasmic regulator CdaR interacts with CdaA via its transmembrane helix to modulate c-di-AMP production. Moreover, we show that the phosphoglucosamine mutase GlmM forms a complex with CdaA and inhibits the diadenylate cyclase activity in vitro. We also found that GlmM inhibits c-di-AMP production in L. monocytogenes when the bacteria encounter osmotic stress. Thus, GlmM is the major factor controlling the activity of CdaA in vivo. GlmM can be assigned to the class of moonlighting proteins because it is active in metabolism and adjusts the cellular turgor depending on environmental osmolarity.
Volume 7 of the Jenny Stanford Series on Biocatalysis deals with several different aspects of pharmaceuticals, which include not only various applications of drugs and their metabolism but also natural resources for active pharmaceutical ingredients as well as the removal of pharmaceutical pollution. In detail, novel approaches for developing microbial fermentation processes to produce vitamin B6 using microorganisms are described together with novel routes for vitamin B6 biosynthesis. The other topics discussed are new approaches for producing the successful anticancer drug Taxol from naturally occurring precursors, molecular farming through plant engineering as a cost-effective means to produce therapeutic and prophylactic proteins, and successful screening of potent microorganisms producing L-asparaginase for various chemotherapeutic applications. Furthermore, microbial biotransformations in the production and degradation of fluorinated pharmaceuticals are described. The other chapters inform the reader about the biotransformation of xenobiotics/drugs in living systems, the degradation of pharmaceuticals by white-rot fungi and their ligninolytic enzymes, and the removal of pharmaceutical pollution from municipal sewage using laccase