Chapter 9 - Insights into the molecular mechanisms of β-lactam antibiotic synthesizing and modifying enzymes in fungi

Abstract

β-Lactams (mainly penicillins and cephalosporins) are among the most commonly prescribed classes of antibiotics due to their safety, effectiveness, and the broad spectrum of action. The penicillin and cephalosporin biosynthetic pathways in Penicillium chrysogenum and Acremonium chrysogenum, respectively, have been deeply characterized from the genetics, molecular, and biochemical points of view and represent a paradigm of fungal secondary metabolism. First, the general information on the penicillin and cephalosporin gene clusters and the associated regulatory genes is described. The available knowledge on the localization of the β-lactam biosynthetic enzymes in the producer cells is studied, emphasizing the localization in peroxisomes of the isopenicillin N (IPN) acyltransferase and its autocatalytic processing. Then, we review the molecular mechanism of the core enzymes, ACV synthetase, IPN synthase, and IPN acyltransferase, including details on their structure. Recent findings on the transport of intermediates through organelles and the controversial mechanisms of penicillin secretion through the cell membrane in P. chrysogenum are analyzed. The last section of this chapter is dedicated to studying different penicillin acylases used industrially for the production of semisynthetic β-lactam antibiotics.