Molecular Regulation of β-Lactam Biosynthesis in Filamentous Fungi

Abstract

SUMMARY The most commonly used β-lactam antibiotics for the therapy of infectious diseases are penicillin and cephalosporin. Penicillin is produced as an end product by some fungi, most notably by Aspergillus (Emericella) nidulans and Penicillium chrysogenum. Cephalosporins are synthesized by both bacteria and fungi, e.g., by the fungus Acremonium chrysogenum (Cephalosporium acremonium). The biosynthetic pathways leading to both secondary metabolites start from the same three amino acid precursors and have the first two enzymatic reactions in common. Penicillin biosynthesis is catalyzed by three enzymes encoded by acvA (pcbAB), ipnA (pcbC), and aatA (penDE). The genes are organized into a cluster. In A. chrysogenum, in addition to acvA and ipnA, a second cluster contains the genes encoding enzymes that catalyze the reactions of the later steps of the cephalosporin pathway (cefEF and cefG). Within the last few years, several studies have indicated that the fungal β-lactam biosynthesis genes are controlled by a complex regulatory network, e.g., by the ambient pH, carbon source, and amino acids. A comparison with the regulatory mechanisms (regulatory proteins and DNA elements) involved in the regulation of genes of primary metabolism in lower eukaryotes is thus of great interest. This has already led to the elucidation of new regulatory mechanisms. Furthermore, such investigations have contributed to the elucidation of signals leading to the production of β-lactams and their physiological meaning for the producing fungi, and they can be expected to have a major impact on rational strain improvement programs. The knowledge of biosynthesis genes has already been used to produce new compounds.

Comparative performance of different scale‐down simulators of substrate gradients in Penicillium chrysogenum cultures: the need of a biological systems response analysis

“…In previous studies, it was found that the transcription of the penicillin gene cluster is repressed by extracellular glucose (Revilla et al, 1986;Feng et al, 1994;Brakhage, 1998;Guti errez et al, 1999;Litzka et al, 1999;Mart ın et al, 1999). Further, Wang et al (2017) observed that a very low C s may induce the expression of the high-affinity glucose transporter genes, and the related glucose sensing can trigger metabolic rearrangement, for example futile cycling, which leads to an extra ATP consumption and eventually results in the decrease of penicillin production.…”

Transcriptional regulation of the CRLR gene in human microvascular endothelial cells by hypoxia

“…Potential binding sites for transcription factors, such as nuclear factor-1 (NF-1), Pit-1, and glucocorticoid receptor (GR) were also identified in the 5′flanking region of human CRLR gene. Few consensus sequences for C/EBP (CCAAT; 21) binding complex, which regulates more than 200 genes (22), were found on both sense and antisense strands.…”

Deacetoxycephalosporin C synthase isozymes exhibit diverse catalytic activity and substrate specificity

“…Penicillin N is expanded to deacetoxycephalosporin C (DAOC) by deacetoxycephalosporin C synthase (DAOCS), an iron-dependent and K-ketoglutarate-requiring dioxygenase. DAOC is then hydroxylated to form deacetylcephalosporin C (DAC) by deacetylcephalosporin C synthase (DACS) or DAOC hydroxylase [1] as elucidated in Scheme 1. Such ring expansion activity was ¢rst observed in Acremonium chrysogenum [2].…”