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Molecular regulation of beta-lactam biosynthesis in filamentous fungi
1Lehrstuhl für Mikrobiologie, Universität München, D-80638 Munich, Germany. Brakhage@bio1.bio.tu-darmstadt.de
Abstract:
The most commonly used beta-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 beta-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 beta-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.
Insights
Fungal biosynthesis of penicillin and cephalosporin involves shared amino acid precursors and common enzymatic steps. Understanding the complex regulatory networks controlling these beta-lactam antibiotics is key for strain improvement.
Area of Science:
- Microbiology
- Biochemistry
- Molecular Biology
Background:
- Beta-lactam antibiotics, including penicillin and cephalosporin, are crucial for treating infectious diseases.
- These vital compounds are produced by various fungi, such as Penicillium chrysogenum and Acremonium chrysogenum.
- Their biosynthesis pathways share common amino acid precursors and initial enzymatic reactions.
Purpose of the Study:
- To investigate the regulatory mechanisms governing fungal beta-lactam biosynthesis.
- To compare these mechanisms with those regulating primary metabolism in lower eukaryotes.
- To elucidate signals and physiological roles of beta-lactam production in fungi.
Main Methods:
- Analysis of gene clusters encoding penicillin and cephalosporin biosynthesis enzymes (e.g., acvA, ipnA, aatA, cefEF, cefG).
- Examination of regulatory networks influenced by environmental factors like pH, carbon source, and amino acids.
- Comparative studies of regulatory proteins and DNA elements in fungal beta-lactam and primary metabolism genes.
Main Results:
- Identified shared biosynthetic pathways and gene clusters for penicillin and cephalosporin.
- Revealed complex regulatory networks controlling fungal beta-lactam production.
- Elucidated novel regulatory mechanisms and signals influencing antibiotic synthesis.
Conclusions:
- Understanding fungal beta-lactam biosynthesis regulation offers insights into antibiotic production.
- This knowledge facilitates rational strain improvement programs for enhanced antibiotic yields.
- Investigations contribute to understanding the ecological role of beta-lactams for producing fungi.