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Transcriptional control of expression of fungal beta-lactam biosynthesis genes
O Litzka1, K Then Bergh, J Van den Brulle
1Lehrstuhl für Mikrobiologie, Universität München, Germany.
Abstract:
The most commonly used beta-lactam antibiotics for the therapy of infectious diseases are penicillin and cephalosporin. Penicillin is produced as end product by some fungi most notably by Aspergillus (Emericella) nidulans and Penicillium chrysogenum. Cephalosporins are synthesised by several bacteria and fungi, e.g. by the fungus Acremonium chrysogenum (syn. 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. The penicillin biosynthesis is catalysed by three enzymes encoded by acvA (pcbAB), ipnA (pcbC) and aatA (penDE). The genes are organised into a cluster. In A. chrysogenum, in addition to acvA and ipnA, which are also clustered, a second cluster contains the genes for enzymes catalysing the reactions of the later steps of the cephalosporin pathway (cefEF, cefG). Transcription of biosynthesis genes is subject to sophisticated control by nutritional factors (e.g. glucose, nitrogen), amino acids such as lysine and methionine, and ambient pH. Some regulators have been identified such as the A. nidulans pH regulatory protein PACC and the transcriptional complex PENR1. PENR1 is a HAP-like transcriptional complex similar or identical to AnCF. Additional positive regulatory factors seem to be represented by recessive trans-acting mutations of A. nidulans (prgA1, prgB1, npeE1) and P. chrysogenum (carried by mutants Npe2 and Npe3). The GATA-binding factor NRE appears to be involved in the regulation of the penicillin biosynthesis genes by the nitrogen source in P. chrysogenum. Formal genetic evidence suggests the existence of transcriptional repressors as well.
Insights
Penicillin and cephalosporin antibiotics share common biosynthetic pathways and precursors. Gene clusters and regulatory factors control their production in fungi and bacteria, influenced by nutrients and pH.
Area of Science:
- Microbiology
- Biochemistry
- Molecular Biology
Background:
- Penicillin and cephalosporin are vital beta-lactam antibiotics used to treat infections.
- These antibiotics are produced by fungi like Aspergillus nidulans, Penicillium chrysogenum, and Acremonium chrysogenum.
- Their biosynthetic pathways share initial enzymatic steps and amino acid precursors.
Purpose of the Study:
- To elucidate the genetic organization and regulatory mechanisms governing penicillin and cephalosporin biosynthesis.
- To identify key enzymes, genes, and regulatory factors involved in these secondary metabolite pathways.
Main Methods:
- Analysis of gene clusters for penicillin biosynthesis (acvA, ipnA, aatA) and cephalosporin biosynthesis (cefEF, cefG).
- Investigation of transcriptional regulation by nutritional factors (glucose, nitrogen), amino acids (lysine, methionine), and pH.
- Identification of regulatory proteins such as PACC, PENR1, NRE, and analysis of regulatory mutations (prgA1, prgB1, npeE1, Npe2, Npe3).
Main Results:
- Penicillin biosynthesis involves three enzymes encoded by a gene cluster.
- Cephalosporin biosynthesis genes are organized into a separate cluster in Acremonium chrysogenum.
- Transcriptional regulation is complex, involving nutritional signals, pH, and identified regulatory factors like PACC, PENR1, and NRE.
- Evidence suggests the presence of both positive regulatory factors and transcriptional repressors.
Conclusions:
- The biosynthesis of penicillin and cephalosporins is tightly regulated by a complex interplay of genetic organization and environmental factors.
- Understanding these regulatory mechanisms is crucial for optimizing antibiotic production and developing novel therapeutic strategies.