Analysis of the regulation of penicillin biosynthesis in Aspergillus nidulans by targeted disruption of the acvA gene

Brakhage, Axel A.; Browne, P; Turner, Geoffrey

doi:10.1007/bf00277348

Cited by 20 publications

(11 citation statements)

References 38 publications

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“…This strain had a disrupted acvA gene on chromosome VI and, in addition, reporter gene fusions of the penicillin biosynthesis genes integrated in single copy at the chromosomal argB gene locus on chromosome III. acvA, ipnA, and aatA gene fusions were expressed at the same level in this strain as in the nondisrupted strain (47,194). This was confirmed by determining IPNS and IAT specific activities and by Western blot analysis of IPNS, which showed the presence of both enzymes in an acvA-disrupted strain (47,194).…”

Section: Expression Of Biosynthesis Genes Under Standard Fermentationsupporting

confidence: 59%

“…To further study these observations, acvA was disrupted in a strain of A. nidulans (47,305). This strain had a disrupted acvA gene on chromosome VI and, in addition, reporter gene fusions of the penicillin biosynthesis genes integrated in single copy at the chromosomal argB gene locus on chromosome III.…”

Section: Expression Of Biosynthesis Genes Under Standard Fermentationmentioning

confidence: 99%

“…acvA, ipnA, and aatA gene fusions were expressed at the same level in this strain as in the nondisrupted strain (47,194). This was confirmed by determining IPNS and IAT specific activities and by Western blot analysis of IPNS, which showed the presence of both enzymes in an acvA-disrupted strain (47,194). Hence, the genes were expressed despite the lack of precursor ACV and IPN molecules, indicating that in contrast to the cephalosporin biosynthesis genes, none of the penicillin biosynthesis genes are sequentially induced and their expression is most probably coordinated.…”

Section: Expression Of Biosynthesis Genes Under Standard Fermentationmentioning

confidence: 99%

“…Discrepancies observed between the expression of structural genes and enzyme specific activities of the corresponding proteins suggested that besides transcriptional regulation, posttranscriptional regulation of penicillin biosynthesis genes occurs (47,194,346).…”

Section: Posttranscriptional Regulationmentioning

confidence: 99%

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Molecular Regulation of β-Lactam Biosynthesis in Filamentous Fungi

Brakhage¹

1998

Microbiol Mol Biol Rev

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211

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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.

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Section: Expression Of Biosynthesis Genes Under Standard Fermentationsupporting

confidence: 59%

Section: Expression Of Biosynthesis Genes Under Standard Fermentationmentioning

confidence: 99%

Section: Expression Of Biosynthesis Genes Under Standard Fermentationmentioning

confidence: 99%

Section: Posttranscriptional Regulationmentioning

confidence: 99%

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Molecular Regulation of β-Lactam Biosynthesis in Filamentous Fungi

Brakhage¹

1998

Microbiol Mol Biol Rev

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211

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“…To study this assumption, acvA was disrupted in a strain of A. nidulans [8]. In such a strain, i.e., the acvA gene on chromosome VI was disrupted and in addition, gene fusions were integrated in single copy at the chromosomal argB gene locus on chromosome III, acvA , ipnA and aat gene fusions were expressed at the same level as in the non‐disrupted strain [16, 19]. This was confirmed by determining the IPNS‐ and AAT‐specific activities and by Western blot analysis of IPNS which showed the presence of both enzymes in an acvA disrupted strain [16, 19].…”

Section: Expression Of Penicillin Biosynthesis Genes and Regulatory mentioning

confidence: 92%

Molecular regulation of penicillin biosynthesis in Aspergillus (Emericella) nidulans

Brakhage

2006

FEMS Microbiology Letters

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The beta-lactam antibiotic penicillin is produced as end product by only some filamentous fungi, most notably by Aspergillus nidulans and Penicillium chrysogenum. The biosynthesis of this secondary metabolite is catalyzed by three enzymes which are encoded by the following three genes: acvA (pcbAB), ipnA (pcbC) and aat (penDE). The genes are organized into a gene cluster. In A. nidulans, several studies have indicated that the genes are controlled by a complex regulatory network. The wide-domain regulatory protein PACC binds to the intergenic region between acvA and ipnA and, at alkaline pH, increases at least ipnA gene transcription. An additional DNA binding protein (PENR1) was suggested to repress acvA and to activate ipnA and aat expression. Furthermore, three recessive trans-acting mutations have been characterized (prgA1, prgB1, npeE1) which most likely correspond to positively acting regulatory genes of the penicillin biosynthesis genes.

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From Gene to Product: The Advantage of Integrative Biotechnology

Schmidt

2006

Handbook of Pharmaceutical Biotechnology

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PRODUCTION ORGANISMS AND EXPRESSION SYSTEMSDesign and development of all microbial production processes start with the selection of appropriate organisms, strains, and expression systems enabling high yields and high quality of a desired product with defi ned pharmacological properties. Industrially Established Recombinant Expression SystemsIndustrially established expressions systems for production of the marketed compounds are, besides inclusion, body-forming Escherichia coli strains, the yeast Saccharomyces cerevisiae and mammalian cells like CHO-and BHK-cells (Table 1.1-1). These systems were the genetically and physiologically most advanced and therefore mostly applied when recombinant production processes were starting to be developed in the mid-1980s and are now widely accepted by regulatory bodies. E. coli and S. cerevisiae can be grown cheaply and rapidly, are amenable to high cell density fermentations with biomasses of up to 130 g/L, possess short generation times, have high capacities to accumulate foreign proteins, are easy to handle, and are established fermentation organisms.However, because gene recombinant pharmaceuticals continuously gain an increasing importance in medicine and are expected to help curing diseases that are not yet treatable today, new expression systems have to be exploited enabling the production of such pharmaceuticals with innovative properties that simultaneously meet key criteria like consistent product quality and cost effectiveness. Of particular interest in this regard are expression systems enabling the secretion of TABLE 1.1-1. Industrially Used Recombinant Expression Systems

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Analysis of the regulation of penicillin biosynthesis in Aspergillus nidulans by targeted disruption of the acvA gene

Cited by 20 publications

References 38 publications

Molecular Regulation of β-Lactam Biosynthesis in Filamentous Fungi

Molecular Regulation of β-Lactam Biosynthesis in Filamentous Fungi

Molecular regulation of penicillin biosynthesis in Aspergillus (Emericella) nidulans

From Gene to Product: The Advantage of Integrative Biotechnology

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