Functional characterization of the penicillin biosynthetic gene cluster of Penicillium chrysogenum Wisconsin54-1255

Berg, M. A.; Westerlaken, Ilja; Leeflang, Chris; Kerkman, Richard; Bovenberg, Roel A. L.

doi:10.1016/j.fgb.2007.03.008

Cited by 54 publications

(47 citation statements)

References 57 publications

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“…Thirty-nine additional ORFs were identified in this region (Supplementary Table 5 online), including genes encoding transporters and transcriptional regulators. However, the predicted annotation of these ORFs does not suggest clear functions in penicillin biosynthesis as reported recently 21,22 .…”

Section: Penicillin Biosynthetic Genesmentioning

confidence: 66%

Genome sequencing and analysis of the filamentous fungus Penicillium chrysogenum

et al. 2008

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Section: Penicillin Biosynthetic Genesmentioning

confidence: 66%

Genome sequencing and analysis of the filamentous fungus Penicillium chrysogenum

et al. 2008

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“…Improvement of penicillin production in P. chrysogenum has been largely achieved by blind mutations that have resulted in amplification of chromosomal regions containing the pen gene cluster (10,11,48). Some external aromatic acids, such as phenylacetic acid or phenoxyacetic acid, increase production of specific penicillins (phenylacetyl-or phenoxyacetylpenicillins) by a precursor effect (21), but these aromatic acids are not autoinducers, since they are external precursors not synthesized by P. chrysogenum.…”

Section: Discussionmentioning

confidence: 99%

“…In order to confirm the effect of the inducer on the levels of the pcbC gene transcript during the growth phase, the conditioned broth was added at inoculation time (0 h), and RNA was extracted from cells taken at 24 h (the pcbC gene is a relatively early-expressed gene), 48 Conditioned broths of A. chrysogenum N2 (AC) were added (10%; not concentrated) at inoculation time to cultures of P. chrysogenum Wis 54-1255. Dry weight and penicillin production were determined at different time points.…”

Section: Development Of a Bioassay For Testing Autoinducers Of Penicimentioning

confidence: 99%

“…Penicillin is produced by several filamentous fungi, of which P. chrysogenum (26), A. nidulans (4), and Penicillium nalgiovense (20) have been studied in more detail. The three enzymes ␣-aminoadipyl-cysteinyl-valine synthetase (ACVS), isopenicillin N synthase (IPNS), and isopenicillin N acyltransferase (IAT) are encoded, respectively, by the pcbAB, pcbC, and penDE genes, which are linked together in the so-called pen cluster (10,11,48 …”

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confidence: 99%

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Characterization of an Autoinducer of Penicillin Biosynthesis in Penicillium chrysogenum

Martı́n

Garcı́a-Estrada

Rumbero

et al. 2011

Appl Environ Microbiol

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Filamentous fungi produce an impressive variety of secondary metabolites; many of them have important biological activities. The biosynthesis of these secondary metabolites is frequently induced by plant-derived external elicitors and appears to also be regulated by internal inducers, which may work in a way similar to that of bacterial autoinducers. The biosynthesis of penicillin in Penicillium chrysogenum is an excellent model for studying the molecular mechanisms of control of gene expression due to a good knowledge of the biochemistry and molecular genetics of ␤-lactam antibiotics and to the availability of its genome sequence and proteome. In this work, we first developed a plate bioassay that allows direct testing of inducers of penicillin biosynthesis using single colonies of P. chrysogenum. Using this bioassay, we have found an inducer substance in the conditioned culture broths of P. chrysogenum and Acremonium chrysogenum. No inducing effect was exerted by ␥-butyrolactones, jasmonic acid, or the penicillin precursor ␦-(L-␣-aminoadipyl)-L-cysteinyl-Dvaline. The conditioned broth induced penicillin biosynthesis and transcription of the pcbAB, pcbC, and penDE genes when added at inoculation time, but its effect was smaller if added at 12 h and it had no effect when added at 24 h, as shown by Northern analysis and lacZ reporter studies. The inducer molecule was purified and identified by mass spectrometry (MS) and nuclear magnetic resonance (NMR) as 1,3-diaminopropane. Addition of pure 1,3-diaminopropane stimulated the production of penicillin by about 100% compared to results for the control cultures. Genes for the biosynthesis of 1,3-diaminopropane have been identified in the P. chrysogenum genome.Filamentous fungi, particularly ascomycetes and basidiomycetes, are well-known producers of hundreds of bioactive secondary metabolites (40). The recent sequencing of the genomes of Aspergillus niger (28), Aspergillus nidulans (12, 50), Aspergillus oryzae (25), Penicillium chrysogenum (49), and the basidiomycete Pleurotus ostreatus (G. Pisabarro, personal communication) has provided evidence about the presence in their genomes of numerous gene clusters encoding nonribosomal peptide synthetases (NRPS), polyketide synthases (PKS), hybrid polyketide-nonribosomal peptide synthetases (HPS), isoprenoid synthetases, and other nonconventional antibiotic-synthesizing enzymes. Genome mining is a powerful tool for discovering new bioactive natural products (38).Penicillin biosynthesis in P. chrysogenum is an excellent model for understanding how those complex molecules are synthesized and how the cell controls their production, because its biochemistry and molecular genetics are very well known (26). Penicillin is produced by several filamentous fungi, of which P. chrysogenum (26), A. nidulans (4), and Penicillium nalgiovense (20) have been studied in more detail. The three enzymes ␣-aminoadipyl-cysteinyl-valine synthetase (ACVS), isopenicillin N synthase (IPNS), and isopenicillin N acyltransferase (IAT) are encoded, respe...

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“…Since then, conventional mutagenesis programs have been used to develop strains with elevated penicillin titers. All P. chrysogenum production strains currently used worldwide are derivatives of NRRL1951 and show amplification of the genomic region encoding penicillin biosynthesis genes (5). Recent phylogenetic analyses have revealed that P. chrysogenum sensu lato is composed of at least two distinct species, Penicillium rubens and P. chrysogenum sensu stricto, with Fleming's strain and NRRL1951 reidentified as P. rubens (6, 7).…”

mentioning

confidence: 99%

Sexual reproduction and mating-type–mediated strain development in the penicillin-producing fungus Penicillium chrysogenum

Böhm

Hoff

O’Gorman

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

119

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Penicillium chrysogenum is a filamentous fungus of major medical and historical importance, being the original and present-day industrial source of the antibiotic penicillin. The species has been considered asexual for more than 100 y, and despite concerted efforts, it has not been possible to induce sexual reproduction, which has prevented sexual crosses being used for strain improvement. However, using knowledge of mating-type (MAT) gene organization, we now describe conditions under which a sexual cycle can be induced leading to production of meiotic ascospores. Evidence of recombination was obtained using both molecular and phenotypic markers. The identified heterothallic sexual cycle was used for strain development purposes, generating offspring with novel combinations of traits relevant to penicillin production. Furthermore, the MAT1-1-1 mating-type gene, known primarily for a role in governing sexual identity, was also found to control transcription of a wide range of genes with biotechnological relevance including those regulating penicillin production, hyphal morphology, and conidial formation. These discoveries of a sexual cycle and MAT gene function are likely to be of broad relevance for manipulation of other asexual fungi of economic importance.sexual recombination | secondary metabolism | ascomycete

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Functional characterization of the penicillin biosynthetic gene cluster of Penicillium chrysogenum Wisconsin54-1255

Cited by 54 publications

References 57 publications

Genome sequencing and analysis of the filamentous fungus Penicillium chrysogenum

Genome sequencing and analysis of the filamentous fungus Penicillium chrysogenum

Characterization of an Autoinducer of Penicillin Biosynthesis in Penicillium chrysogenum

Sexual reproduction and mating-type–mediated strain development in the penicillin-producing fungus Penicillium chrysogenum

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