Transport of neutral amino acids and penicillin formation in Penicillium chrysogenum

Mateos, Rosa del Carmen; Sánchez, Sergio

doi:10.1099/00221287-136-9-1713

Cited by 7 publications

(5 citation statements)

References 10 publications

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“…It is tempting to speculate, however, that under certain physiological conditions an increase of acvA expression and a simultaneous reduction in the expression of ipnA and aatA could lead to larger cellular amounts of ACV. The tripeptide could have, apart from being the precursor of ␤-lactams, additional functions, e.g., in amino acid transport, as suggested by Del Carmen Mateos and Sanchez (83). ACV is structurally very similar to glutathione (GSH), consisting of the tripeptide ␥-(L-glutamyl)-L-cysteinyl-glycine.…”

Section: The Ccaat Box Binding Protein Complex Penr1mentioning

confidence: 99%

“…In higher eukaryotes, GSH is a part of the ␥-glutamyl cycle, which, among other functions, serves to transport extracellular amino acids across the plasma membrane (228). Experiments with resting cells of P. chrysogenum implied that the ACV tripeptide might be important for the uptake of glutamine from the medium (83). Consistent with this hypothesis is the observation that early during a fermentation run, both ACV tripeptide and the ␦-lactam OPC (cyclized L-␣-AAA) are found in the fermentation broth (52,159).…”

Section: The Ccaat Box Binding Protein Complex Penr1mentioning

confidence: 99%

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Molecular Regulation of β-Lactam Biosynthesis in Filamentous Fungi

Brakhage¹

1998

Microbiol Mol Biol Rev

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: The Ccaat Box Binding Protein Complex Penr1mentioning

confidence: 99%

Section: The Ccaat Box Binding Protein Complex Penr1mentioning

confidence: 99%

Molecular Regulation of β-Lactam Biosynthesis in Filamentous Fungi

Brakhage¹

1998

Microbiol Mol Biol Rev

211

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“…The tripeptide could have, apart from being the precursor of p-lactams, additional functions, e.g. in amino acid transport, as suggested by Del Carmen Mateos and Sanchez (1990). However, it has to be emphasised that at the present stage, this is a hypothesis which can only be verified by cloning and knocking out of the penRI structural gene(s).…”

Section: Discussionmentioning

confidence: 92%

The Aspergillus nidulans Penicillin‐Biosynthesis Gene aat (penDE) is Controlled by a CCAAT‐Containing DNA Element

Litzka¹,

Bergh²,

Brakhage³

1996

European Journal of Biochemistry

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Analysis of the promoter of the penicillin biosynthesis nut (penDE) gene of Aspergillus niduluns using band-shift assays led to the identification of a CCAAT-containing DNA element which was specifically bound by a protein (complex). The identified DNA element was localised about 250 bp upstream of the transcriptional-start sites of uat: Substitution of the CCAAT core sequence by GATCC led to a fourfold reduction of expression of an aat-1acZ gene fusion. The identified binding site thus was functional in vivo and positively influenced aat expression. Partial purification of the CCAAT binding protein and cross-competition experiments provided evidence that the binding protein is identical to the identified putative penicillin-regulatory protein PENRl , binding to the CCAAT element in the bidirectional intergenic promoter region between acvA (pcbAb) and ipnA (pcbC). Hence, PENRI seems to be involved in the regulation of all three penicillin-biosynthesis genes. Cross-competition experiments demonstrated that the promoter region of the corresponding aat (penDE) gene of Penicillium chrysogenum was capable to dilute the shift of the A. nidulans probe with PENRI, suggesting the presence of a similar regulatory mechanism in this fungus. Taken together with previous data, CCAAT-containing DNA elements thus seem to represent major cis-acting sites in the promoters of p-lactam-biosynthesis genes.Keywords: Aspergillus nidulans ; penicillin biosynthesis ; gene-regulatory protein ; CCAAT-binding protein; secondary metabolism.Aspergillus (Emericella) nidulans and Penicillium chrysogenum are filamentous fungi well known for their ability to produce the secondary metabolite penicillin. The entire biosynthesis pathway is catalysed by the three enzymes d+a-aminoadipyl)-L-cysteinyl-D-valine synthetase, isopenicillin N synthase and acyl-coenzyme A:isopenicillin N-acyltransferase (IAT), encoded by the genes acvA (JchAB), ipnA (pcbC) and aat (penDE) respectively. The genes are organised into a gene cluster and expressed from gene-specific promoters (Fig. 1, Fig. 6; Litzka et al., 1995 and reviewed in Demain, 1983;Kleinkauf and von Dohren, 1990;Queener, 1990;Skatrud, 1991 ;Aharonowitz et al., 1992;Brakhage and Turner, 1995). Because penicillin biosynthesis is one of the best studied secondary-metabolite-biosynthetic pathways in fungi, it represents an advanced model system to study regulation of secondary-metabolite biosynthesis in this class of organisms. In recent years, it has become evident that at the molecular level, regulation of penicillin biosynthesis is complex. Several protein factors seem to be involved (Brakhage and Van den Brulle, 1995;Chu et al., 1995;Feng et al., 1995;Haas and Marzluf, 1995; P6rez-Esteban et al., 1995;Tilburn et al., 1995;Then Bergh et al., 1996).For the studies presented here, A. nidu1an.s was used because this fungus has, in contrast to the deuteromycete P chrysogenum which is employed for industrial production of penicillin, a welldefined sexual cycle facilitating genetic analyses (MacDonald and Hol...

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“…The tripeptide could have additional functions, apart from being the precursor of β‐lactams, e.g. in amino acid transport, as suggested by Del Carmen Mateos and Sanchez [34]. Under certain physiological conditions it might thus be advantageous for the fungus to produce first the tripeptide, and, when upon binding of PENR1 acvA expression is reduced and simultaneously that of ipnA and aat increased, to channel the tripeptide to penicillin.…”

Section: Dna Binding Proteins and Regulatory Genesmentioning

confidence: 98%

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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Transport of neutral amino acids and penicillin formation in Penicillium chrysogenum

Cited by 7 publications

References 10 publications

Molecular Regulation of β-Lactam Biosynthesis in Filamentous Fungi

Molecular Regulation of β-Lactam Biosynthesis in Filamentous Fungi

The Aspergillus nidulans Penicillin‐Biosynthesis Gene aat (penDE) is Controlled by a CCAAT‐Containing DNA Element

Molecular regulation of penicillin biosynthesis in Aspergillus (Emericella) nidulans

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