The glutathione metabolism of the β-lactam producer filamentous fungus Penicillium chrysogenum

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Abstract

Glutathione (γ-L-glutamyl-L-cysteinyl-glycine; GSH) shares structural similarities with the β-lactam biosynthetic intermediate ACV-tripeptide {δ-(L-α-aminoadrpyl)-L-cysteinyl-D-valine}. Not surprisingly, GSH has been reported to inhibit the β-lactam biosynthetic machinery quite effectively and, hence, strategies to decrease the intracellular GSH concentrations without influencing negatively the physiological status of idiophasic mycelia would attract industrial interests. Here we present a detailed map of the GSH metabolic network of P. chrysogenum and show a promising way to keep the GSH pool selectively down under penicillin producing conditions. This procedure includes a well-controlled and transient lowering of pH at the beginning of the production phase, and it relies on the GSH-dependent detoxification of the protonophore penicillin side-chain precursors phenoxyacetic acid (POA) and phenylacetic acid (PA). Encouraging preliminary fed-batch fermentation experiments have been performed to test this technological proposal. Interestingly, the mechanism of the activation of POA and PA to the appropriate CoA derivatives has remained yet to be answered but the involvement of GSH seems to be rather unlikely in this case. Our data also challenge the hypothesis that the formation of different kinds of penicillins would be an alternative to GSH-dependent detoxification processes in P. chrysogenum.

Original languageEnglish
Pages (from-to)393-411
Number of pages19
JournalActa Microbiologica et Immunologica Hungarica
Volume48
Issue number3-4
DOIs
Publication statusPublished - 2001

Fingerprint

Penicillium chrysogenum
Lactams
Penicillins
Glutathione
Fungi
cysteinylglycine
Mycelium
Valine
Coenzyme A
Metabolic Networks and Pathways
Fermentation
phenylacetic acid
phenoxyacetic acid

Keywords

  • Gluthathione metabolism
  • Penicillium chrysogenum

ASJC Scopus subject areas

  • Immunology and Microbiology(all)
  • Medicine(all)
  • Microbiology

Cite this

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title = "The glutathione metabolism of the β-lactam producer filamentous fungus Penicillium chrysogenum",
abstract = "Glutathione (γ-L-glutamyl-L-cysteinyl-glycine; GSH) shares structural similarities with the β-lactam biosynthetic intermediate ACV-tripeptide {δ-(L-α-aminoadrpyl)-L-cysteinyl-D-valine}. Not surprisingly, GSH has been reported to inhibit the β-lactam biosynthetic machinery quite effectively and, hence, strategies to decrease the intracellular GSH concentrations without influencing negatively the physiological status of idiophasic mycelia would attract industrial interests. Here we present a detailed map of the GSH metabolic network of P. chrysogenum and show a promising way to keep the GSH pool selectively down under penicillin producing conditions. This procedure includes a well-controlled and transient lowering of pH at the beginning of the production phase, and it relies on the GSH-dependent detoxification of the protonophore penicillin side-chain precursors phenoxyacetic acid (POA) and phenylacetic acid (PA). Encouraging preliminary fed-batch fermentation experiments have been performed to test this technological proposal. Interestingly, the mechanism of the activation of POA and PA to the appropriate CoA derivatives has remained yet to be answered but the involvement of GSH seems to be rather unlikely in this case. Our data also challenge the hypothesis that the formation of different kinds of penicillins would be an alternative to GSH-dependent detoxification processes in P. chrysogenum.",
keywords = "Gluthathione metabolism, Penicillium chrysogenum",
author = "I. P{\'o}csi and T. Emri and L{\'a}szl{\'o} S{\'a}mi and E. Leiter and A. Szentirmai",
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T1 - The glutathione metabolism of the β-lactam producer filamentous fungus Penicillium chrysogenum

AU - Pócsi, I.

AU - Emri, T.

AU - Sámi, László

AU - Leiter, E.

AU - Szentirmai, A.

PY - 2001

Y1 - 2001

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AB - Glutathione (γ-L-glutamyl-L-cysteinyl-glycine; GSH) shares structural similarities with the β-lactam biosynthetic intermediate ACV-tripeptide {δ-(L-α-aminoadrpyl)-L-cysteinyl-D-valine}. Not surprisingly, GSH has been reported to inhibit the β-lactam biosynthetic machinery quite effectively and, hence, strategies to decrease the intracellular GSH concentrations without influencing negatively the physiological status of idiophasic mycelia would attract industrial interests. Here we present a detailed map of the GSH metabolic network of P. chrysogenum and show a promising way to keep the GSH pool selectively down under penicillin producing conditions. This procedure includes a well-controlled and transient lowering of pH at the beginning of the production phase, and it relies on the GSH-dependent detoxification of the protonophore penicillin side-chain precursors phenoxyacetic acid (POA) and phenylacetic acid (PA). Encouraging preliminary fed-batch fermentation experiments have been performed to test this technological proposal. Interestingly, the mechanism of the activation of POA and PA to the appropriate CoA derivatives has remained yet to be answered but the involvement of GSH seems to be rather unlikely in this case. Our data also challenge the hypothesis that the formation of different kinds of penicillins would be an alternative to GSH-dependent detoxification processes in P. chrysogenum.

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