Publication

Degeneration of penicillin production in ethanol-limited chemostat cultivations of Penicillium chrysogenum: A systems biology approach

Douma, R. D., Batista, J. M., Touw, K. M., Kiel, J. A. K. W., Zhao, Z., Veiga, T., Klaassen, P., Bovenberg, R. A. L., Daran, J-M., van Gulik, W. M., Heijnen, J. J. & Krikken, A., 19-Aug-2011, In : BMC Systems Biology. 5, 16 p., 132.

Research output: Contribution to journalArticleAcademicpeer-review

APA

Douma, R. D., Batista, J. M., Touw, K. M., Kiel, J. A. K. W., Zhao, Z., Veiga, T., Klaassen, P., Bovenberg, R. A. L., Daran, J-M., van Gulik, W. M., Heijnen, J. J., & Krikken, A. (2011). Degeneration of penicillin production in ethanol-limited chemostat cultivations of Penicillium chrysogenum: A systems biology approach. BMC Systems Biology, 5, [132]. https://doi.org/10.1186/1752-0509-5-132

Author

Douma, Rutger D. ; Batista, Joana M. ; Touw, Kai M. ; Kiel, Jan A. K. W. ; Zhao, Zheng ; Veiga, Tania ; Klaassen, Paul ; Bovenberg, Roel A. L. ; Daran, Jean-Marc ; van Gulik, Walter M. ; Heijnen, J.J. ; Krikken, Arjen. / Degeneration of penicillin production in ethanol-limited chemostat cultivations of Penicillium chrysogenum : A systems biology approach. In: BMC Systems Biology. 2011 ; Vol. 5.

Harvard

Douma, RD, Batista, JM, Touw, KM, Kiel, JAKW, Zhao, Z, Veiga, T, Klaassen, P, Bovenberg, RAL, Daran, J-M, van Gulik, WM, Heijnen, JJ & Krikken, A 2011, 'Degeneration of penicillin production in ethanol-limited chemostat cultivations of Penicillium chrysogenum: A systems biology approach', BMC Systems Biology, vol. 5, 132. https://doi.org/10.1186/1752-0509-5-132

Standard

Degeneration of penicillin production in ethanol-limited chemostat cultivations of Penicillium chrysogenum : A systems biology approach. / Douma, Rutger D.; Batista, Joana M.; Touw, Kai M.; Kiel, Jan A. K. W.; Zhao, Zheng; Veiga, Tania; Klaassen, Paul; Bovenberg, Roel A. L.; Daran, Jean-Marc; van Gulik, Walter M.; Heijnen, J.J.; Krikken, Arjen.

In: BMC Systems Biology, Vol. 5, 132, 19.08.2011.

Research output: Contribution to journalArticleAcademicpeer-review

Vancouver

Douma RD, Batista JM, Touw KM, Kiel JAKW, Zhao Z, Veiga T et al. Degeneration of penicillin production in ethanol-limited chemostat cultivations of Penicillium chrysogenum: A systems biology approach. BMC Systems Biology. 2011 Aug 19;5. 132. https://doi.org/10.1186/1752-0509-5-132


BibTeX

@article{d65b3f3d6e1a4ba9a62e35cc333f2f3b,
title = "Degeneration of penicillin production in ethanol-limited chemostat cultivations of Penicillium chrysogenum: A systems biology approach",
abstract = "Background: In microbial production of non-catabolic products such as antibiotics a loss of production capacity upon long-term cultivation (for example chemostat), a phenomenon called strain degeneration, is often observed. In this study a systems biology approach, monitoring changes from gene to produced flux, was used to study degeneration of penicillin production in a high producing Penicillium chrysogenum strain during prolonged ethanol-limited chemostat cultivations.Results: During these cultivations, the biomass specific penicillin production rate decreased more than 10-fold in less than 22 generations. No evidence was obtained for a decrease of the copy number of the penicillin gene cluster, nor a significant down regulation of the expression of the penicillin biosynthesis genes. However, a strong down regulation of the biosynthesis pathway of cysteine, one of the precursors of penicillin, was observed. Furthermore the protein levels of the penicillin pathway enzymes L-alpha-(d-aminoadipyl)-L-alpha-cystenyl-D-alpha-valine synthetase (ACVS) and isopenicillin-N synthase (IPNS), decreased significantly. Re-cultivation of fully degenerated cells in unlimited batch culture and subsequent C-limited chemostats did only result in a slight recovery of penicillin production.Conclusions: Our findings indicate that the observed degeneration is attributed to a significant decrease of the levels of the first two enzymes of the penicillin biosynthesis pathway, ACVS and IPNS. This decrease is not caused by genetic instability of the penicillin amplicon, neither by down regulation of the penicillin biosynthesis pathway. Furthermore no indications were obtained for degradation of these enzymes as a result of autophagy. Possible causes for the decreased enzyme levels could be a decrease of the translation efficiency of ACVS and IPNS during degeneration, or the presence of a culture variant impaired in the biosynthesis of functional proteins of these enzymes, which outcompeted the high producing part of the population.",
keywords = "SACCHAROMYCES-CEREVISIAE, GENE-EXPRESSION, NADPH METABOLISM, STEADY-STATE, BIOSYNTHESIS, STRAIN, GLUCOSE, GROWTH, AMPLIFICATION, PROTEIN",
author = "Douma, {Rutger D.} and Batista, {Joana M.} and Touw, {Kai M.} and Kiel, {Jan A. K. W.} and Zheng Zhao and Tania Veiga and Paul Klaassen and Bovenberg, {Roel A. L.} and Jean-Marc Daran and {van Gulik}, {Walter M.} and J.J. Heijnen and Arjen Krikken",
year = "2011",
month = aug,
day = "19",
doi = "10.1186/1752-0509-5-132",
language = "English",
volume = "5",
journal = "BMC Systems Biology",
issn = "1752-0509",
publisher = "BMC",

}

RIS

TY - JOUR

T1 - Degeneration of penicillin production in ethanol-limited chemostat cultivations of Penicillium chrysogenum

T2 - A systems biology approach

AU - Douma, Rutger D.

AU - Batista, Joana M.

AU - Touw, Kai M.

AU - Kiel, Jan A. K. W.

AU - Zhao, Zheng

AU - Veiga, Tania

AU - Klaassen, Paul

AU - Bovenberg, Roel A. L.

AU - Daran, Jean-Marc

AU - van Gulik, Walter M.

AU - Heijnen, J.J.

AU - Krikken, Arjen

PY - 2011/8/19

Y1 - 2011/8/19

N2 - Background: In microbial production of non-catabolic products such as antibiotics a loss of production capacity upon long-term cultivation (for example chemostat), a phenomenon called strain degeneration, is often observed. In this study a systems biology approach, monitoring changes from gene to produced flux, was used to study degeneration of penicillin production in a high producing Penicillium chrysogenum strain during prolonged ethanol-limited chemostat cultivations.Results: During these cultivations, the biomass specific penicillin production rate decreased more than 10-fold in less than 22 generations. No evidence was obtained for a decrease of the copy number of the penicillin gene cluster, nor a significant down regulation of the expression of the penicillin biosynthesis genes. However, a strong down regulation of the biosynthesis pathway of cysteine, one of the precursors of penicillin, was observed. Furthermore the protein levels of the penicillin pathway enzymes L-alpha-(d-aminoadipyl)-L-alpha-cystenyl-D-alpha-valine synthetase (ACVS) and isopenicillin-N synthase (IPNS), decreased significantly. Re-cultivation of fully degenerated cells in unlimited batch culture and subsequent C-limited chemostats did only result in a slight recovery of penicillin production.Conclusions: Our findings indicate that the observed degeneration is attributed to a significant decrease of the levels of the first two enzymes of the penicillin biosynthesis pathway, ACVS and IPNS. This decrease is not caused by genetic instability of the penicillin amplicon, neither by down regulation of the penicillin biosynthesis pathway. Furthermore no indications were obtained for degradation of these enzymes as a result of autophagy. Possible causes for the decreased enzyme levels could be a decrease of the translation efficiency of ACVS and IPNS during degeneration, or the presence of a culture variant impaired in the biosynthesis of functional proteins of these enzymes, which outcompeted the high producing part of the population.

AB - Background: In microbial production of non-catabolic products such as antibiotics a loss of production capacity upon long-term cultivation (for example chemostat), a phenomenon called strain degeneration, is often observed. In this study a systems biology approach, monitoring changes from gene to produced flux, was used to study degeneration of penicillin production in a high producing Penicillium chrysogenum strain during prolonged ethanol-limited chemostat cultivations.Results: During these cultivations, the biomass specific penicillin production rate decreased more than 10-fold in less than 22 generations. No evidence was obtained for a decrease of the copy number of the penicillin gene cluster, nor a significant down regulation of the expression of the penicillin biosynthesis genes. However, a strong down regulation of the biosynthesis pathway of cysteine, one of the precursors of penicillin, was observed. Furthermore the protein levels of the penicillin pathway enzymes L-alpha-(d-aminoadipyl)-L-alpha-cystenyl-D-alpha-valine synthetase (ACVS) and isopenicillin-N synthase (IPNS), decreased significantly. Re-cultivation of fully degenerated cells in unlimited batch culture and subsequent C-limited chemostats did only result in a slight recovery of penicillin production.Conclusions: Our findings indicate that the observed degeneration is attributed to a significant decrease of the levels of the first two enzymes of the penicillin biosynthesis pathway, ACVS and IPNS. This decrease is not caused by genetic instability of the penicillin amplicon, neither by down regulation of the penicillin biosynthesis pathway. Furthermore no indications were obtained for degradation of these enzymes as a result of autophagy. Possible causes for the decreased enzyme levels could be a decrease of the translation efficiency of ACVS and IPNS during degeneration, or the presence of a culture variant impaired in the biosynthesis of functional proteins of these enzymes, which outcompeted the high producing part of the population.

KW - SACCHAROMYCES-CEREVISIAE

KW - GENE-EXPRESSION

KW - NADPH METABOLISM

KW - STEADY-STATE

KW - BIOSYNTHESIS

KW - STRAIN

KW - GLUCOSE

KW - GROWTH

KW - AMPLIFICATION

KW - PROTEIN

U2 - 10.1186/1752-0509-5-132

DO - 10.1186/1752-0509-5-132

M3 - Article

C2 - 21854586

VL - 5

JO - BMC Systems Biology

JF - BMC Systems Biology

SN - 1752-0509

M1 - 132

ER -

ID: 5412767