Substrate cycles in Penicillium chrysogenum quantified by isotopic non-stationary flux analysis

Background Penicillium chrysogenum, the main production strain for penicillin-G, has a high content of intracellular carbohydrates, especially reduced sugars such as mannitol, arabitol, erythritol, as well as trehalose and glycogen. In previous steady state 13C wash-in experiments a delay of labelin...
Ausführliche Beschreibung

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Autor*in:	Zhao, Zheng [verfasserIn] ten Pierick, Angela de Jonge, Lodewijk Heijnen, Joseph J Wahl, S Aljoscha

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2012

Schlagwörter:	Trehalose Metabolic Model Flux Analysis Metabolic Flux Analysis Central Carbon Metabolism

Anmerkung:	© Zhao et al.; licensee BioMed Central Ltd. 2012. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (

Übergeordnetes Werk:	Enthalten in: Microbial cell factories - London : Biomed Central, 2002, 11(2012), 1 vom: 25. Okt.
Übergeordnetes Werk:	volume:11 ; year:2012 ; number:1 ; day:25 ; month:10

Links:	Volltext

DOI / URN:	10.1186/1475-2859-11-140

Katalog-ID:	SPR028561961

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520			\|a Background Penicillium chrysogenum, the main production strain for penicillin-G, has a high content of intracellular carbohydrates, especially reduced sugars such as mannitol, arabitol, erythritol, as well as trehalose and glycogen. In previous steady state 13C wash-in experiments a delay of labeling enrichments in glycolytic intermediates was observed, which suggests turnover of storage carbohydrates. The turnover of storage pools consumes ATP which is expected to reduce the product yield for energy demanding production pathways like penicillin-G. Results In this study, a 13C labeling wash-in experiment of 1 hour was performed to systematically quantify the intracellular flux distribution including eight substrate cycles. The experiments were performed using a mixed carbon source of 85% $ Cmol_{Glc} $/$ Cmol_{Glc+EtOH} $ labeled glucose (mixture of 90% [1-13$ C_{1} $] and 10% [U-13$ C_{6} $]) and 15% ethanol [U-13$ C_{2} $]. It was found, that (1) also several extracellular pools are enriched with 13C labeling rapidly (trehalose, mannitol, and others), (2) the intra- to extracellular metabolite concentration ratios were comparable for a large set of metabolites while for some carbohydrates (mannitol, trehalose, and glucose) the measured ratios were much higher. Conclusions The fast enrichment of several extracellular carbohydrates and a concentration ratio higher than the ratio expected from cell lysis (2%) indicate active (e.g. ATP consuming) transport cycles over the cellular membrane. The flux estimation indicates, that substrate cycles account for about 52% of the gap in the ATP balance based on metabolic flux analysis.
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allfields	10.1186/1475-2859-11-140 doi (DE-627)SPR028561961 (SPR)1475-2859-11-140-e DE-627 ger DE-627 rakwb eng Zhao, Zheng verfasserin aut Substrate cycles in Penicillium chrysogenum quantified by isotopic non-stationary flux analysis 2012 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Zhao et al.; licensee BioMed Central Ltd. 2012. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( Background Penicillium chrysogenum, the main production strain for penicillin-G, has a high content of intracellular carbohydrates, especially reduced sugars such as mannitol, arabitol, erythritol, as well as trehalose and glycogen. In previous steady state 13C wash-in experiments a delay of labeling enrichments in glycolytic intermediates was observed, which suggests turnover of storage carbohydrates. The turnover of storage pools consumes ATP which is expected to reduce the product yield for energy demanding production pathways like penicillin-G. Results In this study, a 13C labeling wash-in experiment of 1 hour was performed to systematically quantify the intracellular flux distribution including eight substrate cycles. The experiments were performed using a mixed carbon source of 85% $ Cmol_{Glc} $/$ Cmol_{Glc+EtOH} $ labeled glucose (mixture of 90% [1-13$ C_{1} $] and 10% [U-13$ C_{6} $]) and 15% ethanol [U-13$ C_{2} $]. It was found, that (1) also several extracellular pools are enriched with 13C labeling rapidly (trehalose, mannitol, and others), (2) the intra- to extracellular metabolite concentration ratios were comparable for a large set of metabolites while for some carbohydrates (mannitol, trehalose, and glucose) the measured ratios were much higher. Conclusions The fast enrichment of several extracellular carbohydrates and a concentration ratio higher than the ratio expected from cell lysis (2%) indicate active (e.g. ATP consuming) transport cycles over the cellular membrane. The flux estimation indicates, that substrate cycles account for about 52% of the gap in the ATP balance based on metabolic flux analysis. Trehalose (dpeaa)DE-He213 Metabolic Model (dpeaa)DE-He213 Flux Analysis (dpeaa)DE-He213 Metabolic Flux Analysis (dpeaa)DE-He213 Central Carbon Metabolism (dpeaa)DE-He213 ten Pierick, Angela aut de Jonge, Lodewijk aut Heijnen, Joseph J aut Wahl, S Aljoscha aut Enthalten in Microbial cell factories London : Biomed Central, 2002 11(2012), 1 vom: 25. Okt. (DE-627)355987651 (DE-600)2091377-1 1475-2859 nnns volume:11 year:2012 number:1 day:25 month:10 https://dx.doi.org/10.1186/1475-2859-11-140 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2012 1 25 10
spelling	10.1186/1475-2859-11-140 doi (DE-627)SPR028561961 (SPR)1475-2859-11-140-e DE-627 ger DE-627 rakwb eng Zhao, Zheng verfasserin aut Substrate cycles in Penicillium chrysogenum quantified by isotopic non-stationary flux analysis 2012 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Zhao et al.; licensee BioMed Central Ltd. 2012. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( Background Penicillium chrysogenum, the main production strain for penicillin-G, has a high content of intracellular carbohydrates, especially reduced sugars such as mannitol, arabitol, erythritol, as well as trehalose and glycogen. In previous steady state 13C wash-in experiments a delay of labeling enrichments in glycolytic intermediates was observed, which suggests turnover of storage carbohydrates. The turnover of storage pools consumes ATP which is expected to reduce the product yield for energy demanding production pathways like penicillin-G. Results In this study, a 13C labeling wash-in experiment of 1 hour was performed to systematically quantify the intracellular flux distribution including eight substrate cycles. The experiments were performed using a mixed carbon source of 85% $ Cmol_{Glc} $/$ Cmol_{Glc+EtOH} $ labeled glucose (mixture of 90% [1-13$ C_{1} $] and 10% [U-13$ C_{6} $]) and 15% ethanol [U-13$ C_{2} $]. It was found, that (1) also several extracellular pools are enriched with 13C labeling rapidly (trehalose, mannitol, and others), (2) the intra- to extracellular metabolite concentration ratios were comparable for a large set of metabolites while for some carbohydrates (mannitol, trehalose, and glucose) the measured ratios were much higher. Conclusions The fast enrichment of several extracellular carbohydrates and a concentration ratio higher than the ratio expected from cell lysis (2%) indicate active (e.g. ATP consuming) transport cycles over the cellular membrane. The flux estimation indicates, that substrate cycles account for about 52% of the gap in the ATP balance based on metabolic flux analysis. Trehalose (dpeaa)DE-He213 Metabolic Model (dpeaa)DE-He213 Flux Analysis (dpeaa)DE-He213 Metabolic Flux Analysis (dpeaa)DE-He213 Central Carbon Metabolism (dpeaa)DE-He213 ten Pierick, Angela aut de Jonge, Lodewijk aut Heijnen, Joseph J aut Wahl, S Aljoscha aut Enthalten in Microbial cell factories London : Biomed Central, 2002 11(2012), 1 vom: 25. Okt. (DE-627)355987651 (DE-600)2091377-1 1475-2859 nnns volume:11 year:2012 number:1 day:25 month:10 https://dx.doi.org/10.1186/1475-2859-11-140 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2012 1 25 10
allfields_unstemmed	10.1186/1475-2859-11-140 doi (DE-627)SPR028561961 (SPR)1475-2859-11-140-e DE-627 ger DE-627 rakwb eng Zhao, Zheng verfasserin aut Substrate cycles in Penicillium chrysogenum quantified by isotopic non-stationary flux analysis 2012 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Zhao et al.; licensee BioMed Central Ltd. 2012. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( Background Penicillium chrysogenum, the main production strain for penicillin-G, has a high content of intracellular carbohydrates, especially reduced sugars such as mannitol, arabitol, erythritol, as well as trehalose and glycogen. In previous steady state 13C wash-in experiments a delay of labeling enrichments in glycolytic intermediates was observed, which suggests turnover of storage carbohydrates. The turnover of storage pools consumes ATP which is expected to reduce the product yield for energy demanding production pathways like penicillin-G. Results In this study, a 13C labeling wash-in experiment of 1 hour was performed to systematically quantify the intracellular flux distribution including eight substrate cycles. The experiments were performed using a mixed carbon source of 85% $ Cmol_{Glc} $/$ Cmol_{Glc+EtOH} $ labeled glucose (mixture of 90% [1-13$ C_{1} $] and 10% [U-13$ C_{6} $]) and 15% ethanol [U-13$ C_{2} $]. It was found, that (1) also several extracellular pools are enriched with 13C labeling rapidly (trehalose, mannitol, and others), (2) the intra- to extracellular metabolite concentration ratios were comparable for a large set of metabolites while for some carbohydrates (mannitol, trehalose, and glucose) the measured ratios were much higher. Conclusions The fast enrichment of several extracellular carbohydrates and a concentration ratio higher than the ratio expected from cell lysis (2%) indicate active (e.g. ATP consuming) transport cycles over the cellular membrane. The flux estimation indicates, that substrate cycles account for about 52% of the gap in the ATP balance based on metabolic flux analysis. Trehalose (dpeaa)DE-He213 Metabolic Model (dpeaa)DE-He213 Flux Analysis (dpeaa)DE-He213 Metabolic Flux Analysis (dpeaa)DE-He213 Central Carbon Metabolism (dpeaa)DE-He213 ten Pierick, Angela aut de Jonge, Lodewijk aut Heijnen, Joseph J aut Wahl, S Aljoscha aut Enthalten in Microbial cell factories London : Biomed Central, 2002 11(2012), 1 vom: 25. Okt. (DE-627)355987651 (DE-600)2091377-1 1475-2859 nnns volume:11 year:2012 number:1 day:25 month:10 https://dx.doi.org/10.1186/1475-2859-11-140 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2012 1 25 10
allfieldsGer	10.1186/1475-2859-11-140 doi (DE-627)SPR028561961 (SPR)1475-2859-11-140-e DE-627 ger DE-627 rakwb eng Zhao, Zheng verfasserin aut Substrate cycles in Penicillium chrysogenum quantified by isotopic non-stationary flux analysis 2012 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Zhao et al.; licensee BioMed Central Ltd. 2012. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( Background Penicillium chrysogenum, the main production strain for penicillin-G, has a high content of intracellular carbohydrates, especially reduced sugars such as mannitol, arabitol, erythritol, as well as trehalose and glycogen. In previous steady state 13C wash-in experiments a delay of labeling enrichments in glycolytic intermediates was observed, which suggests turnover of storage carbohydrates. The turnover of storage pools consumes ATP which is expected to reduce the product yield for energy demanding production pathways like penicillin-G. Results In this study, a 13C labeling wash-in experiment of 1 hour was performed to systematically quantify the intracellular flux distribution including eight substrate cycles. The experiments were performed using a mixed carbon source of 85% $ Cmol_{Glc} $/$ Cmol_{Glc+EtOH} $ labeled glucose (mixture of 90% [1-13$ C_{1} $] and 10% [U-13$ C_{6} $]) and 15% ethanol [U-13$ C_{2} $]. It was found, that (1) also several extracellular pools are enriched with 13C labeling rapidly (trehalose, mannitol, and others), (2) the intra- to extracellular metabolite concentration ratios were comparable for a large set of metabolites while for some carbohydrates (mannitol, trehalose, and glucose) the measured ratios were much higher. Conclusions The fast enrichment of several extracellular carbohydrates and a concentration ratio higher than the ratio expected from cell lysis (2%) indicate active (e.g. ATP consuming) transport cycles over the cellular membrane. The flux estimation indicates, that substrate cycles account for about 52% of the gap in the ATP balance based on metabolic flux analysis. Trehalose (dpeaa)DE-He213 Metabolic Model (dpeaa)DE-He213 Flux Analysis (dpeaa)DE-He213 Metabolic Flux Analysis (dpeaa)DE-He213 Central Carbon Metabolism (dpeaa)DE-He213 ten Pierick, Angela aut de Jonge, Lodewijk aut Heijnen, Joseph J aut Wahl, S Aljoscha aut Enthalten in Microbial cell factories London : Biomed Central, 2002 11(2012), 1 vom: 25. Okt. (DE-627)355987651 (DE-600)2091377-1 1475-2859 nnns volume:11 year:2012 number:1 day:25 month:10 https://dx.doi.org/10.1186/1475-2859-11-140 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2012 1 25 10
allfieldsSound	10.1186/1475-2859-11-140 doi (DE-627)SPR028561961 (SPR)1475-2859-11-140-e DE-627 ger DE-627 rakwb eng Zhao, Zheng verfasserin aut Substrate cycles in Penicillium chrysogenum quantified by isotopic non-stationary flux analysis 2012 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Zhao et al.; licensee BioMed Central Ltd. 2012. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( Background Penicillium chrysogenum, the main production strain for penicillin-G, has a high content of intracellular carbohydrates, especially reduced sugars such as mannitol, arabitol, erythritol, as well as trehalose and glycogen. In previous steady state 13C wash-in experiments a delay of labeling enrichments in glycolytic intermediates was observed, which suggests turnover of storage carbohydrates. The turnover of storage pools consumes ATP which is expected to reduce the product yield for energy demanding production pathways like penicillin-G. Results In this study, a 13C labeling wash-in experiment of 1 hour was performed to systematically quantify the intracellular flux distribution including eight substrate cycles. The experiments were performed using a mixed carbon source of 85% $ Cmol_{Glc} $/$ Cmol_{Glc+EtOH} $ labeled glucose (mixture of 90% [1-13$ C_{1} $] and 10% [U-13$ C_{6} $]) and 15% ethanol [U-13$ C_{2} $]. It was found, that (1) also several extracellular pools are enriched with 13C labeling rapidly (trehalose, mannitol, and others), (2) the intra- to extracellular metabolite concentration ratios were comparable for a large set of metabolites while for some carbohydrates (mannitol, trehalose, and glucose) the measured ratios were much higher. Conclusions The fast enrichment of several extracellular carbohydrates and a concentration ratio higher than the ratio expected from cell lysis (2%) indicate active (e.g. ATP consuming) transport cycles over the cellular membrane. The flux estimation indicates, that substrate cycles account for about 52% of the gap in the ATP balance based on metabolic flux analysis. Trehalose (dpeaa)DE-He213 Metabolic Model (dpeaa)DE-He213 Flux Analysis (dpeaa)DE-He213 Metabolic Flux Analysis (dpeaa)DE-He213 Central Carbon Metabolism (dpeaa)DE-He213 ten Pierick, Angela aut de Jonge, Lodewijk aut Heijnen, Joseph J aut Wahl, S Aljoscha aut Enthalten in Microbial cell factories London : Biomed Central, 2002 11(2012), 1 vom: 25. Okt. (DE-627)355987651 (DE-600)2091377-1 1475-2859 nnns volume:11 year:2012 number:1 day:25 month:10 https://dx.doi.org/10.1186/1475-2859-11-140 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2012 1 25 10
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source	Enthalten in Microbial cell factories 11(2012), 1 vom: 25. Okt. volume:11 year:2012 number:1 day:25 month:10
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topic_facet	Trehalose Metabolic Model Flux Analysis Metabolic Flux Analysis Central Carbon Metabolism
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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Background Penicillium chrysogenum, the main production strain for penicillin-G, has a high content of intracellular carbohydrates, especially reduced sugars such as mannitol, arabitol, erythritol, as well as trehalose and glycogen. In previous steady state 13C wash-in experiments a delay of labeling enrichments in glycolytic intermediates was observed, which suggests turnover of storage carbohydrates. The turnover of storage pools consumes ATP which is expected to reduce the product yield for energy demanding production pathways like penicillin-G. Results In this study, a 13C labeling wash-in experiment of 1 hour was performed to systematically quantify the intracellular flux distribution including eight substrate cycles. 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author	Zhao, Zheng
spellingShingle	Zhao, Zheng misc Trehalose misc Metabolic Model misc Flux Analysis misc Metabolic Flux Analysis misc Central Carbon Metabolism Substrate cycles in Penicillium chrysogenum quantified by isotopic non-stationary flux analysis
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topic_title	Substrate cycles in Penicillium chrysogenum quantified by isotopic non-stationary flux analysis Trehalose (dpeaa)DE-He213 Metabolic Model (dpeaa)DE-He213 Flux Analysis (dpeaa)DE-He213 Metabolic Flux Analysis (dpeaa)DE-He213 Central Carbon Metabolism (dpeaa)DE-He213
topic	misc Trehalose misc Metabolic Model misc Flux Analysis misc Metabolic Flux Analysis misc Central Carbon Metabolism
topic_unstemmed	misc Trehalose misc Metabolic Model misc Flux Analysis misc Metabolic Flux Analysis misc Central Carbon Metabolism
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title	Substrate cycles in Penicillium chrysogenum quantified by isotopic non-stationary flux analysis
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title_full	Substrate cycles in Penicillium chrysogenum quantified by isotopic non-stationary flux analysis
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title_sort	substrate cycles in penicillium chrysogenum quantified by isotopic non-stationary flux analysis
title_auth	Substrate cycles in Penicillium chrysogenum quantified by isotopic non-stationary flux analysis
abstract	Background Penicillium chrysogenum, the main production strain for penicillin-G, has a high content of intracellular carbohydrates, especially reduced sugars such as mannitol, arabitol, erythritol, as well as trehalose and glycogen. In previous steady state 13C wash-in experiments a delay of labeling enrichments in glycolytic intermediates was observed, which suggests turnover of storage carbohydrates. The turnover of storage pools consumes ATP which is expected to reduce the product yield for energy demanding production pathways like penicillin-G. Results In this study, a 13C labeling wash-in experiment of 1 hour was performed to systematically quantify the intracellular flux distribution including eight substrate cycles. The experiments were performed using a mixed carbon source of 85% $ Cmol_{Glc} $/$ Cmol_{Glc+EtOH} $ labeled glucose (mixture of 90% [1-13$ C_{1} $] and 10% [U-13$ C_{6} $]) and 15% ethanol [U-13$ C_{2} $]. It was found, that (1) also several extracellular pools are enriched with 13C labeling rapidly (trehalose, mannitol, and others), (2) the intra- to extracellular metabolite concentration ratios were comparable for a large set of metabolites while for some carbohydrates (mannitol, trehalose, and glucose) the measured ratios were much higher. Conclusions The fast enrichment of several extracellular carbohydrates and a concentration ratio higher than the ratio expected from cell lysis (2%) indicate active (e.g. ATP consuming) transport cycles over the cellular membrane. The flux estimation indicates, that substrate cycles account for about 52% of the gap in the ATP balance based on metabolic flux analysis. © Zhao et al.; licensee BioMed Central Ltd. 2012. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (
abstractGer	Background Penicillium chrysogenum, the main production strain for penicillin-G, has a high content of intracellular carbohydrates, especially reduced sugars such as mannitol, arabitol, erythritol, as well as trehalose and glycogen. In previous steady state 13C wash-in experiments a delay of labeling enrichments in glycolytic intermediates was observed, which suggests turnover of storage carbohydrates. The turnover of storage pools consumes ATP which is expected to reduce the product yield for energy demanding production pathways like penicillin-G. Results In this study, a 13C labeling wash-in experiment of 1 hour was performed to systematically quantify the intracellular flux distribution including eight substrate cycles. The experiments were performed using a mixed carbon source of 85% $ Cmol_{Glc} $/$ Cmol_{Glc+EtOH} $ labeled glucose (mixture of 90% [1-13$ C_{1} $] and 10% [U-13$ C_{6} $]) and 15% ethanol [U-13$ C_{2} $]. It was found, that (1) also several extracellular pools are enriched with 13C labeling rapidly (trehalose, mannitol, and others), (2) the intra- to extracellular metabolite concentration ratios were comparable for a large set of metabolites while for some carbohydrates (mannitol, trehalose, and glucose) the measured ratios were much higher. Conclusions The fast enrichment of several extracellular carbohydrates and a concentration ratio higher than the ratio expected from cell lysis (2%) indicate active (e.g. ATP consuming) transport cycles over the cellular membrane. The flux estimation indicates, that substrate cycles account for about 52% of the gap in the ATP balance based on metabolic flux analysis. © Zhao et al.; licensee BioMed Central Ltd. 2012. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (
abstract_unstemmed	Background Penicillium chrysogenum, the main production strain for penicillin-G, has a high content of intracellular carbohydrates, especially reduced sugars such as mannitol, arabitol, erythritol, as well as trehalose and glycogen. In previous steady state 13C wash-in experiments a delay of labeling enrichments in glycolytic intermediates was observed, which suggests turnover of storage carbohydrates. The turnover of storage pools consumes ATP which is expected to reduce the product yield for energy demanding production pathways like penicillin-G. Results In this study, a 13C labeling wash-in experiment of 1 hour was performed to systematically quantify the intracellular flux distribution including eight substrate cycles. The experiments were performed using a mixed carbon source of 85% $ Cmol_{Glc} $/$ Cmol_{Glc+EtOH} $ labeled glucose (mixture of 90% [1-13$ C_{1} $] and 10% [U-13$ C_{6} $]) and 15% ethanol [U-13$ C_{2} $]. It was found, that (1) also several extracellular pools are enriched with 13C labeling rapidly (trehalose, mannitol, and others), (2) the intra- to extracellular metabolite concentration ratios were comparable for a large set of metabolites while for some carbohydrates (mannitol, trehalose, and glucose) the measured ratios were much higher. Conclusions The fast enrichment of several extracellular carbohydrates and a concentration ratio higher than the ratio expected from cell lysis (2%) indicate active (e.g. ATP consuming) transport cycles over the cellular membrane. The flux estimation indicates, that substrate cycles account for about 52% of the gap in the ATP balance based on metabolic flux analysis. © Zhao et al.; licensee BioMed Central Ltd. 2012. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (
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title_short	Substrate cycles in Penicillium chrysogenum quantified by isotopic non-stationary flux analysis
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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Background Penicillium chrysogenum, the main production strain for penicillin-G, has a high content of intracellular carbohydrates, especially reduced sugars such as mannitol, arabitol, erythritol, as well as trehalose and glycogen. In previous steady state 13C wash-in experiments a delay of labeling enrichments in glycolytic intermediates was observed, which suggests turnover of storage carbohydrates. The turnover of storage pools consumes ATP which is expected to reduce the product yield for energy demanding production pathways like penicillin-G. Results In this study, a 13C labeling wash-in experiment of 1 hour was performed to systematically quantify the intracellular flux distribution including eight substrate cycles. The experiments were performed using a mixed carbon source of 85% $ Cmol_{Glc} $/$ Cmol_{Glc+EtOH} $ labeled glucose (mixture of 90% [1-13$ C_{1} $] and 10% [U-13$ C_{6} $]) and 15% ethanol [U-13$ C_{2} $]. It was found, that (1) also several extracellular pools are enriched with 13C labeling rapidly (trehalose, mannitol, and others), (2) the intra- to extracellular metabolite concentration ratios were comparable for a large set of metabolites while for some carbohydrates (mannitol, trehalose, and glucose) the measured ratios were much higher. Conclusions The fast enrichment of several extracellular carbohydrates and a concentration ratio higher than the ratio expected from cell lysis (2%) indicate active (e.g. ATP consuming) transport cycles over the cellular membrane. 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Substrate cycles in Penicillium chrysogenum quantified by isotopic non-stationary flux analysis

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