Metabolic control analysis of the penicillin biosynthetic pathway in a high-yielding strain of Penicillium chrysogenum
Metabolic control analysis is used to identify the rate‐limiting step in the penicillin biosynthetic pathway in Penicillium chrysogenum. The analysis is carried out using a kinetic model for the first two steps in the pathway, i. e., the ACV synthetase (ACVS) and the isopenicillin N synthetase (IPNS...
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| Veröffentlicht in: | Biotechnology progress 1995-05, Vol.11 (3), p.299-305 |
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| creator | Nielsen, J. (Technical University of Denmark, Lyngby (Denmark)) Jorgensen, H.S |
| description | Metabolic control analysis is used to identify the rate‐limiting step in the penicillin biosynthetic pathway in Penicillium chrysogenum. The analysis is carried out using a kinetic model for the first two steps in the pathway, i. e., the ACV synthetase (ACVS) and the isopenicillin N synthetase (IPNS). The kinetic model is based on Michaelis—Menten type kinetics, with noncompetitive inhibition of the ACVS by ACV and competitive inhibition of the IPNS by glutathione. From measurements of the enzyme activities and intracellular metabolites during a fed‐batch cultivation, the kinetic model is used to predict the flux through the pathway. The model prediction corresponds well with the measured rate of penicillin biosynthesis. From measurement of the activity of the acyl‐CoA:isopenicillin acyltransferase, which catalyzes the third and last reaction in the pathway, it is concluded that the rate‐limiting step is either at the ACVS or at the IPNS. From the kinetic model, the elasticity coefficients and the flux control coefficients are calculated throughout the fed‐batch cultivations, and it is found that there is a shift in the flux control from the ACVS to. the IPNS during the cultivation. |
| doi_str_mv | 10.1021/bp00033a010 |
| format | Article |
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(Technical University of Denmark, Lyngby (Denmark)) ; Jorgensen, H.S</creator><creatorcontrib>Nielsen, J. (Technical University of Denmark, Lyngby (Denmark)) ; Jorgensen, H.S</creatorcontrib><description>Metabolic control analysis is used to identify the rate‐limiting step in the penicillin biosynthetic pathway in Penicillium chrysogenum. The analysis is carried out using a kinetic model for the first two steps in the pathway, i. e., the ACV synthetase (ACVS) and the isopenicillin N synthetase (IPNS). The kinetic model is based on Michaelis—Menten type kinetics, with noncompetitive inhibition of the ACVS by ACV and competitive inhibition of the IPNS by glutathione. From measurements of the enzyme activities and intracellular metabolites during a fed‐batch cultivation, the kinetic model is used to predict the flux through the pathway. The model prediction corresponds well with the measured rate of penicillin biosynthesis. From measurement of the activity of the acyl‐CoA:isopenicillin acyltransferase, which catalyzes the third and last reaction in the pathway, it is concluded that the rate‐limiting step is either at the ACVS or at the IPNS. From the kinetic model, the elasticity coefficients and the flux control coefficients are calculated throughout the fed‐batch cultivations, and it is found that there is a shift in the flux control from the ACVS to. the IPNS during the cultivation.</description><identifier>ISSN: 8756-7938</identifier><identifier>EISSN: 1520-6033</identifier><identifier>DOI: 10.1021/bp00033a010</identifier><identifier>PMID: 7619400</identifier><identifier>CODEN: BIPRET</identifier><language>eng</language><publisher>USA: American Chemical Society</publisher><subject>ACTIVIDAD ENZIMATICA ; ACTIVITE ENZYMATIQUE ; ACV SYNTHETASE ; Anti-Bacterial Agents - biosynthesis ; Antibiotics ; Biological and medical sciences ; BIOSINTESIS ; BIOSYNTHESE ; BIOSYNTHESIS ; Biotechnology ; ENZYMIC ACTIVITY ; Fundamental and applied biological sciences. Psychology ; Health. Pharmaceutical industry ; Industrial applications and implications. Economical aspects ; ISOPENICILLIN N SYNTHETASE ; KINETIC MODELS ; KINETICS ; Lactams ; LIGASAS ; LIGASE ; LIGASES ; MATHEMATICAL MODELS ; MICHAELIS MENTEN KINETICS ; MODELE MATHEMATIQUE ; MODELOS MATEMATICOS ; Models, Biological ; OXIDOREDUCTASES ; Oxidoreductases - biosynthesis ; Oxidoreductases - metabolism ; OXIDORREDUCTASAS ; OXYDOREDUCTASE ; PENICILINA ; PENICILLINE ; PENICILLINS ; Penicillins - biosynthesis ; PENICILLIUM ; Penicillium chrysogenum ; Penicillium chrysogenum - metabolism ; Peptide Synthases - biosynthesis ; Peptide Synthases - metabolism ; Production of active biomolecules ; Species Specificity</subject><ispartof>Biotechnology progress, 1995-05, Vol.11 (3), p.299-305</ispartof><rights>Copyright © 1995 American Institute of Chemical Engineers (AIChE)</rights><rights>1995 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5150-8e13d72237d344fc552f0457fe1630ac86dbd65c14599f491ee7e33f972f879d3</citedby><cites>FETCH-LOGICAL-c5150-8e13d72237d344fc552f0457fe1630ac86dbd65c14599f491ee7e33f972f879d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,781,785,2766,27926,27927</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=3564210$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/7619400$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Nielsen, J. (Technical University of Denmark, Lyngby (Denmark))</creatorcontrib><creatorcontrib>Jorgensen, H.S</creatorcontrib><title>Metabolic control analysis of the penicillin biosynthetic pathway in a high-yielding strain of Penicillium chrysogenum</title><title>Biotechnology progress</title><addtitle>Biotechnol Progress</addtitle><description>Metabolic control analysis is used to identify the rate‐limiting step in the penicillin biosynthetic pathway in Penicillium chrysogenum. The analysis is carried out using a kinetic model for the first two steps in the pathway, i. e., the ACV synthetase (ACVS) and the isopenicillin N synthetase (IPNS). The kinetic model is based on Michaelis—Menten type kinetics, with noncompetitive inhibition of the ACVS by ACV and competitive inhibition of the IPNS by glutathione. From measurements of the enzyme activities and intracellular metabolites during a fed‐batch cultivation, the kinetic model is used to predict the flux through the pathway. The model prediction corresponds well with the measured rate of penicillin biosynthesis. From measurement of the activity of the acyl‐CoA:isopenicillin acyltransferase, which catalyzes the third and last reaction in the pathway, it is concluded that the rate‐limiting step is either at the ACVS or at the IPNS. From the kinetic model, the elasticity coefficients and the flux control coefficients are calculated throughout the fed‐batch cultivations, and it is found that there is a shift in the flux control from the ACVS to. the IPNS during the cultivation.</description><subject>ACTIVIDAD ENZIMATICA</subject><subject>ACTIVITE ENZYMATIQUE</subject><subject>ACV SYNTHETASE</subject><subject>Anti-Bacterial Agents - biosynthesis</subject><subject>Antibiotics</subject><subject>Biological and medical sciences</subject><subject>BIOSINTESIS</subject><subject>BIOSYNTHESE</subject><subject>BIOSYNTHESIS</subject><subject>Biotechnology</subject><subject>ENZYMIC ACTIVITY</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Health. Pharmaceutical industry</subject><subject>Industrial applications and implications. Economical aspects</subject><subject>ISOPENICILLIN N SYNTHETASE</subject><subject>KINETIC MODELS</subject><subject>KINETICS</subject><subject>Lactams</subject><subject>LIGASAS</subject><subject>LIGASE</subject><subject>LIGASES</subject><subject>MATHEMATICAL MODELS</subject><subject>MICHAELIS MENTEN KINETICS</subject><subject>MODELE MATHEMATIQUE</subject><subject>MODELOS MATEMATICOS</subject><subject>Models, Biological</subject><subject>OXIDOREDUCTASES</subject><subject>Oxidoreductases - biosynthesis</subject><subject>Oxidoreductases - metabolism</subject><subject>OXIDORREDUCTASAS</subject><subject>OXYDOREDUCTASE</subject><subject>PENICILINA</subject><subject>PENICILLINE</subject><subject>PENICILLINS</subject><subject>Penicillins - biosynthesis</subject><subject>PENICILLIUM</subject><subject>Penicillium chrysogenum</subject><subject>Penicillium chrysogenum - metabolism</subject><subject>Peptide Synthases - biosynthesis</subject><subject>Peptide Synthases - metabolism</subject><subject>Production of active biomolecules</subject><subject>Species Specificity</subject><issn>8756-7938</issn><issn>1520-6033</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1995</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc1v1DAQxS0EKtvCiRsSUg6ICwr428kRVrQFSllBK46W49i7BicOdkLJf49plhUnOI3mze-9sTwAPELwBYIYvWwGCCEhCiJ4B6wQw7Dkub8LVpVgvBQ1qe6D45S-ZqyCHB-BI8FRTSFcgR8fzKia4J0udOjHGHyheuXn5FIRbDHuTDGY3mnnveuLxoU091kcMz-ocXej5iLrqti57a6cnfGt67dFGqPKcg7Y_DFPXaF3cU5ha_qpewDuWeWTebivJ-D69M3V-ry8-Hj2dv3qotQMMVhWBpFWYExESyi1mjFsIWXCGsQJVLribdNyphFldW1pjYwRhhBbC2wrUbfkBDxbcocYvk8mjbJzSRvvVW_ClKQQFFKK4H9BxCsmOGQZfL6AOoaUorFyiK5TcZYIyt_nkH-dI9NP9rFT05n2wO7_P8-f7ucqaeVtVL126YARxim-jRELduO8mf-1Ub6-2nxiFEOUbbfOcnG6NJqfB6eK3yQXRDD55fJMbt5X63f4spbnmX-88FYFqbYxP-b6c80YpZyRX4tdum0</recordid><startdate>199505</startdate><enddate>199505</enddate><creator>Nielsen, J. (Technical University of Denmark, Lyngby (Denmark))</creator><creator>Jorgensen, H.S</creator><general>American Chemical Society</general><general>American Institute of Chemical Engineers</general><scope>FBQ</scope><scope>BSCLL</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QO</scope><scope>7T7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>M7N</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>199505</creationdate><title>Metabolic control analysis of the penicillin biosynthetic pathway in a high-yielding strain of Penicillium chrysogenum</title><author>Nielsen, J. (Technical University of Denmark, Lyngby (Denmark)) ; Jorgensen, H.S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5150-8e13d72237d344fc552f0457fe1630ac86dbd65c14599f491ee7e33f972f879d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1995</creationdate><topic>ACTIVIDAD ENZIMATICA</topic><topic>ACTIVITE ENZYMATIQUE</topic><topic>ACV SYNTHETASE</topic><topic>Anti-Bacterial Agents - biosynthesis</topic><topic>Antibiotics</topic><topic>Biological and medical sciences</topic><topic>BIOSINTESIS</topic><topic>BIOSYNTHESE</topic><topic>BIOSYNTHESIS</topic><topic>Biotechnology</topic><topic>ENZYMIC ACTIVITY</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Health. Pharmaceutical industry</topic><topic>Industrial applications and implications. Economical aspects</topic><topic>ISOPENICILLIN N SYNTHETASE</topic><topic>KINETIC MODELS</topic><topic>KINETICS</topic><topic>Lactams</topic><topic>LIGASAS</topic><topic>LIGASE</topic><topic>LIGASES</topic><topic>MATHEMATICAL MODELS</topic><topic>MICHAELIS MENTEN KINETICS</topic><topic>MODELE MATHEMATIQUE</topic><topic>MODELOS MATEMATICOS</topic><topic>Models, Biological</topic><topic>OXIDOREDUCTASES</topic><topic>Oxidoreductases - biosynthesis</topic><topic>Oxidoreductases - metabolism</topic><topic>OXIDORREDUCTASAS</topic><topic>OXYDOREDUCTASE</topic><topic>PENICILINA</topic><topic>PENICILLINE</topic><topic>PENICILLINS</topic><topic>Penicillins - biosynthesis</topic><topic>PENICILLIUM</topic><topic>Penicillium chrysogenum</topic><topic>Penicillium chrysogenum - metabolism</topic><topic>Peptide Synthases - biosynthesis</topic><topic>Peptide Synthases - metabolism</topic><topic>Production of active biomolecules</topic><topic>Species Specificity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Nielsen, J. (Technical University of Denmark, Lyngby (Denmark))</creatorcontrib><creatorcontrib>Jorgensen, H.S</creatorcontrib><collection>AGRIS</collection><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Biotechnology progress</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Nielsen, J. (Technical University of Denmark, Lyngby (Denmark))</au><au>Jorgensen, H.S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Metabolic control analysis of the penicillin biosynthetic pathway in a high-yielding strain of Penicillium chrysogenum</atitle><jtitle>Biotechnology progress</jtitle><addtitle>Biotechnol Progress</addtitle><date>1995-05</date><risdate>1995</risdate><volume>11</volume><issue>3</issue><spage>299</spage><epage>305</epage><pages>299-305</pages><issn>8756-7938</issn><eissn>1520-6033</eissn><coden>BIPRET</coden><abstract>Metabolic control analysis is used to identify the rate‐limiting step in the penicillin biosynthetic pathway in Penicillium chrysogenum. The analysis is carried out using a kinetic model for the first two steps in the pathway, i. e., the ACV synthetase (ACVS) and the isopenicillin N synthetase (IPNS). The kinetic model is based on Michaelis—Menten type kinetics, with noncompetitive inhibition of the ACVS by ACV and competitive inhibition of the IPNS by glutathione. From measurements of the enzyme activities and intracellular metabolites during a fed‐batch cultivation, the kinetic model is used to predict the flux through the pathway. The model prediction corresponds well with the measured rate of penicillin biosynthesis. From measurement of the activity of the acyl‐CoA:isopenicillin acyltransferase, which catalyzes the third and last reaction in the pathway, it is concluded that the rate‐limiting step is either at the ACVS or at the IPNS. From the kinetic model, the elasticity coefficients and the flux control coefficients are calculated throughout the fed‐batch cultivations, and it is found that there is a shift in the flux control from the ACVS to. the IPNS during the cultivation.</abstract><cop>USA</cop><pub>American Chemical Society</pub><pmid>7619400</pmid><doi>10.1021/bp00033a010</doi><tpages>7</tpages></addata></record> |
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| ispartof | Biotechnology progress, 1995-05, Vol.11 (3), p.299-305 |
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| source | MEDLINE; American Chemical Society Web Editions |
| subjects | ACTIVIDAD ENZIMATICA ACTIVITE ENZYMATIQUE ACV SYNTHETASE Anti-Bacterial Agents - biosynthesis Antibiotics Biological and medical sciences BIOSINTESIS BIOSYNTHESE BIOSYNTHESIS Biotechnology ENZYMIC ACTIVITY Fundamental and applied biological sciences. Psychology Health. Pharmaceutical industry Industrial applications and implications. Economical aspects ISOPENICILLIN N SYNTHETASE KINETIC MODELS KINETICS Lactams LIGASAS LIGASE LIGASES MATHEMATICAL MODELS MICHAELIS MENTEN KINETICS MODELE MATHEMATIQUE MODELOS MATEMATICOS Models, Biological OXIDOREDUCTASES Oxidoreductases - biosynthesis Oxidoreductases - metabolism OXIDORREDUCTASAS OXYDOREDUCTASE PENICILINA PENICILLINE PENICILLINS Penicillins - biosynthesis PENICILLIUM Penicillium chrysogenum Penicillium chrysogenum - metabolism Peptide Synthases - biosynthesis Peptide Synthases - metabolism Production of active biomolecules Species Specificity |
| title | Metabolic control analysis of the penicillin biosynthetic pathway in a high-yielding strain of Penicillium chrysogenum |
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