Isoprenoid Pathway Optimization for Taxol Precursor Overproduction in Escherichia coli
Author Manuscript February 6, 2011
| Main Authors: | , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | en_US |
| Published: |
American Association for the Advancement of Science (AAAS)
2013
|
| Online Access: | http://hdl.handle.net/1721.1/81256 https://orcid.org/0000-0001-6909-4568 |
| _version_ | 1826193806391771136 |
|---|---|
| author | Wang, Y. Phon, T. H. Pfeifer, B. Ajikumar, Parayil Kumaran Xiao, Wen-Hai Tyo, Keith E. J. Simeon, Fritz Tyo, Keith E. J. Leonard, Effendi Mucha, Oliver Stephanopoulos, Gregory |
| author2 | Massachusetts Institute of Technology. Department of Chemical Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Chemical Engineering Wang, Y. Phon, T. H. Pfeifer, B. Ajikumar, Parayil Kumaran Xiao, Wen-Hai Tyo, Keith E. J. Simeon, Fritz Tyo, Keith E. J. Leonard, Effendi Mucha, Oliver Stephanopoulos, Gregory |
| author_sort | Wang, Y. |
| collection | MIT |
| description | Author Manuscript February 6, 2011 |
| first_indexed | 2024-09-23T09:45:42Z |
| format | Article |
| id | mit-1721.1/81256 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T09:45:42Z |
| publishDate | 2013 |
| publisher | American Association for the Advancement of Science (AAAS) |
| record_format | dspace |
| spelling | mit-1721.1/812562022-09-26T13:31:15Z Isoprenoid Pathway Optimization for Taxol Precursor Overproduction in Escherichia coli Wang, Y. Phon, T. H. Pfeifer, B. Ajikumar, Parayil Kumaran Xiao, Wen-Hai Tyo, Keith E. J. Simeon, Fritz Tyo, Keith E. J. Leonard, Effendi Mucha, Oliver Stephanopoulos, Gregory Massachusetts Institute of Technology. Department of Chemical Engineering Ajikumar, Parayil Kumaran Xiao, Wen-Hai Tyo, Keith E. J. Simeon, Fritz Leonard, Effendi Mucha, Oliver Stephanopoulos, Gregory Author Manuscript February 6, 2011 Taxol (paclitaxel) is a potent anticancer drug first isolated from the Taxus brevifolia Pacific yew tree. Currently, cost-efficient production of Taxol and its analogs remains limited. Here, we report a multivariate-modular approach to metabolic-pathway engineering that succeeded in increasing titers of taxadiene—the first committed Taxol intermediate—approximately 1 gram per liter (~15,000-fold) in an engineered Escherichia coli strain. Our approach partitioned the taxadiene metabolic pathway into two modules: a native upstream methylerythritol-phosphate (MEP) pathway forming isopentenyl pyrophosphate and a heterologous downstream terpenoid–forming pathway. Systematic multivariate search identified conditions that optimally balance the two pathway modules so as to maximize the taxadiene production with minimal accumulation of indole, which is an inhibitory compound found here. We also engineered the next step in Taxol biosynthesis, a P450-mediated 5α-oxidation of taxadiene to taxadien-5α-ol. More broadly, the modular pathway engineering approach helped to unlock the potential of the MEP pathway for the engineered production of terpenoid natural products. 2013-10-01T14:05:59Z 2013-10-01T14:05:59Z 2010-09 2010-08 Article http://purl.org/eprint/type/JournalArticle 0036-8075 1095-9203 http://hdl.handle.net/1721.1/81256 Ajikumar, P. K., W.-H. Xiao, K. E. J. Tyo, Y. Wang, F. Simeon, E. Leonard, O. Mucha, T. H. Phon, B. Pfeifer, and G. Stephanopoulos. “Isoprenoid Pathway Optimization for Taxol Precursor Overproduction in Escherichia coli.” Science 330, no. 6000 (September 30, 2010): 70-74. https://orcid.org/0000-0001-6909-4568 en_US http://dx.doi.org/10.1126/science.1191652 Science Creative Commons Attribution-Noncommercial-Share Alike 3.0 http://creativecommons.org/licenses/by-nc-sa/3.0/ application/pdf American Association for the Advancement of Science (AAAS) PubMed Central |
| spellingShingle | Wang, Y. Phon, T. H. Pfeifer, B. Ajikumar, Parayil Kumaran Xiao, Wen-Hai Tyo, Keith E. J. Simeon, Fritz Tyo, Keith E. J. Leonard, Effendi Mucha, Oliver Stephanopoulos, Gregory Isoprenoid Pathway Optimization for Taxol Precursor Overproduction in Escherichia coli |
| title | Isoprenoid Pathway Optimization for Taxol Precursor Overproduction in Escherichia coli |
| title_full | Isoprenoid Pathway Optimization for Taxol Precursor Overproduction in Escherichia coli |
| title_fullStr | Isoprenoid Pathway Optimization for Taxol Precursor Overproduction in Escherichia coli |
| title_full_unstemmed | Isoprenoid Pathway Optimization for Taxol Precursor Overproduction in Escherichia coli |
| title_short | Isoprenoid Pathway Optimization for Taxol Precursor Overproduction in Escherichia coli |
| title_sort | isoprenoid pathway optimization for taxol precursor overproduction in escherichia coli |
| url | http://hdl.handle.net/1721.1/81256 https://orcid.org/0000-0001-6909-4568 |
| work_keys_str_mv | AT wangy isoprenoidpathwayoptimizationfortaxolprecursoroverproductioninescherichiacoli AT phonth isoprenoidpathwayoptimizationfortaxolprecursoroverproductioninescherichiacoli AT pfeiferb isoprenoidpathwayoptimizationfortaxolprecursoroverproductioninescherichiacoli AT ajikumarparayilkumaran isoprenoidpathwayoptimizationfortaxolprecursoroverproductioninescherichiacoli AT xiaowenhai isoprenoidpathwayoptimizationfortaxolprecursoroverproductioninescherichiacoli AT tyokeithej isoprenoidpathwayoptimizationfortaxolprecursoroverproductioninescherichiacoli AT simeonfritz isoprenoidpathwayoptimizationfortaxolprecursoroverproductioninescherichiacoli AT tyokeithej isoprenoidpathwayoptimizationfortaxolprecursoroverproductioninescherichiacoli AT leonardeffendi isoprenoidpathwayoptimizationfortaxolprecursoroverproductioninescherichiacoli AT muchaoliver isoprenoidpathwayoptimizationfortaxolprecursoroverproductioninescherichiacoli AT stephanopoulosgregory isoprenoidpathwayoptimizationfortaxolprecursoroverproductioninescherichiacoli |