Improved computational performance of MFA using elementary metabolite units and flux coupling

Suthers, Patrick F.; Chang, Young Jung; Maranas, Costas D.

doi:10.1016/j.ymben.2009.10.002

Cited by 30 publications

(27 citation statements)

References 13 publications

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“…Briefly, given a set of mass isotopomer measurements and a set of source metabolites, this implementation calculates network fluxes through an EMU representation. The details of the procedure used to identify all EMU species and variables are outlined in Suthers et al (2010).…”

Section: Resultsmentioning

confidence: 99%

“…While lumped isotope models (Antoniewicz et al, 2007b;Kim et al, 2008;Suthers et al, 2007) typically require the analysis of spectra (i.e., NMR or GC/MS) for only about 20-50 fragments, using the totality of mapped isotopomers in imPR90068 will likely require significantly higher numbers of carefully chosen labeled fragments. This makes even more pertinent the use of methods such as OptMeas (Chang et al, 2008;Suthers et al, 2010) to pinpoint minimal measurement sets and compact isotope representations such as EMU (Antoniewicz et al, 2007a) for complete flux elucidation. We anticipate that the development of systematic reaction step aggregation techniques (e.g., SLIPs (Quek, 2009)) that avoid any loss of information will lead to substantial reduction in the size of the problems that need to be solved for flux elucidation.…”

Section: Discussionmentioning

confidence: 99%

“…Table IV highlights the savings afforded by the EMU representation. The 17,346 carbon isotopomers of imPS1485 are reduced to 1,215 EMU species and 3,912 mass isotopomers (Suthers et al, 2010). All 10 93 carbon isotopomers in imPR90068 are reduced to 1,068,431 EMU species and 6,066,011 mass isotopomers.…”

Section: Reduced and Emu Based Representation Of Impr90068mentioning

confidence: 98%

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Construction of an E. Coli genome‐scale atom mapping model for MFA calculations

Ravikirthi

Suthers

Maranas

2011

Biotech & Bioengineering

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Metabolic flux analysis (MFA) has so far been restricted to lumped networks lacking many important pathways, partly due to the difficulty in automatically generating isotope mapping matrices for genome-scale metabolic networks. Here we introduce a procedure that uses a compound matching algorithm based on the graph theoretical concept of pattern recognition along with relevant reaction information to automatically generate genome-scale atom mappings which trace the path of atoms from reactants to products for every reaction. The procedure is applied to the iAF1260 metabolic reconstruction of Escherichia coli yielding the genome-scale isotope mapping model imPR90068. This model maps 90,068 non-hydrogen atoms that span all 2,077 reactions present in iAF1260 (previous largest mapping model included 238 reactions). The expanded scope of the isotope mapping model allows the complete tracking of labeled atoms through pathways such as cofactor and prosthetic group biosynthesis and histidine metabolism. An EMU representation of imPR90068 is also constructed and made available.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Construction of an E. Coli genome‐scale atom mapping model for MFA calculations

Ravikirthi

Suthers

Maranas

2011

Biotech & Bioengineering

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“…The wellcurated metabolic backgrounds of hosts like E. coli and S. cerevisiae also offer the application of computational modeling to predict and implement beneficial metabolic changes. This has been demonstrated in a number of cases using stoichiometric modeling of background metabolism to identify genes to be either deleted or overexpressed for the purpose of improving final titers (3,13,61,62). The advantage of such models is the ability to identify alternative native metabolism contributing to or detracting from heterologous production.…”

Section: After Biosynthesis: Protein Metabolic and Process Engineeringmentioning

confidence: 99%

Toward Biosynthetic Design and Implementation of Escherichia coli-Derived Paclitaxel and Other Heterologous Polyisoprene Compounds

Jiang

Stephanopoulos

Pfeifer

2012

Appl Environ Microbiol

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bEscherichia coli offers unparalleled engineering capacity in the context of heterologous natural product biosynthesis. However, as with other heterologous hosts, cellular metabolism must be designed or redesigned to support final compound formation. This task is at once complicated and aided by the fact that the cell does not natively produce an abundance of natural products. As a result, the metabolic engineer avoids complicated interactions with native pathways closely associated with the outcome of interest, but this convenience is tempered by the need to implement the required metabolism to allow functional biosynthesis. This review focuses on engineering E. coli for the purpose of polyisoprene formation, as it is related to isoprenoid compounds currently being pursued through a heterologous approach. In particular, the review features the compound paclitaxel and early efforts to design and overproduce intermediates through E. coli. Isoprenoids are an important class of natural products that have been converted to several therapeutic medicines (2,41,42). However, this process can be complicated by the need to harness or reconstruct native biosynthesis. As an example, the well-known isoprenoid natural product paclitaxel is natively produced by the Pacific yew tree (Taxus brevifolia), yet utilizing production from the native host proved both uneconomical and environmentally destructive (5,17,25). An economical total chemical-synthetic route to the compound is challenging due to the molecule's complex final architecture. This common scenario has driven alternative approaches toward the viable production of this and other therapeutically relevant natural products. One such approach is the use of heterologous biosynthesis, in which the genetic content responsible for a given natural compound is transplanted from the native organism to a surrogate host for the purpose of leveraging the new host's innate biological and engineering capabilities. This review focuses on the heterologous biosynthesis approach, using the compound paclitaxel as a primary example. More specifically, emphasis is placed on the logic and initial steps guiding heterologous biosynthesis, including the choice of host organism, the provision of required intracellular substrates, and the initiation of polyisoprene formation. For more comprehensive or alternative discussions of isoprenoid biosynthesis, readers are directed to several additional review articles (1,11,21,30,31,33,40,46,67).Isoprenoids are often associated with plant natural products, but they are also produced by microorganisms (19,58). The compounds play several roles in basic cellular function, including light absorption, electron transport, and protein modification. In addition, they are perhaps better known for their roles in less clearly defined chemical communication scenarios. For example, cellular damage and potential foreign-organism invasion both spur isoprenoid biosynthesis in an attempt to protect plant viability. Such a capacity for isoprenoids to serve as chemical cue...

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“…Flux coupling analysis focuses in finding these limits where network's flexibility does not reach and does not allow feasible flux behaviour. This algorithm has been used to study flux capabilities of Saccharomyces cerevisiae and Escherichia coli (Notebaart et al, 2008) and has facilitated metabolic flux analysis (Suthers et al, 2010). It allows the identification of blocked reactions and functional reactions subset as other works (Kholodenko, 1995;Klamt et al, 2003;Pfeiffer et al, 1999;Rohwer et al, 1996;Schilling et al, 2000;Schuster et al, 1994), but it circumvents the problems that these algorithms have when handling large networks, such as genome-scale metabolic networks (Golub and Van Loan, 1996).…”

Section: Introductionmentioning

confidence: 99%

Modelling and analysis of biological systems to obtain biofuels

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Improved computational performance of MFA using elementary metabolite units and flux coupling

Cited by 30 publications

References 13 publications

Construction of an E. Coli genome‐scale atom mapping model for MFA calculations

Construction of an E. Coli genome‐scale atom mapping model for MFA calculations

Toward Biosynthetic Design and Implementation of Escherichia coli-Derived Paclitaxel and Other Heterologous Polyisoprene Compounds

Modelling and analysis of biological systems to obtain biofuels

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