Trends In Microbial Synthesis of Natural Products and Biofuels

Chemier, Joseph A.; Fowler, Zachary L.; Koffas, Mattheos A. G.

doi:10.1002/9780470392881.ch4

Cited by 14 publications

(13 citation statements)

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“…Saccharomyces cerevisiae is a robust, budding yeast that has been widely used for fermentation of refined corn starch to fuel ethanol [14]. Because this yeast is Crabtree-positive, excess sugar that would otherwise overload its limited respiratory capacity overflows into the fermentative pathway.…”

Section: Introductionmentioning

confidence: 99%

Dynamic metabolic modeling of a microaerobic yeast co-culture: predicting and optimizing ethanol production from glucose/xylose mixtures

Hanly

Henson

2013

Biotechnol Biofuels

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BackgroundA key step in any process that converts lignocellulose to biofuels is the efficient fermentation of both hexose and pentose sugars. The co-culture of respiratory-deficient Saccharomyces cerevisiae and wild-type Scheffersomyces stipitis has been identified as a promising system for microaerobic ethanol production because S. cerevisiae only consumes glucose while S. stipitis efficiently converts xylose to ethanol.ResultsTo better predict how these two yeasts behave in batch co-culture and to optimize system performance, a dynamic flux balance model describing co-culture metabolism was developed from genome-scale metabolic reconstructions of the individual organisms. First a dynamic model was developed for each organism by estimating substrate uptake kinetic parameters from batch pure culture data and evaluating model extensibility to different microaerobic growth conditions. The co-culture model was constructed by combining the two individual models assuming a cellular objective of total growth rate maximization. To obtain accurate predictions of batch co-culture data collected at different microaerobic conditions, the S. cerevisiae maximum glucose uptake rate was reduced from its pure culture value to account for more efficient S. stipitis glucose uptake in co-culture. The dynamic co-culture model was used to predict the inoculum concentration and aeration level that maximized batch ethanol productivity. The model predictions were validated with batch co-culture experiments performed at the optimal conditions. Furthermore, the dynamic model was used to predict how engineered improvements to the S. stipitis xylose transport system could improve co-culture ethanol production.ConclusionsThese results demonstrate the utility of the dynamic co-culture metabolic model for guiding process and metabolic engineering efforts aimed at increasing microaerobic ethanol production from glucose/xylose mixtures.

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Section: Introductionmentioning

confidence: 99%

Dynamic metabolic modeling of a microaerobic yeast co-culture: predicting and optimizing ethanol production from glucose/xylose mixtures

Hanly

Henson

2013

Biotechnol Biofuels

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“…This designation derives from their ability to oxidize a wide variety of chemically diverse substrates with exquisite regio and stereo selectivity [3, 4]. Due to this unique capability, P450 enzymes have an exciting potential in biotechnological applications [5], including the production of biofuels [6], bioremediation [7], and the generation of authentic metabolic standards for drug discovery and development [8–11]. Although much progress has been made in understanding the detailed mechanism of the P450 catalytic cycle, efforts to replicate the efficiency and selectivity of P450 mediated oxidation in biomimetic catalysts have met with only limited success [12, 13].…”

Section: Introductionmentioning

confidence: 99%

Active-site residues move independently from the rest of the protein in a 200 ns molecular dynamics simulation of cytochrome P450 CYP119

Brandman

Lampe

Brandman

et al. 2011

Archives of Biochemistry and Biophysics

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The conformational dynamics of cytochrome P450 enzymes are critical to their catalytic activity. In this study, the correlated motion between residues in a 200ns molecular dynamics trajectory of the thermophilic CYP119 was analyzed to parse out conformational relationships. Residues that are structurally related, for example residues within a helix, generally have highly correlated motion. In addition, clusters of non-adjacent residues that show correlated motion (“hot spots”) are seen in various regions, including at the base of the F and G helices that make up the most dynamic region of the enzyme. A modified k-means algorithm that clusters residues based on their correlated motion indicates that functionally related residues are in the same cluster (e.g., the catalytic threonines and the heme). Tightly coupled clusters form a solvent-exposed “shell” around the enzyme, whereas less coupling between clusters is seen in regions that are critical to ligand interactions, redox partner interactions, and catalysis. Most notably, we find that residues in the active site move independently from the rest of the enzyme, effectively insulating the catalytic machinery from other regions of the protein.

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“…These same diets are often rich in plant polyphenols, such as flavonoids and carotenoids, due to the increased consumption of fruits and vegetables often involved in such diets. Flavonoids in particular are known to have diverse pharmico-dynamic abilities, which has drawn major attention to the molecules for both personal health applications [7], [8], and from pharmaceutical companies keen on either their native nutraceutical properties [9]. Increases to levels of polyphenolic substances have been demonstrated in plants during fungal infection, suggesting that these molecules may be part of the host-defense mechanism [10], [11].…”

Section: Introductionmentioning

confidence: 99%

Development of Non-Natural Flavanones as Antimicrobial Agents

Fowler¹,

Shah

Panepinto

et al. 2011

PLoS ONE

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With growing concerns over multidrug resistance microorganisms, particularly strains of bacteria and fungi, evolving to become resistant to the antimicrobial agents used against them, the identification of new molecular targets becomes paramount for novel treatment options. Recently, the use of new treatments containing multiple active ingredients has been shown to increase the effectiveness of existing molecules for some infections, often with these added compounds enabling the transport of a toxic molecule into the infecting species. Flavonoids are among the most abundant plant secondary metabolites and have been shown to have natural abilities as microbial deterrents and anti-infection agents in plants. Combining these ideas we first sought to investigate the potency of natural flavonoids in the presence of efflux pump inhibitors to limit Escherichia coli growth. Then we used the natural flavonoid scaffold to synthesize non-natural flavanone molecules and further evaluate their antimicrobial efficacy on Escherichia coli, Bacillus subtilis and the fungal pathogens Cryptococcus neoformans and Aspergillus fumigatus. Of those screened, we identified the synthetic molecule 4-chloro-flavanone as the most potent antimicrobial compound with a MIC value of 70 µg/mL in E. coli when combined with the inhibitor Phe-Arg-ß-naphthylamide, and MICs of 30 µg/mL in S. cerevesiae and 30 µg/mL in C. neoformans when used alone. Through this study we have demonstrated that combinatorial synthesis of non-natural flavonones can identify novel antimicrobial agents with activity against bacteria and fungi but with minimal toxicity to human cells.

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Trends In Microbial Synthesis of Natural Products and Biofuels

Cited by 14 publications

References 0 publications

Dynamic metabolic modeling of a microaerobic yeast co-culture: predicting and optimizing ethanol production from glucose/xylose mixtures

Dynamic metabolic modeling of a microaerobic yeast co-culture: predicting and optimizing ethanol production from glucose/xylose mixtures

Active-site residues move independently from the rest of the protein in a 200 ns molecular dynamics simulation of cytochrome P450 CYP119

Development of Non-Natural Flavanones as Antimicrobial Agents

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