Michael A. Henson Group

Dynamic Modeling and Genome-Scale Analysis of Yeast Metabolism

The objective of this project is to develop yeast metabolic models for the dynamic analysis of gene knockouts and insertions on metabolite production in batch and fed-batch culture. We have developed dynamic flux balance models that combine stoichiometric equations for intracellular metabolism with dynamic mass balances on key extracellular nutrients and products. A small-scale stoichiometric model of yeast primary metabolism has been used to develop a dynamic flux balance model for determining fed-batch operating policies that optimize ethanol production. Optimal solutions generated to analyze the tradeoff between maximal productivity and yield objectives show that the prediction of a microaerobic region is significant. We have developed a more comprehensive dynamic model based on a genome-scale reconstruction of yeast metabolism to investigate metabolic engineering strategies for ethanol production in glucose and glucose/xylose media. Our initial results show that optimal cellular engineering strategies can be strongly dependent on the fermenter operating mode, such that conventional steady-state flux balance analysis can produce misleading results for batch and fed-batch cultures. Our long-term goal is to develop an integrated optimization framework that simultaneously identifies promising genetic manipulations and favorable dynamic operating policies.

Funding: UMass Process Design and Control Center

Student: Jared Hjersted (6th year Ph.D.)

Collaborator: Prof. Krishna Mahadevan (U. Toronto)

Publications and Recent Presentations:

1. Hjersted, J. and M. A. Henson, "Optimization of Fed-Batch Yeast Fermentation using Dynamic Flux Balance Models," Biotechnology Progress, 22, 1239-1248 (2006). [PDF]
2. Hjersted, J., M. A. Henson and R. Mahadevan, "Genome-Scale Analysis of Saccharomyces cerevisiae Metabolism and Ethanol Production in Fed-Batch Culture," Biotechnology and Bioengineering, 97, 1190-1204 (2007). [PDF]
3. Michael A. Henson and Jared L. Hjersted, "Steady-State and Dynamic Flux Balance Analysis of Yeast Ethanol Production Strategies," AIChE Annual Meeting, Salt Lake City, UT, November 2007.