S76: The design, engineering, and optimization of microbial catalysts for bio-manufacturing of 1,4-butanediol

Genomatica has established an integrated computational/experimental metabolic engineering platform to design, create, and optimize novel high-producing organisms and bioprocesses.  Here we present the use of our platform to develop E. coli strains for the production of the industrial chemical 1,4-butanediol (BDO) from glucose and sucrose. BDO is a four-carbon diol that currently is manufactured exclusively through various petrochemical routes. It is part of a large volume family of solvents and polymer intermediates with an overall market opportunity exceeding $4.0B. Therefore, this product represents an opportunity to make a significant impact on the replacement of traditional petrochemical processes with benign bioprocesses using renewable feedstocks.

 This presentation will describe application of this integrated technology platform to design and construct a high-performing microorganism capable of producing BDO from carbohydrates for the first time. The Biopathway Predictor algorithm was employed to elucidate all possible routes to BDO from central metabolites, and choose the most favorable for implementation. We then utilized the OptKnock methodology to identify a set of gene deletions designed to couple product formation to growth. After constructing the host and pathway based on the design, a variety of systems biology approaches including microarrays, ¹³C-flux analysis, and metabolomics were applied to characterize the strain and identify targets for further improvement.

 The results to be presented demonstrate commercialization potential of this breakthrough biochemical process, as well as the success of our combined computational and experimental approach to rapidly engineer organisms for low-cost chemical and fuel production.