Objective

Living organisms utilize enzyme-catalyzed reactions to synthesize a large array of complex molecules and macromolecules. Enzyme catalyzed processes are characterized by mild conditions, fast reaction rates, highly stereospecific interactions, and minimal byproduct formation. Visualization and control of these living processes will enable researchers to ‘engineer’ metabolic systems; for example the creation of renewable carbon resources or novel pharmaceuticals. The complexity of biological systems dictates that a computational framework be used for the identification of chemicals novel to biological systems and the rational design of the biosynthetic routes that lead to these novel chemicals. The focus of this group is to build a systematic framework for the discovery and evaluation of novel pathways that could lead to novel chemicals.

Approach

Enzymes are commonly classified by catalytic function. A computer uses the framework to interpret this classification system as a set of rules for functional group transformations of enzyme-catalyzed reactions. Manipulating this framework enables the researcher to see where and how a novel species may be generated from a given substrate (e.g. A new cancer drug from sucrose). Graph theory draws together the math, statistical, chemical and other concepts necessary to evaluate pathways into a comprehensive picture which may be used to effectively perceive the whole network.
For a given set of reactants and their corresponding structures, as well as a set of reaction rules, a set of molecules is generated along with their corresponding pathways of likely enzyme-catalyzed transformations. The addition of new pathways leading to novel molecules will disturb the original mass, energy, and electron balances of a living cell; in other words, some pathways could never occur in the cell due to flux and energy constraints. Metabolic Flux Analysis (MFA), methods based on chemical thermodynamics, and other means will be used by our group to evaluate existing and novel metabolic pathways.

Results

The biosynthetic ability of the shikimate pathway was explored and the results show not only the reconstruction of the natural pathway, but new pathways leading to chemicals novel to biological systems.

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