Computational discovery of biochemical routes to specialty chemicals

A computational framework has been developed for the construction and evaluation of metabolic pathways given input substrates and knowledge of enzyme-catalyzed reactions. Application of the framework creates new and existing routes to both chemicals known to exist in biological systems and chemicals novel to biological systems. In the present application, we focus on biosynthetic routes to 7-carboxyindole, a specialty chemical currently produced by organic synthesis, using chorismate as a starting compound and the enzyme actions native to the biosynthetic route from chorismate to tryptophyan. Graph theory and its associated algorithms are exploited to represent molecules and perform enzyme-catalyzed reactions. Through repetitive application of the set of operators representing the enzymatic reactions of interest to the reactants and their progeny, reaction pathways are generated automatically. The concept of generalized enzyme function is introduced and defined as the third-level enzyme function (EC i.j.k) according to the four-digit transformations of the enzyme classification system (EC i.j.k.l). This concept maps enzyme-catalyzed reactions to transformations of functional groups and enables the generation of novel species and pathways. Thermodynamic properties are calculated using a group contribution method "on-the-fly" in order to provide one assessment of the relative feasibility of the novel pathways.