title: Evaluating enzymatic synthesis of small molecule drugs.
abstract: There have been many achievements in applying biochemical synthetic routes to the synthesis of commodity chemicals. However, most of these endeavors have focused on optimizing and increasing the yields of naturally existing pathways. We sought to evaluate the potential for biosynthesis beyond the limits of known biochemistry towards the production of small molecule drugs that do not exist in nature. Because of the potential for improved yields compared to total synthesis, and therefore lower manufacturing costs, we focused on drugs for diseases endemic to many resource poor regions, like tuberculosis and HIV. Using generalized biochemical reaction rules, we were able to design biochemical pathways for the production of eight small molecule drugs or drug precursors and identify potential enzyme-substrate pairs for nearly every predicted reaction. All pathways begin from native metabolites, abrogating the need for specialized precursors. The simulated pathways showed several trends with the sequential ordering of reactions as well as the types of chemistries used. For some compounds, the main obstacles to finding feasible biochemical pathways were the lack of appropriate, natural starting compounds and a low diversity of biochemical coupling reactions necessary to synthesize molecules with larger molecular size.
authors.affiliation: Department of Chemical and Biological Engineering, Northwestern University, Evanston, IL 60208, United States.
authors.forename: Matthew
authors.initials: M
authors.lastname: Moura
authors.affiliation: Interdisciplinary Biological Sciences Graduate Program, Northwestern University, Evanston, IL 60208, United States.
authors.forename: Justin
authors.initials: J
authors.lastname: Finkle
authors.affiliation: Interdisciplinary Biological Sciences Graduate Program, Northwestern University, Evanston, IL 60208, United States.
authors.forename: Sarah
authors.initials: S
authors.lastname: Stainbrook
authors.affiliation: Department of Chemical and Biological Engineering, Northwestern University, Evanston, IL 60208, United States.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Greene
authors.affiliation: Department of Chemical and Biological Engineering, Northwestern University, Evanston, IL 60208, United States; Interdisciplinary Biological Sciences Graduate Program, Northwestern University, Evanston, IL 60208, United States.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Broadbelt
authors.affiliation: Department of Chemical and Biological Engineering, Northwestern University, Evanston, IL 60208, United States; Interdisciplinary Biological Sciences Graduate Program, Northwestern University, Evanston, IL 60208, United States.
authors.forename: Keith E J
authors.initials: KEJ
authors.lastname: Tyo
mesh_terms: D053898:Biosynthetic Pathways / Q000502:physiology; D003198:Computer Simulation; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism*; D064688:Metabolic Flux Analysis / Q000379:methods*; D008954:Models, Biological; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D004364:Pharmaceutical Preparations; D015398:Signal Transduction / Q000502:physiology*; D012984:Software
chemical_list: D009097:Multienzyme Complexes; D010455:Peptides; D004364:Pharmaceutical Preparations
keywords: Computational biology; Drug synthesis; Metabolic engineering; Pharmaceutical production; Predictive biochemistry