title: Inverse metabolic engineering: a strategy for directed genetic engineering of useful phenotypes.
abstract: The classical method of metabolic engineering, identifying a rate-determining step in a pathway and alleviating the bottleneck by enzyme overexpression, has motivated much research but has enjoyed only limited practical success. Intervention of other limiting steps, of counter-balancing regulation, and of unknown coupled pathways often confounds this direct approach. Here the concept of inverse metabolic engineering is codified and its application is illustrated with several examples. Inverse metabolic engineering means the elucidation of a metabolic engineering strategy by: first, identifying, constructing, or calculating a desired phenotype; second, determining the genetic or the particular environmental factors conferring that phenotype; and third, endowing that phenotype on another strain or organism by directed genetic or environmental manipulation. This paradigm has been successfully applied in several contexts, including elimination of growth factor requirements in mammalian cell culture and increasing the energetic efficiency of microaerobic bacterial respiration.
authors.affiliation: Institute of Biotechnology, ETH Zürich, Switzerland.
authors.forename: James E
authors.initials: JE
authors.lastname: Bailey
authors.forename: Adriana
authors.initials: A
authors.lastname: Sburlati
authors.forename: Vassily
authors.initials: V
authors.lastname: Hatzimanikatis
authors.forename: Kelvin
authors.initials: K
authors.lastname: Lee
authors.forename: Wolfgang A
authors.initials: WA
authors.lastname: Renner
authors.forename: Philip S
authors.initials: PS
authors.lastname: Tsai
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D016466:CHO Cells / Q000187:drug effects / Q000502:physiology; D018929:Cell Culture Techniques / Q000379:methods; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D002477:Cells / Q000378:metabolism; D003001:Cloning, Molecular; D006224:Cricetinae; D004798:Enzymes / Q000378:metabolism; D005818:Genetic Engineering / Q000379:methods*; D006133:Growth Substances / Q000494:pharmacology; D006454:Hemoglobins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008322:Mammals; D008660:Metabolism / Q000235:genetics*; D008954:Models, Biological; D010641:Phenotype; D011995:Recombination, Genetic; D054793:Truncated Hemoglobins
chemical_list: D001426:Bacterial Proteins; D004798:Enzymes; D006133:Growth Substances; D006454:Hemoglobins; D054793:Truncated Hemoglobins; C082613:hemoglobin protein, Vitreoscilla