title: Metabolic model for diversity-generating biosynthesis.
abstract: A conventional metabolic pathway leads to a specific product. In stark contrast, there are diversity-generating metabolic pathways that naturally produce different chemicals, sometimes of great diversity. We demonstrate that for one such pathway, tru, each ensuing metabolic step is slower, in parallel with the increasing potential chemical divergence generated as the pathway proceeds. Intermediates are long lived and accumulate progressively, in contrast with conventional metabolic pathways, in which the first step is rate-limiting and metabolic intermediates are short-lived. Understanding these fundamental differences enables several different practical applications, such as combinatorial biosynthesis, some of which we demonstrate here. We propose that these principles may provide a unifying framework underlying diversity-generating metabolism in many different biosynthetic pathways.
authors.affiliation: Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112;
authors.forename: Ma Diarey
authors.initials: MD
authors.lastname: Tianero
authors.affiliation: Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112;
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Pierce
authors.affiliation: Department of Biology, University of Utah, Salt Lake City, UT 84112;
authors.forename: Shrinivasan
authors.initials: S
authors.lastname: Raghuraman
authors.affiliation: Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112;
authors.forename: Debosmita
authors.initials: D
authors.lastname: Sardar
authors.affiliation: Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112;
authors.forename: John A
authors.initials: JA
authors.lastname: McIntosh
authors.affiliation: Symbion Discovery, Inc., Salt Lake City, UT 84115;
authors.forename: John R
authors.initials: JR
authors.lastname: Heemstra
authors.affiliation: Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112;
authors.forename: Zachary
authors.initials: Z
authors.lastname: Schonrock
authors.affiliation: Department of Chemistry, Vanderbilt University, Nashville, TN 37235;
authors.forename: Brett C
authors.initials: BC
authors.lastname: Covington
authors.affiliation: Department of Biochemistry, University of Utah, Salt Lake City, UT 84112.
authors.forename: J Alan
authors.initials: JA
authors.lastname: Maschek
authors.affiliation: Department of Biochemistry, University of Utah, Salt Lake City, UT 84112.
authors.forename: James E
authors.initials: JE
authors.lastname: Cox
authors.affiliation: Department of Chemistry, Vanderbilt University, Nashville, TN 37235;
authors.forename: Brian O
authors.initials: BO
authors.lastname: Bachmann
authors.affiliation: Department of Biology, University of Utah, Salt Lake City, UT 84112; olivera@biology.utah.edu ews1@utah.edu.
authors.forename: Baldomero M
authors.initials: BM
authors.lastname: Olivera
authors.affiliation: Symbion Discovery, Inc., Salt Lake City, UT 84115;
authors.forename: Duane E
authors.initials: DE
authors.lastname: Ruffner
authors.affiliation: Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112; Department of Biology, University of Utah, Salt Lake City, UT 84112; olivera@biology.utah.edu ews1@utah.edu.
authors.forename: Eric W
authors.initials: EW
authors.lastname: Schmidt
mesh_terms: D004926:Escherichia coli / Q000378:metabolism; D008660:Metabolism; D008798:Mevalonic Acid / Q000378:metabolism; D008954:Models, Biological; D017368:Protein Prenylation
chemical_list: D008798:Mevalonic Acid
keywords: RiPP; biosynthesis; cyanobactin; natural products; secondary metabolism
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