Title page for ETD etd-04192011-135539


Type of Document Dissertation
Author Rui, Zhe
Author's Email Address zrui2@tigers.lsu.edu
URN etd-04192011-135539
Title Biochemical and Genetic Insights into Asukamycin Biosynthesis
Degree Doctor of Philosophy (Ph.D.)
Department Biological Sciences
Advisory Committee
Advisor Name Title
Newcomer, Marcia E Committee Chair
Aboul-ela, Fareed M. Committee Member
Bartlett, Sue G. Committee Member
Ding, Huangen Committee Member
Gillis, Thomas P. Dean's Representative
Keywords
  • asukamycin
  • secondary metabolites
  • biosynthesis
  • streptomyces
  • manumycin
Date of Defense 2010-11-01
Availability unrestricted
Abstract
Asukamycin, a member of the manumycin family metabolites, is an antimicrobial and potential antitumor agent isolated from Streptomyces nodosus subsp. asukaensis. The entire asukamycin biosynthetic gene cluster was cloned, assembled and expressed heterologously in Streptomyces lividans. Bioinformatic analysis and mutagenesis studies elucidated the biosynthetic pathway at the genetic and biochemical level. Four gene sets, asuA-D, govern the formation and assembly of the asukamycin building blocks, a 3-amino-4-hydroxybenzoic acid (3,4-AHBA) core component, a cyclohexane ring, two triene polyketide chains and a 2-amino-3-hydroxycyclopent-2-enone (C5N) moiety to form the intermediate protoasukamycin. AsuE1 and AsuE2 catalyze the conversion of protoasukamycin to 4-hydroxyprotoasukamycin, which is epoxidized at C5-C6 by AsuE3 to the final product, asukamycin. Branched acyl CoA starter units, derived from Val, Leu and Ile, can be incorporated by the actions of the polyketide synthase KSIII AsuC3/C4 as well as the cellular fatty acid synthase FabH to produce the asukamycin congeners A2-A7. In addition, the type II thioesterase AsuC15 limits the cellular level of -cyclohexyl fatty acids and likely maintains homeostasis of the cellular membrane.
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