Biosynthetic Innovation on A Polyketide Assembly Line: Biochemical Studies of Curacin A Pathway.
dc.contributor.author | Gu, Liangcai | en_US |
dc.date.accessioned | 2009-02-05T19:25:29Z | |
dc.date.available | NO_RESTRICTION | en_US |
dc.date.available | 2009-02-05T19:25:29Z | |
dc.date.issued | 2008 | en_US |
dc.date.submitted | en_US | |
dc.identifier.uri | https://hdl.handle.net/2027.42/61623 | |
dc.description.abstract | The chemical diversity of natural products is fueled by the emergence and ongoing evolution of biosynthetic pathways in secondary metabolism. However, enzyme evolution in natural product assembly lines, especially the co-evolution of enzymes as functional assemblies for metabolic diversification, is not well understood, especially at the biochemical level. The biosynthetic pathway of curacin A, a marine cyanobacterial metabolite from Lyngbya majuscula possessing anti-mitotic and anti-proliferative activity, provides us intriguing opportunities to reveal the evolutionary events on the polyketide pathway. My Ph.D. research is focused on biochemical studies of the chain initiation, cyclopropane formation and chain termination steps in curacin A pathway. We identified and characterized a set of unusual enzymes that catalyze GNAT-like polyketide chain initiation, polyketide HMG β-branching, chlorination, cyclopropanation, and decarboxylative polyketide chain termination steps. Heterologous protein expression and enzyme purification, mutagenesis, biochemical assays, mass spectrometry and X-ray crystallography have been employed in our studies. These enzymes with attractive biochemical features significantly expand the catalytic repertoire of nature product biosynthesis, as well as provide ideal objects for evolutionary biologists and mechanistic enzymologists. Based on our studies, different types of metabolic evolution are observed, including 1) the insertion of gene assemblies by homologous recombination, 2) recruitment of new enzymes to change biochemical schemes and functional group placement, 3) development of new functions from canonical enzyme scaffolds, and 4) diversification of regiochemical controls for pathway diversification. As such, our biochemical studies can significantly advance the knowledge of natural product biosynthesis, enzyme evolution and mechanistic enzymology. | en_US |
dc.format.extent | 22274242 bytes | |
dc.format.extent | 1373 bytes | |
dc.format.mimetype | application/pdf | |
dc.format.mimetype | text/plain | |
dc.language.iso | en_US | en_US |
dc.subject | Biosynthesis of Natural Products | en_US |
dc.subject | GNAT | en_US |
dc.subject | Cyclopropane | en_US |
dc.subject | Polyketide Beta-branching | en_US |
dc.subject | Halogenase | en_US |
dc.subject | Sulfotransferase | en_US |
dc.title | Biosynthetic Innovation on A Polyketide Assembly Line: Biochemical Studies of Curacin A Pathway. | en_US |
dc.type | Thesis | en_US |
dc.description.thesisdegreename | PhD | en_US |
dc.description.thesisdegreediscipline | Medicinal Chemistry | en_US |
dc.description.thesisdegreegrantor | University of Michigan, Horace H. Rackham School of Graduate Studies | en_US |
dc.contributor.committeemember | Sherman, David H. | en_US |
dc.contributor.committeemember | Garcia, George A. | en_US |
dc.contributor.committeemember | Garneau-Tsodikova, Sylvie | en_US |
dc.contributor.committeemember | Smith, Janet | en_US |
dc.contributor.committeemember | Woodard, Ronald W. | en_US |
dc.subject.hlbsecondlevel | Biological Chemistry | en_US |
dc.subject.hlbtoplevel | Science | en_US |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/61623/1/gulc_1.pdf | |
dc.owningcollname | Dissertations and Theses (Ph.D. and Master's) |
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