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Intercepting intermediates in amino ...

Balibar, Carl Joseph.

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Intercepting intermediates in amino acid-derived natural product biosynthesis.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Intercepting intermediates in amino acid-derived natural product biosynthesis./
Author:	Balibar, Carl Joseph.
Description:	292 p.
Notes:	Adviser: Christopher T. Walsh.
Contained By:	Dissertation Abstracts International69-01B.
Subject:	Biology, Microbiology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3295898
ISBN:	9780549408161

Intercepting intermediates in amino acid-derived natural product biosynthesis.
Balibar, Carl Joseph.

Intercepting intermediates in amino acid-derived natural product biosynthesis. - 292 p.

Adviser: Christopher T. Walsh.

Thesis (Ph.D.)--Harvard University, 2008.

Proper timing and coordination of chemical transformations is paramount to the biosynthesis of any natural product. Often, intermediates formed can be unstable and reactive and if enzymatic processes are not properly channeled, off-pathway nonproductive metabolites can result. In many biosynthetic systems a single intermediate is precursor to a myriad of downstream products, further illustrating the need for proper regulation of biosynthesis both within a single pathway and between multiple pathways. In order to understand the biosynthesis of any natural product, for use in both its production and possible reprogramming, the logic and mechanism behind the chemistry taking place must explored. Here we focus on the biosynthesis of several amino acid-derived natural products, examining enzymatic transformations requiring the interception of unique and important intermediates.

ISBN: 9780549408161Subjects--Topical Terms:

1017734
Biology, Microbiology.

Intercepting intermediates in amino acid-derived natural product biosynthesis.
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020 $a 9780549408161
035 $a (UMI)AAI3295898
035 $a AAI3295898
040 $a UMI $c UMI
100 1 $a Balibar, Carl Joseph. $3 1266974
245 1 0 $a Intercepting intermediates in amino acid-derived natural product biosynthesis.
300 $a 292 p.
500 $a Adviser: Christopher T. Walsh.
500 $a Source: Dissertation Abstracts International, Volume: 69-01, Section: B, page: 0283.
502 $a Thesis (Ph.D.)--Harvard University, 2008.
520 $a Proper timing and coordination of chemical transformations is paramount to the biosynthesis of any natural product. Often, intermediates formed can be unstable and reactive and if enzymatic processes are not properly channeled, off-pathway nonproductive metabolites can result. In many biosynthetic systems a single intermediate is precursor to a myriad of downstream products, further illustrating the need for proper regulation of biosynthesis both within a single pathway and between multiple pathways. In order to understand the biosynthesis of any natural product, for use in both its production and possible reprogramming, the logic and mechanism behind the chemistry taking place must explored. Here we focus on the biosynthesis of several amino acid-derived natural products, examining enzymatic transformations requiring the interception of unique and important intermediates.
520 $a The bisindole alkaloids violacein and terrequinone A are both derived from two molecules of L-tryptophan. Although their biosyntheses begin with the oxidation of said L-tryptophan, the pathways take different approaches to this oxidation. Furthermore, the dimerization of these oxidized intermediates is quite different with the violacein pathway utilizing an oxidative head-to-head coupling scheme and the terrequinone A pathway utilizing an acid-base catalyzed head-to-tail coupling scheme. These different strategies ultimately yield either a nitrogen containing five-membered pyrrole in violacein or the six-membered benzoquinone in terrequinone A. Perhaps most intriguing in these pathways is the use of proteins with unknown mechanism which divert intermediates from off-pathway shunt products, to on-pathway metabolites.
520 $a Nonribosomal peptide synthetases are large multifunctional enzymes responsible for the biosynthesis of many amino acid derived natural products. Here we study the biosynthesis of several NRPS generated products including coumermycin, gliotoxin, arthrofactin, and vibriobactin. In the coumermycin system, we focus on the acyltransferase CouN7 responsible for the installation of the 5-methylpyrrole pharmacophore on the aminocoumarin scaffold. We find that this acyltransferase is promiscuous for both the acyl intermediate it intercepts for transfer and the scaffold to which it is transferring, allowing for the generation of novel aminocoumarin antibiotics. In the biosynthesis of gliotoxin, we study the multimodular NRPS GliP responsible for generating the diketopiperazine scaffold common the epipolythiodioxopiperazine family of fungal metabolites. In arthrofactin biosynthesis, we focus on the cryptic epimerization activity harbored within unique condensation domains of the NRPS, responsible for the online generation of D-amino acids from peptidyl-S -enzyme tethered intermediates. Finally, in our studies of vibriobactin, we examine the flux of aminoacyl-O-AMP intermediates captured in cis or in trans across the interface of the dimeric NRPS VibF.
590 $a School code: 0084.
650 4 $a Biology, Microbiology. $3 1017734
650 4 $a Biology, Molecular. $3 1017719
650 4 $a Chemistry, Biochemistry. $3 1017722
690 $a 0307
690 $a 0410
690 $a 0487
710 2 $a Harvard University. $3 528741
773 0 $t Dissertation Abstracts International $g 69-01B.
790 $a 0084
790 1 0 $a Walsh, Christopher T., $e advisor
791 $a Ph.D.
792 $a 2008
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3295898