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Protein-protein interactions in bios...

Kumar, Pawan.

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Protein-protein interactions in biosynthesis of complex polyketides.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Protein-protein interactions in biosynthesis of complex polyketides./
Author:	Kumar, Pawan.
Description:	93 p.
Notes:	Source: Dissertation Abstracts International, Volume: 65-09, Section: B, page: 4708.
Contained By:	Dissertation Abstracts International65-09B.
Subject:	Engineering, Chemical. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3145556
ISBN:	0496045075

Protein-protein interactions in biosynthesis of complex polyketides.
Kumar, Pawan.

Protein-protein interactions in biosynthesis of complex polyketides. - 93 p.

Source: Dissertation Abstracts International, Volume: 65-09, Section: B, page: 4708.

Thesis (Ph.D.)--Stanford University, 2004.

Modular polyketide synthases such as 6-deoxyerythronolide B synthase (DEBS) catalyze the synthesis of biologically active polyketide natural compounds, in an assembly-line fashion through multiple multifunctional enzymes called modules. This modular architecture, provides an attractive opportunity for the engineered biosynthesis of novel polyketide products via genetic replacement of individual domains within the module or entire module with desired catalytic properties.

ISBN: 0496045075Subjects--Topical Terms:

1018531
Engineering, Chemical.

Protein-protein interactions in biosynthesis of complex polyketides.
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100 1 $a Kumar, Pawan. $3 1932857
245 1 0 $a Protein-protein interactions in biosynthesis of complex polyketides.
300 $a 93 p.
500 $a Source: Dissertation Abstracts International, Volume: 65-09, Section: B, page: 4708.
500 $a Adviser: Chaitan Khosla.
502 $a Thesis (Ph.D.)--Stanford University, 2004.
520 $a Modular polyketide synthases such as 6-deoxyerythronolide B synthase (DEBS) catalyze the synthesis of biologically active polyketide natural compounds, in an assembly-line fashion through multiple multifunctional enzymes called modules. This modular architecture, provides an attractive opportunity for the engineered biosynthesis of novel polyketide products via genetic replacement of individual domains within the module or entire module with desired catalytic properties.
520 $a To modify the polyketides, acyl transferase (AT) domain that controls the selective incorporation of extender units in a module, has been replaced with a nonnative AT domain with different building block selectivity but usually resulted into attenuated catalytic function of the hybrid module due to structural perturbations caused by the foreign domain. As an alternative to AT swapping, in the first part of this work, we have demonstrated that malonyl-CoA:ACP transacylase, which is a standalone acyl transferase protein, was able to transacylate malonyl groups onto an AT-null mutant modular polyketide synthase without any loss in catalytic efficiency, both in vitro and in vivo. The generalization of this transacylation strategy in combination with identification and characterization of novel acyl transferases may provide a simple method for generating site-specific modifications in polyketides.
520 $a By replacing the entire module in a PKS, a more rigorous site specific change in the polyketide can be accomplished. Replacing an entire module creates a nonnative protein-protein interface which may result in poor channeling of intermediates between adjacent modules. Recent studies have highlighted the pivotal role of short intermodular "linker pairs" in the selective channeling of biosynthetic intermediates between adjacent PKS modules. In the second part of this work, we investigated the mechanism by which a linker pair from the 6-deoxyerythronolide B synthase promotes chain transfer. Our studies provide evidence for a "coiled-coil" model in which the individual peptides comprising this linker pair adopt helical conformations that associate through a combination of hydrophobic and electrostatic interactions in an antiparallel fashion. Given the important contribution of such linker pair interactions to the kinetics of chain transfer between PKS modules, the ability to rationally modulate linker pair affinity by site-directed mutagenesis could be useful in the construction of optimized hybrid PKSs.
590 $a School code: 0212.
650 4 $a Engineering, Chemical. $3 1018531
650 4 $a Chemistry, Biochemistry. $3 1017722
650 4 $a Chemistry, Pharmaceutical. $3 550957
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710 2 0 $a Stanford University. $3 754827
773 0 $t Dissertation Abstracts International $g 65-09B.
790 1 0 $a Khosla, Chaitan, $e advisor
790 $a 0212
791 $a Ph.D.
792 $a 2004
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3145556