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From peptide precursors to lanthioni...

Xie, Lili.

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From peptide precursors to lanthionine-containing peptide antibiotics using the first isolated and active lacticin 481 synthetase: Mechanistic studies and peptide engineering.

Record Type:	Electronic resources : Monograph/item
Title/Author:	From peptide precursors to lanthionine-containing peptide antibiotics using the first isolated and active lacticin 481 synthetase: Mechanistic studies and peptide engineering./
Author:	Xie, Lili.
Description:	136 p.
Notes:	Source: Dissertation Abstracts International, Volume: 64-08, Section: B, page: 3814.
Contained By:	Dissertation Abstracts International64-08B.
Subject:	Chemistry, Biochemistry. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3101996

From peptide precursors to lanthionine-containing peptide antibiotics using the first isolated and active lacticin 481 synthetase: Mechanistic studies and peptide engineering.
Xie, Lili.

From peptide precursors to lanthionine-containing peptide antibiotics using the first isolated and active lacticin 481 synthetase: Mechanistic studies and peptide engineering. - 136 p.

Source: Dissertation Abstracts International, Volume: 64-08, Section: B, page: 3814.

Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2003.

Lantibiotics are gene-encoded, post-translationally modified antimicrobial peptides. The modifications include dehydration of several serines and threonines by the putative dehydratase LanB, followed by intramolecular conjugate addition of cysteines to the newly formed dehydro amino acids by the putative cyclase LanC. Both modifications can also be performed by a putative bifunctional enzyme LanM. In addition to their structural divergence, lantibiotics also display distinct and often novel mechanisms of cycotoxicity. A feature unique to ribosomally synthesized lantibiotics is that they are amenable to structural variation via site-directed mutagenesis. This potentially allows the use of combinatorial techniques to access a large number of diverse structures that can be used for structure-function studies and rational antibiotic design.Subjects--Topical Terms:

1017722
Chemistry, Biochemistry.

From peptide precursors to lanthionine-containing peptide antibiotics using the first isolated and active lacticin 481 synthetase: Mechanistic studies and peptide engineering.
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035 $a (UnM)AAI3101996
035 $a AAI3101996
040 $a UnM $c UnM
100 1 $a Xie, Lili. $3 1909686
245 1 0 $a From peptide precursors to lanthionine-containing peptide antibiotics using the first isolated and active lacticin 481 synthetase: Mechanistic studies and peptide engineering.
300 $a 136 p.
500 $a Source: Dissertation Abstracts International, Volume: 64-08, Section: B, page: 3814.
500 $a Adviser: Wilfred A. van der Donk.
502 $a Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2003.
520 $a Lantibiotics are gene-encoded, post-translationally modified antimicrobial peptides. The modifications include dehydration of several serines and threonines by the putative dehydratase LanB, followed by intramolecular conjugate addition of cysteines to the newly formed dehydro amino acids by the putative cyclase LanC. Both modifications can also be performed by a putative bifunctional enzyme LanM. In addition to their structural divergence, lantibiotics also display distinct and often novel mechanisms of cycotoxicity. A feature unique to ribosomally synthesized lantibiotics is that they are amenable to structural variation via site-directed mutagenesis. This potentially allows the use of combinatorial techniques to access a large number of diverse structures that can be used for structure-function studies and rational antibiotic design.
520 $a The putative dehydratase SpaB involved in the biosynthesis of subtilin was heterologously overexpressed in <italic>E. coli</italic> and purified by metal-chelated affinity chromatography. However, <italic>in vitro</italic> reconstitution using the purified SpaB, SpaC, and the substrate SpaS was unsuccessful. As a result, the biosynthesis of lacticin 481 which employs one single modification enzyme presumably responsible for both dehydration and cyclization was investigated. Both the modification enzyme LctM and the substrate LctA were cloned and purified to homogeneity. The <italic>in vitro</italic> reconstitution of LctM, the lacticin 481 synthetase, was successful. The assay product was characterized in detail through tandem mass spectrometry, suggesting the formation of identical structural motifs found in lacticin 481. Therefore, LctM is indeed a bifunctional protein, performing both dehydration and cyclization reactions. This study presents the very first <italic>in vitro</italic> biosynthetic system of any lantibiotic. In addition, upon treatment with the protease Lys-C, the modified peptide in the absence of the leader sequence and the first Lys residue showed biological activity. Mechanistic studies with the active LctM disclosed that the activity of LctM absolutely requires both Mg<super>2+</super> and ATP. The products of ATP were determined to be ADP and phosphate. The enzyme has low substrate specificity as a series of LctA mutants proved substrates for LctM. Furthermore, peptide engineering was performed, and a large number of lacticin 481 analogs were generated. From these studies, additional structural and mechanistic insights have been elaborated.
590 $a School code: 0090.
650 4 $a Chemistry, Biochemistry. $3 1017722
650 4 $a Biology, Molecular. $3 1017719
690 $a 0487
690 $a 0307
710 2 0 $a University of Illinois at Urbana-Champaign. $3 626646
773 0 $t Dissertation Abstracts International $g 64-08B.
790 1 0 $a van der Donk, Wilfred A., $e advisor
790 $a 0090
791 $a Ph.D.
792 $a 2003
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3101996