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Macrocyclization catalysis by excised thioesterase domains from natural product synthetases

Record Type:	Electronic resources : Monograph/item
Title/Author:	Macrocyclization catalysis by excised thioesterase domains from natural product synthetases
Author:	Kohli, Rahul Manu.
Description:	140 p.
Notes:	Adviser: Christopher T. Walsh.
Notes:	Source: Dissertation Abstracts International, Volume: 65-05, Section: B, page: 2399.
Contained By:	Dissertation Abstracts International65-05B.
Subject:	Chemistry, Biochemistry.
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3131886
ISBN:	0496791265

Macrocyclization catalysis by excised thioesterase domains from natural product synthetases
Kohli, Rahul Manu.

Macrocyclization catalysis by excised thioesterase domains from natural product synthetases [electronic resource] - 140 p.

Adviser: Christopher T. Walsh.

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

Macrocyclization is often nature's way of constraining natural products to their bioactive conformations. A variety of macrocyclic natural products are synthesized by nonribosomal peptide (NRP) synthetases, polyketide (PK) syntheses or hybrid NRP/PK synthetases. These biosynthetic systems involve construction of linear acyl chains by multi-modular enzymatic assembly lines with biosynthetic intermediates tethered to carrier protein domains in each module. At the C-terminus of these synthetases often lies a thioesterase (TE) domain, whose role is to catalyze chain disconnection from the thioester tether to the assembly line. For assembly lines resulting in macrocyclic products, this chain disconnection reaction, in net, results in capture of the acyl chain by an intramolecular nucleophile giving a constrained product.

ISBN: 0496791265Subjects--Topical Terms:

226900
Chemistry, Biochemistry.

Macrocyclization catalysis by excised thioesterase domains from natural product synthetases
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245 1 0 $a Macrocyclization catalysis by excised thioesterase domains from natural product synthetases $h [electronic resource]
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500 $a Source: Dissertation Abstracts International, Volume: 65-05, Section: B, page: 2399.
502 $a Thesis (Ph.D.)--Harvard University, 2004.
520 # $a Macrocyclization is often nature's way of constraining natural products to their bioactive conformations. A variety of macrocyclic natural products are synthesized by nonribosomal peptide (NRP) synthetases, polyketide (PK) syntheses or hybrid NRP/PK synthetases. These biosynthetic systems involve construction of linear acyl chains by multi-modular enzymatic assembly lines with biosynthetic intermediates tethered to carrier protein domains in each module. At the C-terminus of these synthetases often lies a thioesterase (TE) domain, whose role is to catalyze chain disconnection from the thioester tether to the assembly line. For assembly lines resulting in macrocyclic products, this chain disconnection reaction, in net, results in capture of the acyl chain by an intramolecular nucleophile giving a constrained product.
520 # $a These studies originated from a desire to understand the manner in which nature achieves macrocyclic structure in important natural products. At the outset of this work, it was not known if TE domains excised from their native context, as part of the larger synthetase, would retain the ability to catalyze macrocyclization. As a result of these studies, we have discovered a versatile catalyst, suited for use in engineered natural product assembly lines, the synthesis of natural product analogues with improved properties, and the synthesis of novel macrocyclic compounds that can be screened for new activities.
520 # $a We demonstrate that excised domains from the synthetases producing tyrocidine A, gramicidin S and surfactin A remain competent for cyclization of soluble linear peptide thioester substrates modeled on their natural linear substrates tethered to carrier protein domains. Biochemical studies by systematic variation in the peptide substrate reveal the tyrocidine TE to be a versatile catalyst of macrocyclization, tolerating alterations in most side chains of the substrate and the length of the peptide substrate. To exploit this tolerance, we report a strategy that has allowed us to merge combinatorial solid-phase techniques with natural product biosynthesis, generating a library of natural product analogues of the antibiotic tyrocidine A with improved bioactivity. Further, TE catalysis is shown to have utility for the generation of novel bioactive molecules by the synthesis of macrocyclic hybrid NRP/PK molecules and macrocyclic inhibitors of integrin receptors.
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