Engineered biosynthesis of nonribosomal lipopeptides with modified fatty acid side chains.

Engineered biosynthesis of nonribosomal lipopeptides with modified fatty acid side chains. Research Abstract Details 

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Engineered biosynthesis of nonribosomal lipopeptides with modified fatty acid side chains. Abstract Text:

Amanda Powell,Mathew Borg,Bagher Amir-Heidari,Joanne M Neary,Jenny Thirlway,Barrie Wilkinson,Colin P Smith,Jason Micklefield,Amanda Powell,Mathew Borg,Bagher Amir-Heidari,Joanne M Neary,Jenny Thirlway,Barrie Wilkinson,Colin P Smith,Jason Micklefield,

The biological properties of the calcium-dependent antibiotics (CDAs), daptomycin and related nonribosomal lipopeptides, depend to a large extent on the nature of the N-terminal fatty acid moiety. It is suggested that the chain length of the unusually short (C6) 2,3-epoxyhexanoyl fatty acid moiety of CDA is determined by the specificity of the KAS-II enzyme encoded by fabF3 in the CDA biosynthetic gene cluster. Indeed, deletion of the downstream gene hxcO results in three new lipopeptides, all of which possess hexanoyl side chains (hCDAs). This confirms that HxcO functions as a hexanoyl-CoA or -ACP oxidase. The absence of additional CDA products with longer fatty acid groups further suggests that the CDA lipid chain is biosynthesized on a single ACP and is then transferred directly from this ACP to the first CDA peptide synthetase (CdaPS1). Interestingly, the hexanoyl-containing CDAs retain antibiotic activity. To further modulate the biological properties of CDA by introducing alternative fatty acid groups, a mutasynthesis approach was developed. This involved mutating the key active site Ser residue of the CdaPS1, module 1 PCP domain to Ala, which prevents subsequent phosphopantetheinylation. In the absence of the natural module 1 PCP tethered intermediate, it is possible to effect incorporation of different N-acyl-L-serinyl N-acetylcysteamine (NAC) thioester analogues, leading to CDA products with pentanoyl as well as hexanoyl side chains.

Engineered biosynthesis of nonribosomal lipopeptides with modified fatty acid side chains. Publishing Authors By Initials

A Powell,M Borg,B Amir-Heidari,JM Neary,J Thirlway,B Wilkinson,CP Smith,J Micklefield,A Powell,M Borg,B Amir-Heidari,JM Neary,J Thirlway,B Wilkinson,CP Smith,J Micklefield,

For similar bacteria: cyanobacteria: synechocystis research abstracts see: bacteria: cyanobacteria: synechocystis research

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Engineered biosynthesis of nonribosomal lipopeptides with modified fatty acid side chains. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Journal of the American Chemical Society

VOLUME: 129

Page Numbers: 15182-91

Journal Abbreviation: J. Am. Chem. Soc.

ISSN: 1520-5126

DAY: 17

MONTH: 11

YEAR: 2007

Engineered biosynthesis of nonribosomal lipopeptides with modified fatty acid side chains. Information

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LANGUAGE: eng

NlmUniqueID: 7503056

Engineered biosynthesis of nonribosomal lipopeptides with modified fatty acid side chains. Keywords Mesh Terms:

KEYWORDS: Synechocystis

MESH TERMS: metabolism

Chemical & Substance for Abstract: Engineered biosynthesis of nonribosomal lipopeptides with modified fatty acid side chains. Information

Substance Name: 3-Oxoacyl-(Acyl-Carrier-Protein) Synthas

Registry Number: EC 2.3.1.41

Grant and Affiliation Information for Engineered biosynthesis of nonribosomal lipopeptides with modified fatty acid side chains.

AFFILIATION: School of Chemistry, The University of Manchester, Oxford Road, Manchester, United Kingdom.

Country: United States

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MEDLINETA: J Am Chem Soc

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