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Structure and Activity of Amide Bond Synthetases

Rowlinson, Benjamin (2018) Structure and Activity of Amide Bond Synthetases. MSc by research thesis, University of York.

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Abstract

The synthesis of amide bonds is one of the most common processes in pharmaceutical chemistry. Despite this, the production of amide bonds remains a very wasteful process, relying on coupling reagents that lead to poor atom economies. An alternative method for the production of amide bonds with high atom economies may be found in enzymatic biocatalysis. Exploration of natural paths to amide synthesis is key to the development of this. McbA is an ATP-dependent amide bond synthetase from Marinactinospora thermotolerans. McbA has been found to catalyse the production of amide bonds in β-carboline amides. The ability of McbA to accept a wide range of substrates has previously been demonstrated making it a promising candidate for the development of a broad-range amide bond forming catalyst. In this work is described the crystallisation of McbA and the determination of an McbA structure, as well as the identification and characterisation of a new homologue of McbA. Crystals of a K483A mutant of McbA were produced and the structure was determined. From the structure it was seen that McbA is remarkably similar to the ANL superfamily of adenylating enzymes with two distinct domains; a larger N-terminal domain and a smaller C-terminal domain. Two conformations of McbA were seen in the asymmetric unit, which have been termed the adenylation conformation and amidation conformation based on their similarity to the adenylation and thiolation conformations seen in the ANL enzymes. The structures offer potential insights for future engineering work. The discovery and characterisation of these enzymes may represent the beginnings of an enzymatic toolbox for amide bond synthesis.

Item Type: Thesis (MSc by research)
Related URLs:
Academic Units: The University of York > Chemistry (York)
Depositing User: Mr Benjamin Rowlinson
Date Deposited: 25 Apr 2019 13:04
Last Modified: 25 Apr 2019 13:04
URI: http://etheses.whiterose.ac.uk/id/eprint/23392

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