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Biocatalytic approaches to ketodiols and aminodiols

Cazares Robles, A.; (2012) Biocatalytic approaches to ketodiols and aminodiols. Doctoral thesis , UCL (University College London).

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The ketodiol and aminodiol moieties are present in a number of biologically important compounds such as steroids, antibiotics and sphingosines. Although their chemical syntheses are well documented in the literature, the procedures are usually step-intensive and/or require the use of noxious reagents. These limitations can be potentially overcome by the use of the two enzymes transketolase and transaminase. Transketolase transfers a two-carbon ketol unit between ketoses and aldoses in vivo, but is also able to decarboxylate hydroxypyruvate in the presence of a suitable acceptor. In this work, the tolerance and stereoselectivity of wild-type transketolase from Escherichia coli towards aliphatic aldehydes were assessed, and a mechanism that accounts for the observed trend in stereoselectivity was postulated with the aid of molecular docking. The stereoselectivity of the transformation was enhanced and reversed by using selected active-site single-point mutants and their mode of action partly rationalised with molecular modelling. Transaminases catalyse reductive aminations in vivo typically using amino acids and α-ketoacids as substrates. A subgroup of these enzymes, however, has broad substrate specificity and is able to aminate the ketodiols produced by transketolase. In the present work, the stereoselectivity and stereospecificity of transaminase CV2025 from Chromobacterium violaceum were assessed using aliphatic ketodiols as substrates. Furthermore, reaction conditions were optimised and a series of truncated dihydrosphingosines were synthesised in two steps under mild aqueous conditions. Finally, the range of substrates for transketolase was further expanded by using a number of functionalised aldehydes as substrates and work towards the stereoselective synthesis of galantinic acid was carried out and is presented. Chapter 1 of this thesis presents an introduction to ketodiols and aminodiols, their occurrence and importance as well as methods to synthesise them, along with an introduction to biocatalysis focusing on transketolase and transaminase. Chapter 2 describes the studies carried out with wild-type and mutant transketolases on aliphatic aldehydes. Chapter 3 focuses on the assessment of the stereoselectivity and optimisation of the transaminase reaction with aliphatic ketodiols. Chapter 4 explains the work towards the stereoselective synthesis of galantinic acid and Chapter 5 details the work on novel substrates for transketolase. Chapter 6 summarises the main findings and conclusions of this thesis and outlines suggestions for future work on the project.

Type: Thesis (Doctoral)
Title: Biocatalytic approaches to ketodiols and aminodiols
Language: English
Additional information: Permission for digitisation not received
UCL classification: UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry
URI: https://discovery.ucl.ac.uk/id/eprint/1343838
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