Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.709574
Title: Exploring and mapping the functional chemical space of amorphadiene synthase with non-canonical farnesyl diphosphate analogues
Author: Demiray, Melodi
ISNI:       0000 0004 6059 0487
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2016
Availability of Full Text:
Access from EThOS:
Full text unavailable from EThOS. Restricted access.
Access from Institution:
Abstract:
Malaria is a threat to approximately 40% of the world’s population. Artemisinin and its derivatives in combination therapy are the world’s number one treatment against malaria. Agricultural production remains the primary source of artemisinin, however alternative methods are constantly being seeked to combat the unreliable and fluctuating processes present today. In addition, reported cases of parasitic resistance to the combination therapies emphasise the urgent need to produce novel and active analogues to replace the existing first line treatments. Artemisinin is a terpenoid extracted from Artemisia annua. Terpenes constitute one of the largest families of natural products that boast a substantial degree of chemical diversity and functionality. The broad diversity of biological applications of terpenes has found several uses, particularly in medicine. Terpene synthases convert linear isoprenyl diphosphates into complex hydrocarbon structures that exhibit exquisite stereochemistry. Amorphadiene synthase converts farnesyl diphosphate to amorpha-4,11-diene. This bicyclic frame, with four stereocenters is the first precursor found in the biosynthesis of artemisinin. Terpene synthases are studied extensively by scientists, because of their ability to generate complex structures that require several synthetic steps to reproduce the same complexity. This project focuses on studying the promiscuity of amorphadiene synthase. By using the recombinant protein in vitro gives the advantage of feeding the enzyme with novel FDP analogues, in attempt to introduce new functionalities in the resulting amorphadiene structure. These added functional groups then serve as platforms to carry out further chemical steps or can be carried forward to the respective artemisinin derivative, and consequently tested for antimalarial activity. A library of FDP analogues were designed, synthesized and incubated with ADS to test for enzymatic activity. In addition to the search for new amorphadiene derivatives, one of the synthesized FDP analogues, 12-hydroxy FDP, was converted to dihydroartemisinic aldehyde. Dihydroartemisinic aldehyde is a precursor found further down the schematic pathway to artemisinin. A three-step chemo-enzymatic approach to producing dihydroartemisinic aldehyde was established, providing an alternative method to sourcing artemisinin.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.709574  DOI: Not available
Keywords: QD Chemistry
Share: