Details of Grant 

EPSRC Reference:	GR/R25743/01
Title:	Engineering Catalytic Sites Based Upon Molecular Recognition and Co-Ordination Chemistry
Principal Investigator:	Mareque-Rivas, Professor J
Other Investigators:
Researcher Co-Investigators:
Project Partners:
Department:	Sch of Chemistry
Organisation:	University of Edinburgh
Scheme:	Fast Stream
Starts:	05 November 2001	Ends:	04 May 2005	Value (£):	166,340
EPSRC Research Topic Classifications:	Biological & Medicinal Chem. Co-ordination Chemistry
EPSRC Industrial Sector Classifications:	Pharmaceuticals and Biotechnology No relevance to Underpinning Sectors
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Panel History:
Summary on Grant Application Form
Inspired by metalloenzymes, this work will use transition state stabilisation by peripheral H-bonding interactions and metal substrate activation to achieve the rate acceleration of important chemical transformations. The strategy involves engineering a ligand system with recognition sites for both metal and substrate or transition state. Whereas the metal recognition site will be created applying co-ordination chemistry, the substrate or transition state recognition site will be created applying supramolecular synthons. This work will focus on two reactions: 1) N-carbamyl-L-aspastate (L-CA) to L-dihydroorotate (L-DHO) and 2) cytidine to uridine, which are catalysed in nature by dihydroorotase (DHOase) and cytidine deaminase (CDA), respectively. These reactions were selected on the basis of their relevance. Transformation of L-CA to L-DHO is necessary in DNA synthesis and thus inhibitiors for this reaction are used among other things to stop the exponential multiplication of erythrocytic malaria parasites. Their activity relies on their ability to complete successfully with the transition with the transition state species. Two ligand systems that capture the essence of metal and transition atate binding regions will be prepared and the activity of several of their metal complexes towards this transformation investigated. CDA is, on the other hand, known to be capable of degrading cytidine-based anti-tumour agents and of synthesising the potent anti-HIV drug 3TC. Metal complexes of a ligand system engineered to have the metal and substrate binding elements of CDA will be tested as non-enzymatic alternatives for the production of such species.
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