Details of Grant 

EPSRC Reference:	EP/N019598/1
Title:	Designer hybrid chemo-enzymatic catalysts for cofactor recycling
Principal Investigator:	Pordea, Dr A
Other Investigators:
Researcher Co-Investigators:
Project Partners:
Department:	Faculty of Engineering
Organisation:	University of Nottingham
Scheme:	First Grant - Revised 2009
Starts:	14 November 2016	Ends:	13 February 2018	Value (£):	99,728
EPSRC Research Topic Classifications:	Biological & Medicinal Chem. Catalysis & Applied Catalysis
EPSRC Industrial Sector Classifications:	No relevance to Underpinning Sectors
Related Grants:
Panel History:	Panel Date Panel Name Outcome 03 Dec 2015 EPSRC Physical Sciences Chemistry - December 2015 Announced
Summary on Grant Application Form
The development of new and efficient catalysts for the synthesis of complex molecules is an ongoing need in the chemical industry, with both bio- and chemo-catalysts being applied at scale. This research is concerned with the design of a novel, hybrid chemo-enzymatic catalyst, which combines the best features of both chemical and enzymatic catalysis, by introducing metal catalysts into natural enzymes. Enzymes have evolved in nature and can be modified by scientists to perform many useful transformations in a very efficient way. However, the modifications are never too far from the natural world, in terms of functionality (i.e, mutation of amino acids to other amino acids). Recently, specific chemical modification of proteins has been developed as an exciting new tool to introduce chemo-catalytic functionalities within a biomolecule, thus expanding the functionality space. The objective of this project is to implement such a modification procedure into an existing enzyme, to change its reactivity and improve a key reaction needed for industrial exploitation of enzymes. The novelty of this design is the use of an enzyme specifically evolved for substrate binding and transition state stabilisation. The longer term vision is to apply hybrid catalysts to completely unnatural catalytic reactions. The use of enzymes that stabilise hydride transfer transition states in conjunction with suitable chemical catalysts could be envisaged for expanding the enzyme functionality to the reduction of more challenging substrates, rarely occurring in nature (e.g. nitriles, amides). Therefore, this research addresses a timely and fascinating question for enzyme study and application: can we design enzymes containing ANY desired catalytic functionality? The hybrid catalysts prepared here will be used for the synthesis of molecules containing alcohol functions. Chiral alcohols are important constituents of pharmaceuticals and agrochemicals. Therefore, catalysts that facilitate their preparation are important tools for these industries. The use of enzymes as catalysts is very efficient and sustainable, due to their high activities and selectivities, benign reaction conditions and their renewable origin. However, many of the enzymes that can make chiral alcohols enantioselectively have one major shortcoming: they employ the expensive and sensitive nicotinamide adenine dinucleotide phosphate, NADPH cofactor (£1085 per g), which is an essential component of the reaction mixture. The high cost precludes its use as a disposable reagent and continuous regeneration of NADPH in the reaction vessel (in situ) is necessary for economically acceptable transformations using isolated enzymes. Existing regeneration systems are based on either enzymes or chemical catalysts, but they have limited applicability, because they generate by-products, have a low stability or activity, or are inactivated by the presence of the enzyme. Therefore, we will engineer a chemical cofactor regeneration system that will be protected from deactivation, by incorporating it into a protein. We will use the same protein to incorporate the regeneration catalyst and to perform the alcohol synthesis, and in this way we will avoid complex mixtures containing two enzymes. The system will be of relevance to the industries involved in the synthesis of active pharmaceutical ingredients (pharma, custom manufacturing organisations etc), which could potentially apply it as a simple technology for recycling NADPH.
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Organisation Website:	http://www.nottingham.ac.uk