Award details

Studies on the chemical mechanism of kynureninase

Reference	B09453
Principal Investigator / Supervisor	Dr Nigel Botting
Co-Investigators / Co-Supervisors
Institution	University of St Andrews
Department	Biology
Funding type	Research
Value (£)	94,327
Status	Completed
Type	Research Grant
Start date	11/05/1998
End date	06/06/2000
Duration	25 months

Abstract

Kynureninase is a PLP dependent enzyme which catalyses the beta gamma-hydrolytic cleavage of the amino acid kynurenine to give alanine and anthranilic acid. This is a unique reaction in PLP chemistry and the mechanism of the enzyme is not well understood. The enzyme plays a key role on the neurologically important kynurenine pathway of tryptophan metabolism and is a potential target for drug action. Quinolinic acid is one of the products of the pathway and this has been implicated as an etiological factor in a number of neurodegenerative diseases including Huntington's disease, poliovirus and AIDS related dementia. Inhibiting kynureninase would block the synthesis of this endogenous neurotoxin. The aim of the project is to examine the enzyme's chemical mechanism using kinetic isotope effect studies to determine the rate limiting step. Also some novel bicyclic inhibitors have been designed and these will be prepared and their interaction with kynureninase will be examined. A further aim is to investigate the synthetic utility of the enzyme. It has been shown that the aminoacrylate intermediate produced during the reaction can be trapped out with benzaldehyde to give a new amino acid product in an enantiospecific process. The generality of this reaction will be examined with a wide range of trapping agents. The same intermediate can also be generated from omithine and pyruvate, via a transamination reaction, and this system will be investigated and optimised to provide a new enantiospecific route to obtain novel amino acids.

Summary

unavailable

Committee	Closed Committee - Biomolecular Sciences (BMS)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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