Chemistry Department Seminar: 7 November 2012

Posted on November 06, 2012

It has been demonstrated that reactions of kinase and synthetase enzymes undergo a significant Kinetic Isotope Effect (KIE) when the reactions are mediated by adenosine 5'-triphosphate (ATP) deuterated at the C8 position.[1] For adenylated and deadenylated E. coli glutamine synthetase (GS), use of C8-D ATP significantly affected the specific activity of both forms of the enzyme with a KIE of at least 2 but significantly higher in adenylated GS at low ATP concentrations. A general mechanism whereby the C8-H of the adenyl moiety of ATP is responsible for the initiation of phosphoryl transfer was proposed.[2] A site-directed mutagenesis programme has established the role of key amino acids in the catalysis and the KIE.[3]  Concomitant to this a large structural bioinformatics investigation was carried out to determine the extent to which this mechanism may be conserved across a large number of kinase families. To this end a number of closely related conserved family specific reaction mechanisms have been identified.[2] The critical question is, “Is quantum mechanical tunneling used in this complex phosphoryl transfer reaction as a mechanism for catalysis and regulation”. The research has been expanded to identify potential inhibitor fragments that will form part of the drug design programme.

[1] Kenyon CP, Steyn A, Roth RL, Steenkamp PA, Nkosi TC, Oldfield LC: The role of the C8 proton of ATP in the regulation of phophoryl transfer within kinases and syntehtases. BMC Biochem. 2011, 12, 36-53.

[2] Kenyon CP, Roth RL, Westhuyzen CW, Parkinson CJ: Conserved phosphoryl transfer mechanism within kinase families and the role of the C8 proton of ATP in the activation of phosphoryl transfer. BMC esearch Notes 2012, 5, 131.

[3] Kenyon CP, Roth RL: The role of the C8 proton of ATP in the catalysis of shikimate kinase and adenylate kinase. BMC Biochem. 2012, 13, 15.

 

Date:     Wednesday, 7 November 2012

Time:    11:30 - 12:30

Venue: The Avagadro (3.22) – Chemistry Building

 

CONTACT PERSON: Dr Lynne Pilcher       [email protected]

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