The Reaction Mechanism and Inhibition of ATP-PRTase Enzymes
Gert-Jan Moggre Final Ph.D. Seminar
Time & Place
Wed, 11 May 2016 11:00:00 NZST in Rutherford Room 531
All are welcome
Adenosine triphosphate phosphoribosyltransferase (ATP-PRTase) catalyses the first step in histidine biosynthesis. The biosynthetic pathway is essential to microorganisms, but absent in humans making it an interesting target for novel drug design. Understanding the nature of the transition state can provide essential information on the mechanism of this enzyme. Highly specific and potent inhibitors may also be designed based on this transition state.
The kinetic isotope effects (KIEs) for ATP-PRTase from Campylobacter jejuni, Mycobacterium tuberculosis and Lactococcus lactis were determined. To overcome commitment to catalysis the reaction was studied in reverse with phosphonoacetic acid (PA), an alternative to the natural substrate pyrophosphate. The transition state structures were modelled with density functional theory at the B3LYP/6-31+G(d,p) level by closely matching the calculated KIEs to the experimental KIEs. Based on this a dissociated DN*AN ‡ mechanism was predicted for the reaction.
This presentation discusses work towards the steps involved in synthesising the isotopically labelled substrates, measuring the KIE values for ATP-PRT enzymes and the transition state structure predictions.