SCIENTIFIC SUBPROJECT 74

ABSTRACT: HGPRTase catalyzes the pyrophosphorolysis of 5'-purine nucleotides. Mutations in HGPRTase are associated with Lesch-Hyhan disease, a major clinical neurodegenerative disorder.

Parasitic organsims such as malaria and schistosomes cannot perform de novo purine biosynthesis and thus depend on the ability to salvage purines from host nucleotides.

Thus HGPRTase is an excellent therapeutic target, provided that sufficient discrimination can be achieved between the human and parasitic enzymes.

This is especially important in the case of malaria, as strains resistant to the existing antibiotics are becoming prevalent world wide.

We have recently collected data on the complex between human HGPRTase bound to inorganic pyrophosphate and the transition state inhibitor to 2.2� on X-9B. The refined structure clearly identified the binding mode of the transition state analog, ***bound magnesium ion and pyrophosphate***, as well as the interacting protein ligands.

This structure also identifies the interactions responsible for stabilization of the oxycarbonium intermediate. We have very recently collected data to 2.0� of the malarial enzyme bound to the same set of inhibitory ligands.

This represents the first report of the malarial enzyme crystallizing and will provide the opportunity to design malaria specific inhibitors. http://www.aecom.yu.edu/home/csb/ar_9798/ss9798.htm

Remember Valletta's U.S. patent? He used Mg pyrophosphate and sub(lingual) B6 to cure RA, ulcerative colitis and invasive bowel cancer. Humm...wish I understood the above abstract! I don't!

Any biochemists reading this?