PURINE AND PYRIMIDINE METABOLISM

Cornell University, Ithaca NY

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Pyrimidine and purine nucleotides are essential building blocks for the synthesis of nucleic acids and can also take part in energy transfer and storage, protein synthesis and signaling. Because of the importance of these molecules, the enzymes in their metabolic pathways represent potential drug targets for the treatment of many conditions including cancer and several types of parasitic infections. We have undertaken structural studies of various enzymes that play roles in the metabolism of pyrimidines and purines. Adenosine kinase (AK), a key enzyme in purine metabolism in parasites and a potential chemotherapeutic target for the treatment of Toxoplasma gondii infections, catalyzes the ATP dependent phosphorylation of adenosine. Purine nucleoside phosphorylase (PNP), which catalyzes the reversible phosphorolysis of ribonucleosides and 2'- deoxyribonucleosides to the free base and (2'-deoxy)ribose-1-phosphate, is an important enzyme for the salvage of purine nucleotides. RutA is a FMN dependent mono-oxygenase involved in a recently discovered pyrimidine degradation pathway that converts uracil (or thymine) to 3-hydroxypropionate (or 2-methyl-3-hydroxypropionate) in E. coli. Uridine phosphorylase (UP) catalyzes the reversible phosphorolysis of uridine with the formation of ribose-1-phosphate and uracil. Orotidine-5'-phosphate decarboxylase orotate phosphoribosyltransferase (OMPDC-OPRT) is a bifunctional enzyme that catalyzes the last two steps in the synthesis of uridine-5'-monophosphate (UMP). In addition to their many cellular uses, some organisms can metabolize nucleotides as a nitrogen source. Recent studies by two groups on Klebsiella sp. have revealed a gene cluster that is responsible for expressing the enzymes for utilizing purines as a sole nitrogen source in this organism. We have structurally characterized several of the enzymes that catalyze the breakdown of hypoxanthine to allantoin in Klebsiella pneumoniae in order to better understand this interesting pathway.