Transition states of Plasmodium falciparum and human orotate phosphoribosyltransferases.

ABSTRACT: Orotate phosphoribosyltransferases (OPRT) catalyze the formation of orotidine 5'-monophosphate (OMP) from alpha-D-phosphoribosylpyrophosphate (PRPP) and orotate, an essential step in the de novo biosynthesis of pyrimidines. Pyrimidine de novo biosynthesis is required in Plasmodium falciparum , and thus OPRT of the parasite (PfOPRT) is a target for antimalarial drugs. De novo biosynthesis of pyrimidines is also a feature of rapidly proliferating cancer cells. Human OPRT (HsOPRT) is therefore a target for neoplastic and autoimmune diseases. One approach to the inhibition of OPRTs is through analogues that mimic the transition states of PfOPRT and HsOPRT. The transition state structures of these OPRTs were analyzed by kinetic isotope effects (KIEs), substrate specificity, and computational ch

SUBMITTER: Zhang Y 

PROVIDER: S-EPMC2669657 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature