Structure ofPlasmodium falciparumorotate phosphoribosyltransferase with autologous inhibitory protein–protein interactions

Abstract

The most severe form of malaria is caused by the obligate parasitePlasmodium falciparum. Orotate phosphoribosyltransferase (OPRTase) is the fifth enzyme in thede novopyrimidine-synthesis pathway in the parasite, which lacks salvage pathways. Among all of the malariade novopyrimidine-biosynthesis enzymes, the structure ofP. falciparumOPRTase (PfOPRTase) was the only one unavailable until now.PfOPRTase that could be crystallized was obtained after some low-complexity sequences were removed. Four catalytic dimers were seen in the asymmetic unit (a total of eight polypeptides). In addition to revealing unique amino acids in thePfOPRTase active sites, asymmetric dimers in the larger structure pointed to novel parasite-specific protein–protein interactions that occlude the catalytic active sites. The latter could potentially modulatePfOPRTase activity in parasites and possibly provide new insights for blockingPfOPRTase functions.