title: Structure of Plasmodium falciparum orotate phosphoribosyltransferase with autologous inhibitory protein-protein interactions.
abstract: The most severe form of malaria is caused by the obligate parasite Plasmodium falciparum. Orotate phosphoribosyltransferase (OPRTase) is the fifth enzyme in the de novo pyrimidine-synthesis pathway in the parasite, which lacks salvage pathways. Among all of the malaria de novo pyrimidine-biosynthesis enzymes, the structure of P. falciparum OPRTase (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 the PfOPRTase 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 modulate PfOPRTase activity in parasites and possibly provide new insights for blocking PfOPRTase functions.
authors.affiliation: Department of Chemistry, University of Washington, Seattle, WA 98195, USA.
authors.forename: Shiva
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Department of Chemistry, University of Washington, Seattle, WA 98195, USA.
authors.forename: Kalyanaraman
authors.initials: K
authors.lastname: Krishnamoorthy
authors.affiliation: Department of Chemistry, University of Washington, Seattle, WA 98195, USA.
authors.forename: Devaraja G
authors.initials: DG
authors.lastname: Mudeppa
authors.affiliation: Department of Chemistry, University of Washington, Seattle, WA 98195, USA.
authors.forename: Pradipsinh K
authors.initials: PK
authors.lastname: Rathod
mesh_terms: D000595:Amino Acid Sequence; D003460:Crystallization; D008969:Molecular Sequence Data; D009962:Orotate Phosphoribosyltransferase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000737:chemistry* / Q000201:enzymology* / Q000235:genetics; D054730:Protein Interaction Domains and Motifs / Q000502:physiology*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: D009962:Orotate Phosphoribosyltransferase
keywords: OMP; PRPP; de novo; peptide inhibition; prodrugs; pyrimidine; salvage