Characterization of three genes encoding enzymes of the folate biosynthetic pathway in Plasmodium falciparum.
Although the folate metabolic pathway in malaria parasites is a major chemotherapeutic target, resistance to currently available antifolate drugs is an increasing problem. This pathway, however, includes a number of enzymes that, to date, have not been characterized despite their potential for clinical exploitation. As a step towards evaluation of additional targets in this pathway, we report the isolation and characterization of 3 new genes that encode homologues of GTP cyclohydrolase I (GTP-CH), dihydrofolate synthase/folylpolyglutamate synthase (DHFS/FPGS) and serine hydroxymethyltransferase (SHMT). The genes encoding GTP-CH and SHMT are unambiguously assigned to chromosome 12, while that for DHFS/FPGS is tentatively assigned to chromosome 13. All 3 genes are expressed in blood-stage parasites, yielding transcripts of which only ca 60-70% is accounted for by coding sequence. All 3 of the proteins predicted to be encoded by these genes display sequence differences compared to the human host homologues that may be of functional significance. These data bring the complement of cloned genes that encode activities in the pathway to seven, leaving only the gene encoding dihydroneopterin aldolase (DHNA) to be identified in the route from GTP to folate synthesis and folate turnover in the thymidylate cycle.
Lee
C S
CS
Department of Biomolecular Sciences, University of Manchester Institute of Science and Technology (UMIST), UK.
Salcedo
E
E
Wang
Q
Q
Wang
P
P
Sims
P F
PF
Hyde
J E
JE
D000446:Aldehyde-Lyases / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans; D002875:Chromosomes; D003001:Cloning, Molecular; D004926:Escherichia coli; D005492:Folic Acid / Q000096:biosynthesis*; D006136:GTP Cyclohydrolase / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic; D012696:Glycine Hydroxymethyltransferase / Q000235:genetics*; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D010453:Peptide Synthases / Q000235:genetics*; D010963:Plasmodium falciparum / Q000201:enzymology* / Q000235:genetics*; D012441:Saccharomyces cerevisiae; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid
D006160:Guanosine Triphosphate; D005492:Folic Acid; D012696:Glycine Hydroxymethyltransferase; D006136:GTP Cyclohydrolase; D000446:Aldehyde-Lyases; C020044:dihydroneopterin aldolase; D010453:Peptide Synthases; C020041:dihydrofolate synthetase; C023103:folylpolyglutamate synthetase