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Lee, CS, Salcedo, E, Wang, Q, Wang, P, Sims, PF and Hyde, JE (2001) Characterization of three genes encoding enzymes of the folate biosynthetic pathway in Plasmodium falciparum. Parasitology 122 Pt 1:1-13


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.


PubMed Online version:10.1017/s0031182000006946


Aldehyde-Lyases/genetics; Amino Acid Sequence; Animals; Caenorhabditis elegans; Chromosomes; Cloning, Molecular; Escherichia coli; Folic Acid/biosynthesis; GTP Cyclohydrolase/genetics; Gene Expression Regulation, Enzymologic; Glycine Hydroxymethyltransferase/genetics; Guanosine Triphosphate/metabolism; Humans; Molecular Sequence Data; Peptide Synthases/genetics; Plasmodium falciparum/enzymology; Plasmodium falciparum/genetics; Saccharomyces cerevisiae; Sequence Alignment; Sequence Homology, Amino Acid; Sequence Homology, Nucleic Acid



Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status



GO:0006730: one-carbon metabolic process

ECO:0000304: author statement supported by traceable reference used in manual assertion


Seeded From UniProt




GO:0004372: glycine hydroxymethyltransferase activity

ECO:0000304: author statement supported by traceable reference used in manual assertion


Seeded From UniProt





Fig. 2. Gene structure of gtp-ch, shmt and dhfs}fpgs from Plasmodium falciparum showing relative lengths (excluding the stop codon) and intron positions (shaded boxes; numbers above and below these indicate the 5« and 3« terminal nt positions, respectively, of the introns). Fig. 3. Chromosomal location of the shmt (a) and gtp-ch (c) genes in parasite lines 3D7 (D) and K1 (K). The characteristic size difference in chromosome 12 for these lines assists unambiguous assignation of these genes. Fig. 6. Alignment of the predicted protein sequence of Plasmodium falciparum SHMT with a representative sample of homologous molecules from other organisms, including the cytosolic enzyme from the human host. The corresponding nucleotide sequence encoding the malarial protein has been deposited in the GenBank}EMBL database, accession no. AF195023. Accession nos. for the other protein sequences above are: Y14485 (Homo sapiens), L22529 (Saccharomyces cerevisiae ; cytosolic), M81918 (Neurospora crassa; cytosolic), CAB44976 (Neisseria meningitidis), AAC75604 (Escherichia coli). The upper half of the ethidium bromide-stained gel encompassing chromosomes 10–14 is shown in panel b.



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