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Characterization of three genes encoding enzymes of the folate biosynthetic pathway in Plasmodium falciparum

Published online by Cambridge University Press:  11 January 2002

C.-S. LEE
Affiliation:
Department of Biomolecular Sciences, University of Manchester Institute of Science and Technology (UMIST), P.O. Box 88, Manchester M60 1QD, UK Present address: Department of Parasitology and Tropical Medicine, National Defense Medical Center, PO Box 90048-506, Taipei, Taiwan, Republic of China.
E. SALCEDO
Affiliation:
Department of Biomolecular Sciences, University of Manchester Institute of Science and Technology (UMIST), P.O. Box 88, Manchester M60 1QD, UK
Q. WANG
Affiliation:
Department of Biomolecular Sciences, University of Manchester Institute of Science and Technology (UMIST), P.O. Box 88, Manchester M60 1QD, UK
P. WANG
Affiliation:
Department of Biomolecular Sciences, University of Manchester Institute of Science and Technology (UMIST), P.O. Box 88, Manchester M60 1QD, UK
P.F.G. SIMS
Affiliation:
Department of Biomolecular Sciences, University of Manchester Institute of Science and Technology (UMIST), P.O. Box 88, Manchester M60 1QD, UK
J.E. HYDE
Affiliation:
Department of Biomolecular Sciences, University of Manchester Institute of Science and Technology (UMIST), P.O. Box 88, Manchester M60 1QD, UK

Abstract

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.

Type
Research article
Copyright
© 2001 Cambridge University Press

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