Division of Biological Science, University of California at San Diego, La Jolla, CA 92093-0116, USA
Correspondence
Milton H. Saier, Jr
(msaier{at}ucsd.edu)
Malaria is a global health threat placing approximately 40 % of the world's population at risk. Nearly one million deaths can be attributed to malaria every year with an additional 300 million acute illnesses resulting annually. About 90 % of these cases occur in the tropical and subtropical regions of the world (World Health Organization, http://www.who.int). While mosquitoes transmit malaria, the disease is caused by protozoan parasites of the genus Plasmodium. Virulent Plasmodium species include Plasmodium vivax, Plasmodium ovale, Plasmodium malariae and Plasmodium falciparum. Most cases of malaria are caused by P. falciparum and P. vivax, with P. falciparum inducing the most severe symptoms. Traditionally, chloroquine and other quinoline-based drugs have been used for the prophylaxis and treatment of malaria; however, Plasmodium resistance to chloroquine has been increasingly problematic. Since chloroquine is the most efficacious low-cost drug available for treatment of malaria, chloroquine resistance has been exceptionally detrimental in third-world countries where the spread of malaria is rampant.
Point mutations in a 13 exon gene, crt, in Asian, African and South American chloroquine-resistant P. falciparum lines have implicated its product, a putative transmembrane protein, PfCRT, as the primary culprit behind chloroquine resistance (Fidock et al., 2000). It is believed that mutations in PfCRT affect either drug binding to haematin through alteration of pH levels in the digestive vacuole or changes in chloroquine flux (Fidock et al., 2000
). Evidence supporting the hypothesis that PfCRT could be a membrane transport protein includes two key factors. First, resistance to chloroquine appears to involve translocation away from the target area rather than alteration of the drug's chemical structure, and, second, PfCRT is predicted to have 10 membrane-spanning
-helices, a characteristic of many transporters.
After four iterations of searching the non-redundant NCBI database with PSI-BLAST using PfCRT as the query sequence, a putative nucleotide sugar transporter (NST) in the drug/metabolite transporter (DMT) superfamily (TC : 2.A.7) was uncovered (Table 1) (Altschul et al., 1997
; Jack et al., 2001
). Comparison of the putative NST against TC-DB (Saier, 2000
; Tran et al., 2003
) using BLAST showed strong sequence similarity with a UDP-N-acetylglucosamine (UDP-GlcNAc) transporter (TC : 2.A.7.15.1). The hypothetical NST, PfCRT, and many proteins of the DMT superfamily are predicted to have 10 transmembrane spanners (TMSs) (Table 1
); the UDP-GlcNAc transporters as well as many other DMT superfamily members have been shown to have arisen by duplication of a primordial 5 TMS element (Jack et al., 2001
).
|
|
|
|
REFERENCES
Altschul, S. F., Madden, T. L., Schaffer, A. A., Zhang, J., Zhang, Z., Miller, W. & Lipman, D. J. (1997). Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res 25, 33893402.
Devereux, J., Haeberli, P. & Smithies, O. (1984). A comprehensive set of sequence analysis programs for the VAX. Nucleic Acids Res 12, 387395.[Abstract]
Eddy, S. R. (1998). Profile Hidden Markov models. Bioinformatics 14, 755763.[Abstract]
Fidock, D. A., Nomura, T., Talley, A. K. & 11 other authors (2000). Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance. Mol Cell 6, 861871.[Medline]
Jack, D. L., Yang, N. M. & Saier, M. H., Jr (2001). The drug/metabolite transporter superfamily. Eur J Biochem 268, 36203639.
Pearson, W. R. (2000). Flexible sequence similarity searching with the FASTA3 program package. Methods Mol Biol 132, 185219.[Medline]
Saier, M. H., Jr (1994). Computer-aided analyses of transport protein sequences: gleaning evidence concerning function, structure, biogenesis, and evolution. Microbiol Rev 58, 7193.[Medline]
Saier, M. H., Jr (2000). A functional-phylogenetic classification system for transmembrane solute transporters. Microbiol Mol Biol Rev 64, 354411.
Saier, M. H., Jr (2003). Tracing pathways of transport protein evolution. Mol Microbiol 48, 11451156.[CrossRef][Medline]
Tatusova, T. A. & Madden, T. L. (1999). BLAST 2 SEQUENCES, a new tool for comparing protein and nucleotide sequences. FEMS Microbiol Lett 174, 247250.[CrossRef][Medline]
Tran, C. V., Yang, N. M. & Saier, M. H., Jr (2003). TC-DB: an architecture for membrane transport protein analysis. In Proceedings of the 2nd International IEEE Computer Society Computational Systems Bioinformatics Conference (CSB 2003), p. 658.
Tusnady, G. E. & Simon, I. (2001). The HMMTOP transmembrane topology prediction server. Bioinformatics 17, 849850.
Zhou, X., Yang, N. M., Tran, C. V., Hvorup, R. N. & Saier, M. H., Jr (2003). Web-based programs for the display and analysis of transmembrane alpha-helices in aligned protein sequences. J Mol Microbiol Biotechnol 5, 16.[CrossRef][Medline]
HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
INT J SYST EVOL MICROBIOL | MICROBIOLOGY | J GEN VIROL |
J MED MICROBIOL | ALL SGM JOURNALS |