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DHPS  -  dihydropteroate synthetase

Plasmodium falciparum 3D7

 
 
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High impact information on PF08_0095

  • The enzyme dihydropteroate synthetase (DHPS) from Plasmodium falciparum is involved in the mechanism of action of the sulfone/sulfonamide group of drugs [1].
  • The PPPK-DHPS gene is encoded on chromosome 8 and has two introns [1].
  • Plasmodium falciparum can use exogenous folate, which is normally present in vivo, bypassing SDX inhibition of DHPS and, apparently, precluding synergy under these conditions [2].
  • To clarify how parasite resistance to this combination arises, various lines of Plasmodium falciparum were used to investigate the role of naturally occurring mutations in the target enzyme, dihydropteroate synthetase (DHPS), in the parasite response to sulfadoxine inhibition [3].
  • Using direct sequencing of PCR products, we have analyzed sequence polymorphism of the dihydrofolate reductase-thymidylate synthase, dihydropteroate synthetase, and multidrug resistance 1 genes in a large number of clinical P. falciparum isolates collected in various areas of Cambodia [4].
 

Biological context of PF08_0095

 

Associations of PF08_0095 with chemical compounds

  • We have determined the sequence of the DHPS portion of the gene from sulfadoxine-sensitive and -resistant P. falciparum clones and identified sequence differences that may have a role in sulfone/sulfonamide resistance [1].
  • An improved drug assay was employed to identify a clear correlation between sulfadoxine-resistance levels and the number of DHPS mutations [3].
  • The first is the selection of existing parasites with genetic mutations in the dihydrofolate reductase or dihydropteroate synthetase gene [9].
  • The genotype Ser436, Gly437, and Glu540 of DHPS was selected by pyrimethamine-sulfadoxine but not chlorproguanil-dapsone treatment, showing that a combination of these three variants is important for in vivo resistance to sulfadoxine in the area studied [5].
  • There was no selection for mutations in dihydropteroate synthetase, the target enzyme of dapsone [10].
 

Analytical, diagnostic and therapeutic context of PF08_0095

References

  1. Primary structure and expression of the dihydropteroate synthetase gene of Plasmodium falciparum. Triglia, T., Cowman, A.F. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  2. Utilization of exogenous folate in the human malaria parasite Plasmodium falciparum and its critical role in antifolate drug synergy. Wang, P., Brobey, R.K., Horii, T., Sims, P.F., Hyde, J.E. Mol. Microbiol. (1999) [Pubmed]
  3. Sulfadoxine resistance in the human malaria parasite Plasmodium falciparum is determined by mutations in dihydropteroate synthetase and an additional factor associated with folate utilization. Wang, P., Read, M., Sims, P.F., Hyde, J.E. Mol. Microbiol. (1997) [Pubmed]
  4. Countrywide survey shows very high prevalence of Plasmodium falciparum multilocus resistance genotypes in Cambodia. Khim, N., Bouchier, C., Ekala, M.T., Incardona, S., Lim, P., Legrand, E., Jambou, R., Doung, S., Puijalon, O.M., Fandeur, T. Antimicrob. Agents Chemother. (2005) [Pubmed]
  5. In vivo selection for a specific genotype of dihydropteroate synthetase of Plasmodium falciparum by pyrimethamine-sulfadoxine but not chlorproguanil-dapsone treatment. Curtis, J., Duraisingh, M.T., Warhurst, D.C. J. Infect. Dis. (1998) [Pubmed]
  6. Pyrosequencing, a High-Throughput Method for Detecting Single Nucleotide Polymorphisms in the Dihydrofolate Reductase and Dihydropteroate Synthetase Genes of Plasmodium falciparum. Zhou, Z., Poe, A.C., Limor, J., Grady, K.K., Goldman, I., McCollum, A.M., Escalante, A.A., Barnwell, J.W., Udhayakumar, V. J. Clin. Microbiol. (2006) [Pubmed]
  7. A mutation-specific PCR system to detect sequence variation in the dihydropteroate synthetase gene of Plasmodium falciparum. Wang, P., Brooks, D.R., Sims, P.F., Hyde, J.E. Mol. Biochem. Parasitol. (1995) [Pubmed]
  8. Resistance to antifolates in Plasmodium falciparum monitored by sequence analysis of dihydropteroate synthetase and dihydrofolate reductase alleles in a large number of field samples of diverse origins. Wang, P., Lee, C.S., Bayoumi, R., Djimde, A., Doumbo, O., Swedberg, G., Dao, L.D., Mshinda, H., Tanner, M., Watkins, W.M., Sims, P.F., Hyde, J.E. Mol. Biochem. Parasitol. (1997) [Pubmed]
  9. Evolution of resistance to sulfadoxine-pyrimethamine in Plasmodium falciparum. Gatton, M.L., Martin, L.B., Cheng, Q. Antimicrob. Agents Chemother. (2004) [Pubmed]
  10. Mutations in dhfr in Plasmodium falciparum infections selected by chlorproguanil-dapsone treatment. Curtis, J., Maxwell, C.A., Msuya, F.H., Mkongewa, S., Alloueche, A., Warhurst, D.C. J. Infect. Dis. (2002) [Pubmed]
  11. Plasmodium falciparum infection dynamics and transmission potential following treatment with sulfadoxine-pyrimethamine. Gatton, M.L., Cheng, Q. J. Antimicrob. Chemother. (2006) [Pubmed]
  12. A simple, high-throughput method to detect Plasmodium falciparum single nucleotide polymorphisms in the dihydrofolate reductase, dihydropteroate synthase, and P. falciparum chloroquine resistance transporter genes using polymerase chain reaction- and enzyme-linked immunosorbent assay-based technology. Alifrangis, M., Enosse, S., Pearce, R., Drakeley, C., Roper, C., Khalil, I.F., Nkya, W.M., Rønn, A.M., Theander, T.G., Bygbjerg, I.C. Am. J. Trop. Med. Hyg. (2005) [Pubmed]
  13. Prevalence of point mutations in the dihydrofolate reductase and dihydropteroate synthetase genes of Plasmodium falciparum isolates from India and Thailand: a molecular epidemiologic study. Biswas, S., Escalante, A., Chaiyaroj, S., Angkasekwinai, P., Lal, A.A. Trop. Med. Int. Health (2000) [Pubmed]
 
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