Molecule Information

General Information of the Molecule (ID: Mol00903)

• Name: Dihydrofolate reductase (DHFR) ,Plasmodium falciparum
• Molecule Type: Protein
• Gene Name: dhfr
• Sequence:
  MMEQVCDVFDIYAICACCKVESKNEGKKNEVFNNYTFRGLGNKGVLPWKCNSLDMKYFCA
  VTTYVNESKYEKLKYKRCKYLNKETVDNVNDMPNSKKLQNVVVMGRTSWESIPKKFKPLS
  NRINVILSRTLKKEDFDEDVYIINKVEDLIVLLGKLNYYKCFIIGGS
• Function: Bifunctional enzyme. Involved in de novo dTMP biosynthesis. Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, DNA precursor synthesis, and for the conversion of dUMP to dTMP.
• Uniprot ID: D0QXK2_PLAFA

Kingdom: N.A.
Phylum: Apicomplexa
Class: Aconoidasida
Order: Haemosporida
Family: Plasmodiidae
Genus: Plasmodium
Species: Plasmodium falciparum

Type(s) of Resistant Mechanism of This Molecule

  ADTT: Aberration of the Drug's Therapeutic Target

Drug Resistance Data Categorized by Drug

Approved Drug(s) 2 drug(s) in total

Pyrimethamine/Sulfadoxine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Malaria [1]

• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Resistant Drug: Pyrimethamine/Sulfadoxine
• Molecule Alteration: Missense mutation; p.C59R
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: PCR
• Mechanism Description: The quintuple mutant of pfdhfr (S108N, N51I and C59R) and pfdhps (A437G and k540E) were associated with a high relative risk of treatment failure, and this haplotype was suggested as a relevant molecular marker for failure of SP treatment in uncomplicated P. falciparum.

Disease Class: Malaria [1]

• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Resistant Drug: Pyrimethamine/Sulfadoxine
• Molecule Alteration: Missense mutation; p.C59R+I164L
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: PCR
• Mechanism Description: The quintuple mutant of pfdhfr (S108N, N51I and C59R) and pfdhps (A437G and k540E) were associated with a high relative risk of treatment failure, and this haplotype was suggested as a relevant molecular marker for failure of SP treatment in uncomplicated P. falciparum.

Disease Class: Malaria [1]

• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Resistant Drug: Pyrimethamine/Sulfadoxine
• Molecule Alteration: Missense mutation; p.C59R+S108N
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: PCR
• Mechanism Description: The quintuple mutant of pfdhfr (S108N, N51I and C59R) and pfdhps (A437G and k540E) were associated with a high relative risk of treatment failure, and this haplotype was suggested as a relevant molecular marker for failure of SP treatment in uncomplicated P. falciparum.

Disease Class: Malaria [1]

• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Resistant Drug: Pyrimethamine/Sulfadoxine
• Molecule Alteration: Missense mutation; p.C59R+S108N+I164L
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: PCR
• Mechanism Description: The quintuple mutant of pfdhfr (S108N, N51I and C59R) and pfdhps (A437G and k540E) were associated with a high relative risk of treatment failure, and this haplotype was suggested as a relevant molecular marker for failure of SP treatment in uncomplicated P. falciparum.

Disease Class: Malaria [1]

• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Resistant Drug: Pyrimethamine/Sulfadoxine
• Molecule Alteration: Missense mutation; p.N51I+C59R
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: PCR
• Mechanism Description: The quintuple mutant of pfdhfr (S108N, N51I and C59R) and pfdhps (A437G and k540E) were associated with a high relative risk of treatment failure, and this haplotype was suggested as a relevant molecular marker for failure of SP treatment in uncomplicated P. falciparum.

Disease Class: Malaria [1]

• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Resistant Drug: Pyrimethamine/Sulfadoxine
• Molecule Alteration: Missense mutation; p.N51I+C59R+I164L
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: PCR
• Mechanism Description: The quintuple mutant of pfdhfr (S108N, N51I and C59R) and pfdhps (A437G and k540E) were associated with a high relative risk of treatment failure, and this haplotype was suggested as a relevant molecular marker for failure of SP treatment in uncomplicated P. falciparum.

Disease Class: Malaria [1]

• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Resistant Drug: Pyrimethamine/Sulfadoxine
• Molecule Alteration: Missense mutation; p.N51I+C59R+S108N
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: PCR
• Mechanism Description: The quintuple mutant of pfdhfr (S108N, N51I and C59R) and pfdhps (A437G and k540E) were associated with a high relative risk of treatment failure, and this haplotype was suggested as a relevant molecular marker for failure of SP treatment in uncomplicated P. falciparum.

Disease Class: Malaria [1]

• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Resistant Drug: Pyrimethamine/Sulfadoxine
• Molecule Alteration: Missense mutation; p.N51I+C59R+S108N+I164L
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: PCR
• Mechanism Description: The quintuple mutant of pfdhfr (S108N, N51I and C59R) and pfdhps (A437G and k540E) were associated with a high relative risk of treatment failure, and this haplotype was suggested as a relevant molecular marker for failure of SP treatment in uncomplicated P. falciparum.

Sulphadoxine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Malaria [2]

• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Resistant Drug: Sulphadoxine
• Molecule Alteration: Missense mutation; p.N51I+p.C59R+p.S108N
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: PCR
• Mechanism Description: The high prevalence of the pfdhfr 108N (99%) and 51I + 108N/59R + 108N (92%) in our study indicate that decreased susceptibility to sulphadoxine-pyrimethamine is widespread in Pakistan. However, only seven patients had infections with the triple pfdhfr resistance associated haplotype and only one patient was infected with P. falciparum that had the quintuple pfdhfr + pfdhps haplotype associated with high grade sulphadoxine-pyrimethamine resistance. These results indicate that high grade resistance to sulphadoxine-pyrimethamine is not wide.

References

• Ref 1: Molecular epidemiology of drug resistance markers of Plasmodium falciparum in Yunnan Province, China. Malar J. 2012 Jul 28;11:243. doi: 10.1186/1475-2875-11-243.
• Ref 2: Prevalence of resistance associated polymorphisms in Plasmodium falciparum field isolates from southern Pakistan. Malar J. 2011 Jan 28;10:18. doi: 10.1186/1475-2875-10-18.