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Cited by 369Malaria Research and ControlBiochemical and Molecular ResearchPharmacogenetics and Drug Metabolism

Sequence Variation of the Hydroxymethyldihydropterin Pyrophosphokinase: Dihydropteroate Synthase Gene in Lines of the Human Malaria Parasite, Plasmodium falciparum , with Differing Resistance to Sulfadoxine

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Brooks, Darren R., Wang, Ping, Read, Martin, Watkins, William M., Sims, Paul F. G., Hyde, John E.·1994·European Journal of Biochemistry
DOI 10.1111/j.1432-1033.1994.00397.x
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Abstract

Dihydropteroate synthase (H2Pte synthase) is the target of the sulfur-based antimalarial drugs, which are frequently used in synergistic combination with inhibitors of dihydrofolate reductase (H2folate reductase) to combat chloroquine-resistant malaria. We have isolated the H2Pte synthase coding sequence of the most pathogenic human parasite Plasmodium falciparum. It forms part of a longer coding sequence, located on chromosome 8, that also specifies 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (CH2OH-H2pterinPP kinase) at its 5' proximal end. This domain is unusually large, with two long insertions relative to other CH2OH-H2pterinPP kinase molecules. To investigate a possible genetic basis for clinical resistance to sulfa drugs, we sequenced the complete H2Pte synthase domains from eleven isolates of P. falciparum with diverse geographical origins and levels of sulfadoxine resistance. Overall, point mutations in five positions were observed, affecting four codons. Parasite lines exhibiting high-level resistance were found to carry either a double mutation, altering both Ser436 and Ala613, or a single mutation affecting Ala581. The mutations at positions 436 and 581 have the same location relative to each of two degenerate repeated amino acid motifs that are conserved across all other known H2Pte synthase molecules. The amino acid alteration at residue 613 is identically positioned relative to a different conserved motif. The fourth amino acid residue (437) affected by mutation, though adjacent to the apparently crucial residue 436, shows no obvious correlation with resistance. Although these mutations have no exact counterparts in any other organism, that at position 581 falls within a region of three amino acids where H2Pte synthase is modified in various ways in a number of sulfonamide-resistant pathogenic bacteria. Copy-number analysis indicated that there was no amplification of the H2Pte synthase domain in resistant parasite lines of P. falciparum, compared to sensitive lines.

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Crossref · 10.1111/j.1432-1033.1994.00397.x

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  • Similar point mutations in positions equivalent to this site in Plasmodium falciparum and Mycobacterium leprae confer sulfa resistance.

    “Likewise, similar point mutations in positions equivalent to this site in Plasmodium falciparum (15) and Mycobacterium leprae (28) confer sulfa resistance.”

    From Dihydropteroate Synthase Gene Mutations in<i>Pneumocystis</i>and Sulfa Resistance (2004) · cites this paper as [15]

  • In E. coli and Plasmodium falciparum, nonsynonymous point mutations resulting in amino acid substitutions in DHPS can confer sulfa resistance.

    “In other organisms, such as E. coli and Plasmodium falciparum, nonsynonymous point mutations resulting in amino acid substitutions in DHPS can confer sulfa resistance (14,15).”

    From Dihydropteroate Synthase Gene Mutations in<i>Pneumocystis</i>and Sulfa Resistance (2004) · cites this paper as [15]

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Authors
Brooks, D. R., Wang, P., Read, M., Watkins, W. M., Sims, P. F. G., & Hyde, J. E.
Affiliations
  • University of Manchester (GB)
  • Wellcome Trust (GB)
Corresponding author
Hyde, John E.
ORCID
Venue
European Journal of Biochemistry
Publisher
Wiley
Published
1994-09
Volume
224
Issue
2
Pages
397-405
ISSN
  • 0014-2956 (ISSN-L)
  • 1432-1033
DOI
10.1111/j.1432-1033.1994.00397.x
OpenAlex
W2123470783
Cited by
369
References
47
Citations by year
2026: 5 · 2025: 7 · 2024: 11 · 2023: 7 · 2022: 6 · 2021: 7 · 2020: 1 · 2019: 4 · 2018: 10 · 2017: 4 · 2016: 12 · 2015: 10 · 2014: 12 · 2013: 14 · 2012: 12
FWCI
13.39
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor, 3836 d)
Locations
  • European Journal of Biochemistry (publishedVersion)
  • PubMed (publishedVersion)
  • Research Explorer (The University of Manchester) (submittedVersion)
Funders
Wellcome Trust
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Malaria Research and Control
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Keywords
dihydropteroate synthase, Plasmodium falciparum, sulfadoxine resistance, 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase, point mutations, amino acid substitutions, conserved motifs, copy number, dihydrofolate reductase, antimalarial drug resistance, gene sequence variation
MeSH terms
Amino Acid Sequence, Animals, Base Sequence, Chromosome Mapping, Dihydropteroate Synthase, Drug Resistance, Humans, Molecular Sequence Data, Mutation, Plasmodium falciparum, Sulfadoxine, Genetic Variation, DNA, Protozoan, Consensus Sequence, Malaria, Falciparum, Sequence Homology, Amino Acid, Diphosphotransferases, DNA Primers

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