Malarial Dihydrofolate Reductase as Drug Target

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Introduction

Dihydrofolate reductase (DHFR) plays an essential role in the formation of DNA by managing folate, an organic molecule that shuttles carbons to enzymes that need them for their reactions. Relevant to this context of DHFR involvement, folate gives its carbons to thymidylate synthase, which then uses these carbons to make thymine bases. After folate has removed its carbon atoms, it is the job of DHFR to recycle it. It does this by transferring hydrogen atoms from NADPH to folate to restore it to its useful, reduced form.[1] DHFR is used in all organisms however, each organism makes a lsightly different version. The malaria version of the enzyme has shown to be reliable and the best target for antimalarial drugs. The current antimalarial drugs that target the malarial DHFR include pyrimethamine and cycloguanil. Pyrimethamine is currently used in combination sulfadoxine, a sulfadrug, to treat and prevent malaria but can result in serious side effects including liver damage.[2][3] Recently the effectiveness of these drugs has decreased because of mutations in the enzyme that have led to drug resistance. Since these mutations are becoming much more prevalent in malaria cases, new research in drug development must now incorporate both the wild-type as well as the quadruple mutant DHFR from the Plasmodium falciparum malarial strain, the most common and lethal of the malaria species.[4]

Crystal structure of Wild-type PfDHFR-TS COMPLEXED WITH NADPH, dUMP AND PYRIMETHAMINE (PDB entry 3qgt)



References


  1. Goodsell, David. "Dihydrofolate Reductase." RCSB PDB-101. RCSB PDB, Oct. 2002. Web. <http://www.rcsb.org/pdb/101/motm.do?momID=34>.
  2. "Pyrimethamine & Sulfadoxine." United States National Library of Medicine, n.d. Web. <http://livertox.nih.gov/PyrimethamineSulfadoxine.htm>.
  3. "Pyrimethamine and Sulfadoxine (Oral Route)." Mayo Clinic. Mayo Foundation for Medical Education and Research, 01 Nov. 2011. Web. <http://www.mayoclinic.com/health/drug-information/DR600357>.
  4. Somsak V, Uthaipibull C, Prommana P, Srichairatanakool S, Yuthavong Y, Kamchonwongpaisan S. Transgenic Plasmodium parasites stably expressing Plasmodium vivax dihydrofolate reductase-thymidylate synthase as in vitro and in vivo models for antifolate screening. Malar J. 2011 Oct 7;10:291. PMID: 21981896
  5. Huang F, Tang L, Yang H, Zhou S, Liu H, Li J, Guo S. Molecular epidemiology of drug resistance markers of Plasmodium falciparum in Yunnan Province, China. Malar J. 2012 Jul 28;11:243. PMID: 22839209
  6. 6.00 6.01 6.02 6.03 6.04 6.05 6.06 6.07 6.08 6.09 6.10 6.11 Yuthavong Y, Tarnchompoo B, Vilaivan T, Chitnumsub P, Kamchonwongpaisan S, Charman SA, McLennan DN, White KL, Vivas L, Bongard E, Thongphanchang C, Taweechai S, Vanichtanankul J, Rattanajak R, Arwon U, Fantauzzi P, Yuvaniyama J, Charman WN, Matthews D. Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target. Proc Natl Acad Sci U S A. 2012 Oct 16;109(42):16823-8. doi:, 10.1073/pnas.1204556109. Epub 2012 Oct 3. PMID:23035243 doi:http://dx.doi.org/10.1073/pnas.1204556109

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