Publication: Trypanosomal dihydrofolate reductase reveals natural antifolate resistance
Issued Date
2011-09-02
Resource Type
ISSN
15548937
15548929
15548929
Other identifier(s)
2-s2.0-80053601728
Rights
Mahidol University
Rights Holder(s)
SCOPUS
Bibliographic Citation
ACS Chemical Biology. Vol.6, No.9 (2011), 905-911
Suggested Citation
Jarunee Vanichtanankul, Supannee Taweechai, Jirundon Yuvaniyama, Tirayut Vilaivan, Penchit Chitnumsub, Sumalee Kamchonwongpaisan, Yongyuth Yuthavong Trypanosomal dihydrofolate reductase reveals natural antifolate resistance. ACS Chemical Biology. Vol.6, No.9 (2011), 905-911. doi:10.1021/cb200124r Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/11476
Research Projects
Organizational Units
Authors
Journal Issue
Thesis
Title
Trypanosomal dihydrofolate reductase reveals natural antifolate resistance
Abstract
Dihydrofolate reductase (DHFR) is a potential drug target for Trypanosoma brucei, a human parasite, which is the causative agent for African sleeping sickness. No drug is available against this target, since none of the classical antifolates such as pyrimethamine (PYR), cycloguanil, or trimethoprim are effective as selective inhibitors of T. brucei DHFR (TbDHFR). In order to design effective drugs that target TbDHFR, co-crystal structures with bound antifolates were studied. On comparison with malarial Plasmodium falciparum DHFR (PfDHFR), the co-crystal structures of wild-type TbDHFR reveal greater structural similarities to a mutant PfDHFR causing antifolate resistance than the wild-type enzyme. TbDHFR imposes steric hindrance for rigid inhibitors like PYR around Thr86, which is equivalent to Ser108Asn of the malarial enzymes. In addition, a missing residue on TbDHFR active-site loop together with the presence of Ile51 widens its active site even further than the structural effect of Asn51Ile, which is observed in PfDHFR structures. The structural similarities are paralleled by the similarly poor affinities of the trypanosomal enzyme for rigid inhibitors. Mutations of TbDHFR at Thr86 resulted in 10-fold enhancement or 7-fold reduction in the rigid inhibitors affinities for Thr86Ser or Thr86Asn, respectively. The co-crystal structure of TbDHFR with a flexible antifolate WR99210 suggests that its greater affinity result from its ability to avoid such Thr86 clash and occupy the widened binding space similarly to what is observed in the PfDHFR structures. Natural resistance to antifolates of TbDHFR can therefore be explained, and potential antifolate chemotherapy of trypanosomiasis should be possible taking this into account. © 2011 American Chemical Society.