Projects per year
Abstract
The folate biosynthetic pathway and its key enzyme dihydrofolate reductase (DHFR) is a popular target for drug development due to its essential role in the synthesis of DNA precursors and some amino acids. Despite its importance, little is known about plant DHFRs, which, like the enzymes from the malarial parasite Plasmodium, are bifunctional, possessing DHFR and thymidylate synthase (TS) domains. Here using genetic knockout lines we confirmed that either DHFR-TS1 or DHFR-TS2 (but not DHFR-TS3) was essential for seed development. Screening mutated Arabidopsis thaliana seeds for resistance to antimalarial DHFR-inhibitor drugs pyrimethamine and cycloguanil identified causal lesions in DHFR-TS1 and DHFR-TS2, respectively, near the predicted substrate-binding site. The different drug resistance profiles for the plants, enabled by the G137D mutation in DHFR-TS1 and the A71V mutation in DHFR-TS2, were consistent with biochemical studies using recombinant proteins and could be explained by structural models. These findings provide a great improvement in our understanding of plant DHFR-TS and suggest how plant-specific inhibitors might be developed, as DHFR is not currently targeted by commercial herbicides.
Original language | English |
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Pages (from-to) | 727-742 |
Number of pages | 16 |
Journal | Plant Journal |
Volume | 95 |
Issue number | 4 |
DOIs | |
Publication status | Published - 1 Aug 2018 |
Fingerprint
Dive into the research topics of 'Targeting plant DIHYDROFOLATE REDUCTASE with antifolates and mechanisms for genetic resistance'. Together they form a unique fingerprint.Projects
- 4 Finished
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How scissors learn to glue: the catalysis of ligation by proteases
Mylne, J. (Investigator 01) & Tawfik, D. (Investigator 02)
ARC Australian Research Council
1/01/16 → 31/12/18
Project: Research
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Characterizing the regulators of mitochondrial biogenesis in Arabidopsis thaliana
Murcha, M. (Investigator 01)
ARC Australian Research Council
1/01/13 → 31/05/18
Project: Research
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Genetic evolution of plant proteins with biomedical applications
Mylne, J. (Investigator 01)
ARC Australian Research Council
1/01/12 → 30/06/17
Project: Research