Construction of the inhibitor screening system which target the enzyme from Plasmodium falciparum.

• Project/Area Number: 24790406
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Parasitology (including Sanitary zoology)
• Research Institution: Showa University
• Principal Investigator: UMEDA TOMONOBU 昭和大学, 薬学部, 助教 (80514471)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2014: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 結晶構造解析 / マラリア / 非メバロン酸経路

Outline of Final Research Achievements

Aimed at creation of new anti-malarial drugs, I worked in the construction of inhibitor screening system for the enzyme from Plasmodium falciparum. Specifically, I focused on the non-mevalonate pathway, which is the essential metabolic pathway in the growth of Plasmodium falciparum. I aimed the construction of inhibitor screening system to target the 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) ,which is a particularly important enzyme in the pathway.
Although not lead to the construction of the screening system, I performed crystallization experiments in complex with novel inhibitors which collaborators provided me. I tried crystallization experiments complexed with several inhibitors and succeeded in obtaining crystals.Finally I was succeeded in the three-dimensional structural analysis.

Research Products

• [Journal Article] Binding modes of reverse fosmidomycin analogs towards the antimalarial target IspC (2014)
  • Author(s): Konzuch, S ., Umeda, T., Held, J., Hahn, S., Brucher, K., Lienau, C., Behrendt, C., Grawert, T., Bacher, A., Illarionov, B., Fischer, M., Mordmuller, B., Tanaka, N., & Kurz, T.
  • Journal Title: J. Med. Chem Volume: 57 Issue: 21 Pages: 8827-8838
  • DOI: 10.1021/jm500850y
  • Peer Reviewed
• [Presentation] Crystal structures of 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) from Plasmodium falciparum complexed with inhibitors. (2012)
  • Author(s): 梅田知伸
  • Organizer: アジア結晶学会
  • Place of Presentation: オーストラリア・アデレード