The crystal structure of Leishmania major N(5),N(10)-methylenetetrahydrofolate dehydrogenase/cyclohydrolase and assessment of a potential drug target.

Thomas C Eadsforth, Scott Cameron, William N Hunter

Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.

Molecular and biochemical parasitology 2012 Feb

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Three enzyme activities in the protozoan Leishmania major, namely N(5),N(10)-methylenetetrahydrofolate dehydrogenase/N(5),N(10)-methenyltetrahydrofolate cyclohydrolase (DHCH) and N(10)-formyltetrahydrofolate ligase (FTL) produce the essential intermediate N(10)-formyltetrahydrofolate. Although trypanosomatids possess at least one functional DHCH, the same is not true for FTL, which is absent in Trypanosoma brucei. Here, we present the 2.7 Å resolution crystal structure of the bifunctional apo-DHCH from L. major, which is a potential drug target. Sequence alignments show that the cytosolic enzymes found in trypanosomatids share a high level of identity of approximately 60%. Additionally, residues that interact and participate in catalysis in the human homologue are conserved amongst trypanosomatid sequences and this may complicate attempts to derive potent, parasite specific DHCH inhibitors. Copyright © 2011 Elsevier B.V. All rights reserved.

Citation

Thomas C Eadsforth, Scott Cameron, William N Hunter. The crystal structure of Leishmania major N(5),N(10)-methylenetetrahydrofolate dehydrogenase/cyclohydrolase and assessment of a potential drug target. Molecular and biochemical parasitology. 2012 Feb;181(2):178-85